Patent Publication Number: US-2022221472-A1

Title: Method for diagnosing endometriosis, disease state monitoring method, and kit

Description:
TECHNICAL FIELD 
     The present disclosure relates to methods of diagnosing endometriosis or methods of determining whether or not a subject is affected by endometriosis, methods of determining the extent of endometrial fibrosis or adhesion in a subject affected by endometriosis, methods of predicting pain of a subject affected by endometriosis, methods of monitoring pathological conditions of a subject affected by endometriosis, and the like, and kits and the like for performing these methods. 
     BACKGROUND ART 
     Endometriosis is an estrogen-dependent inflammatory disease observed in 6-10% of women capable of pregnancy, and infertility or pelvic pain is observed in more than 50% of patients (NPL 1). Various hypotheses have been proposed for the pathogenic mechanism of endometriosis (NPL 2) and the relationship with various factors including inflammatory cytokines and chemokines, growth factors, and hormones has been reported (NPL 3). Drugs that target hormones have already been developed, and hormone agents such as GnRH antagonists and progesterone formulations have been shown to alleviate pain and improve pathological conditions (NPLs 4 and 5). However, the strong side effects and difficulty in long-term use of hormone agent treatment present therapeutic problems (NPL 6). Meanwhile, drugs targeting inflammatory cytokines and chemokines are under development and anti-IL-8 antibodies have shown a strong effect of alleviating pathological conditions in a simian endometriosis model (PTL 1). 
     In the diagnosis of endometriosis, a definitive diagnosis can only be carried out by invasive means such as endoscopic observation or laparotomy. Furthermore, it is difficult for patients to notice the difference between symptoms associated with regular menstruation (e.g., pain) and symptoms of early endometriosis. As such, the hurdle to diagnosing a group of candidate patients is high and it is considered to require 7 to 11 years on average from onset to definitive diagnosis. The delay in definitive diagnosis leads to a delay in the period to start treatment of endometriosis, which is a great clinical problem (NPLs 7 and 8). Therefore, non-invasive diagnostic methods with less burden for patients, such as blood markers, are strongly desired, but precise diagnostic methods have not been established (NPL 9). 
     CITATION LIST 
     Patent Literature 
     [PTL 1] WO2018/025982 
     Non-Patent Literature 
     [NPL 1] Giudice L C. Endometriosis. N Engl J Med 2010; 362:2389-98. 
     [NPL 2] Rogers P A et al. Research priorities for endometriosis. Reprod Sci 2017; 24:202-226. 
     [NPL 3] Beste M T et al. Molecular network analysis of endometriosis reveals a role for c-Jun-regulated macrophage activation. Sci Transl Med. 2014; 6:222ra216. 
     [NPL 4] Taylor H S et al. Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. N Engl J Med. 2017; 377:28-40. 
     [NPL 5] Kohler G et al. A dose-ranging study to determine the efficacy and safety of 1, 2, and 4 mg of dienogest daily for endometriosis. Int J Gynaecol Obstet. 2010; 108:21-5. 
     [NPL 6] Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. 
     [NPL 7] Greene R et al. Diagnostic experience among 4,334 women reporting surgically diagnosed endometriosis. Fertility and Sterility, 2009; 91:32-39. 
     [NPL 8] Manderson L et al. Circuit breaking: Pathways of treatment seeking for women with endometriosis in Australia. Qualitative Health Research, 2008; 18:522-534. 
     [NPL 9] Fassbender A et al. Update on biomarkers for the detection of endometriosis. Biomed Res Int 2015; 2015:130854. 
     SUMMARY OF INVENTION 
     Technical Problem 
     The present disclosure was achieved in view of the above circumstances. An objective of the present disclosure is to provide methods of diagnosing endometriosis or methods of determining whether or not a subject is affected by endometriosis, methods of determining the extent of endometrial fibrosis or adhesion in a subject affected by endometriosis, methods of predicting pain of a subject affected by endometriosis, methods of monitoring pathological conditions of a subject affected by endometriosis, and the like, and kits for performing these methods. 
     Solution to Problem 
     As a result of conducting dedicated research on methods of diagnosing and methods of monitoring pathological conditions of endometriosis, the inventors of the present disclosure have discovered that there are a number of markers whose abundance in patients with endometriosis is different from those in healthy individuals, and also discovered that by measuring the abundance of those markers, whether or not a subject is affected by endometriosis can be diagnosed, the extent of endometrial fibrosis or adhesion can be determined, pain of a subject affected by endometriosis can be predicted, and pathological conditions of a subject affected by endometriosis can be monitored. 
     The present disclosure is based on these findings and specifically relates to the following inventions:
         [1] A method of diagnosing endometriosis, comprising measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from a subject.   [2] A method of determining whether or not a subject is affected by endometriosis, comprising measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject.   [3] The method of [1] or [2], further comprising a step in which if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is high or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is low in the sample obtained from the subject, the subject that the sample is derived from is shown to be affected or potentially affected by endometriosis.   [4] A method of determining the extent of endometrial fibrosis in a subject, comprising measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject.   [5] The method of [4], further comprising a step in which if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is high or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is low in the sample obtained from the subject, it is shown that endometrial fibrosis has occurred or potentially occurred in the subject that the sample is derived from.   [6] A method of determining the extent of endometrial adhesion in a subject, comprising measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject.   [7] The method of [6], further comprising a step in which if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is high or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is low in the sample obtained from the subject, it is shown that endometrial adhesion has occurred or potentially occurred in the subject that the sample is derived from.   [8] A method of predicting the degree of pain due to endometriosis in a subject affected or suspected of being affected by endometriosis, comprising measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject.   [9] The method of [8], further comprising a step in which if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is high or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is low in the sample obtained from the subject, the subject that the sample is derived from is shown to develop or potentially develop pain due to endometriosis.   [10] A method of determining the degree of progression of endometriosis in a subject affected or suspected of being affected by endometriosis, comprising measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject.   [11] The method of [10], further comprising a step in which if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is high or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is low in the sample obtained from the subject, it is shown that endometriosis is progressing or potentially progressing in the subject that the sample is derived from.   [12] The method of [3], [5], [7], [9], or [11], wherein when the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is higher than the abundance of the same marker in a sample obtained from a healthy individual, the abundance is determined to be high.   [13] The method of [3], [5], [7], [9], or [11], wherein when the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, and the markers shown in Table 5A is two-fold or higher than the abundance of the same marker in a sample obtained from a healthy individual and/or when the abundance of at least one marker selected from the markers shown in Table 6A is 1.6-fold or higher than the abundance of the same marker in a sample obtained from a healthy individual, the abundance is determined to be high.   [14] The method of [3], [5], [7], [9], or [11], wherein when the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is lower than the abundance of the same marker in a sample obtained from a healthy individual, the abundance is determined to be low.   [15] The method of [3], [5], [7], [9], or [11], wherein when the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, and the markers shown in Table 5B is 0.5-fold or lower than the abundance of the same marker in a sample obtained from a healthy individual and/or when the abundance of at least one marker selected from the markers shown in Table 6B is 0.625-fold or lower than the abundance of the same marker in a sample obtained from a healthy individual, the abundance is determined to be low.   [16] A method of monitoring pathological conditions of endometriosis in a subject affected or suspected of being affected by endometriosis, comprising measuring each of the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in each of a plurality of samples collected from the subject at different points of time.   [17] The method of [16], further comprising a step in which if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A decreases over time or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B increases over time, it is shown that the pathological conditions of endometriosis are improving or potentially improving in the subject that the sample is derived from.   [18] The method of [16], further comprising a step in which if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A increases over time or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B decreases over time, it is shown that the pathological conditions of endometriosis are worsening or potentially worsening in the subject that the sample is derived from.   [19] The method of any one of [1] to [18], wherein the marker is measured as a polypeptide.   [20] The method of any one of [1] to [19], wherein the sample is a blood sample.   [21] The method of [20], wherein the abundance of the marker in the sample is a concentration of a polypeptide of the marker in the blood sample.   [21-1] The method of [20] or [21], wherein the concentration of the type V collagen MMP degradation product in the blood sample is measured by specifically recognizing the peptide represented by SEQ ID NO: 4 or SEQ ID NO: 6.   [22] A kit for diagnosing endometriosis, comprising a reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B.   [23] A kit for determining whether or not a subject is affected by endometriosis, comprising a reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B.   [24] The kit of [22] or [23], further comprising instructions stating that if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is high or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is low in a sample obtained from a subject, the subject that the sample is derived from is shown to be affected or potentially affected by endometriosis.   [25] A kit for determining the extent of endometrial fibrosis in a subject, comprising a reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B.   [26] The kit of [25], further comprising instructions stating that if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is high or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is low in a sample obtained from a subject, it is shown that endometrial fibrosis has occurred or potentially occurred in the subject that the sample is derived from.   [27] A kit for determining the extent of endometrial adhesion in a subject, comprising a reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B.   [28] The kit of [27], further comprising instructions stating that if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is high or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is low in a sample obtained from a subject, it is shown that endometrial adhesion has occurred or potentially occurred in the subject that the sample is derived from.   [29] A kit for predicting the degree of pain due to endometriosis in a subject affected or suspected of being affected by endometriosis, comprising a reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B.   [30] The kit of [29], further comprising instructions stating that if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is high or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is low in a sample obtained from a subject, the subject that the sample is derived from is shown to develop or potentially develop pain due to endometriosis.   [31] A kit for determining the degree of progression of endometriosis in a subject affected or suspected of being affected by endometriosis, comprising a reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B.   [32] The kit of [31], further comprising instructions stating that if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is high or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is low in a sample obtained from a subject, it is shown that endometriosis is progressing or potentially progressing in the subject that the sample is derived from.   [33] The kit of [24], [26], [28], [30], or [32], wherein if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is higher than the abundance of the same marker in a sample obtained from a healthy individual, the abundance is determined to be high.   [34] The kit of [24], [26], [28], [30], or [32], wherein if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, and the markers shown in Table 5A is two-fold or higher than the abundance of the same marker in a sample obtained from a healthy individual and/or if the abundance of at least one marker selected from the markers shown in Table 6A is 1.6-fold or higher than the abundance of the same marker in a sample obtained from a healthy individual, the abundance is determined to be high.   [35] The kit of [24], [26], [28], [30], or [32], wherein if the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is lower than the abundance of the same marker in a sample obtained from a healthy individual, the abundance is determined to be low.   [36] The kit of [24], [26], [28], [30], or [32], wherein if the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, and the markers shown in Table 5B that is 0.5-fold or lower than the abundance of the same marker present in a sample obtained from a healthy individual and/or the abundance of at least one marker selected from the markers shown in Table 6B that is 0.625-fold or lower than the abundance of the same marker in a sample obtained from a healthy individual, the abundance is determined to be low.   [37] A kit for monitoring pathological conditions of endometriosis in a subject affected or suspected of being affected by endometriosis, comprising a reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B.   [38] The kit of [37], further comprising instructions stating that the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in each of a plurality of samples collected from the subject at different points of time is compared.   [39] The kit of [37] or [38], further comprising instructions stating that if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A decreases over time or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B increases over time, it is shown that the pathological conditions of endometriosis are improving or potentially improving in the subject that the sample is derived from.   [40] The kit of [37] or [38], further comprising instructions stating that if the abundance of at least one marker selected from the group consisting of the type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A increases over time or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B decreases over time, it is shown that the pathological conditions of endometriosis are worsening or potentially worsening in the subject that the sample is derived from.   [41] The kit of any one of [22] to [40], wherein the marker is measured as a polypeptide.   [42] The kit of any one of [22] to [41], wherein the sample is a blood sample.   [43] The kit of [42], wherein the abundance of the marker in the sample is a concentration of a polypeptide of the marker in the blood sample.   [43-1] The kit of [42] or [43], wherein the concentration of the type V collagen MMP degradation product in the blood sample is measured by specifically recognizing the peptide represented by SEQ ID NO: 4 or SEQ ID NO: 6.   [44] A reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B, for use in the diagnosis of endometriosis.   [45] A reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B, for use in the determination of whether or not a subject is affected by endometriosis.   [46] A reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B, for use in the determination of the extent of endometrial fibrosis in a subject.   [47] A reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B, for use in the determination of the extent of endometrial adhesion in a subject.   [48] A reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B, for use in the prediction of the degree of pain due to endometriosis in a subject affected or suspected of being affected by endometriosis.   [49] A reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B, for use in the determination of the degree of progression of endometriosis in a subject affected or suspected of being affected by endometriosis.   [50] A reagent for measuring the abundance of at least one marker selected from the group consisting of a type V collagen MMP degradation product, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B, for use in the monitoring of pathological conditions of endometriosis in a subject affected or suspected of being affected by endometriosis.   [51] The reagent of any one of [44] to [50], wherein the marker is measured as a polypeptide.   [52] The reagent of any one of [44] to [51], wherein the abundance of the marker is measured by measuring a concentration of a polypeptide of the marker in a blood sample obtained from the subject.       

     [53] The reagent of [51], wherein the concentration of the type V collagen MMP degradation product in the blood sample is measured by specifically recognizing the peptide represented by SEQ ID NO: 4 or SEQ ID NO: 6 present in the blood sample. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1-1  to  FIG. 1-10  show the results of analyzing the relative expression levels of proteins in the plasma of healthy individuals/endometriosis patients by LC-MS. The title of each graph shows Gene Symbol:UniProt ID of the target protein. The X axis represents the name of the sample and the Y axis represents the relative expression level of the protein. The bars in the graph represent the standard deviation of the relative expression level of the protein in three data sets obtained by three analyses.  FIG. 1-1  shows the data on Gene Symbol: CALU and UniProt ID: 043852. 
         FIG. 1-2  shows the data on Gene Symbol: CAT and UniProt ID: P04040. 
         FIG. 1-3  shows the data on Gene Symbol: HBA1 and UniProt ID: P69905. 
         FIG. 1-4  shows the data on Gene Symbol: HBB and UniProt ID: P68871. 
         FIG. 1-5  shows the data on Gene Symbol: HBD and UniProt ID: P02042. 
         FIG. 1-6  shows the data on Gene Symbol: PPIA and UniProt ID: P62937. 
         FIG. 1-7  shows the data on Gene Symbol: PRDX1;PRDX4 and UniProt ID: Q06830. 
         FIG. 1-8  shows the data on Gene Symbol: S100A6 and UniProt ID: P06703. 
         FIG. 1-9  shows the data on Gene Symbol: TPI1 and UniProt ID: P60174. 
         FIG. 1-10  shows the data on Gene Symbol: UBE2V1;UBE2V2 and UniProt ID: Q13404. 
         FIG. 2-1  to  FIG. 2-10  show the results of analyzing the expression levels of proteins in the plasma of healthy individuals/endometriosis patients by SOMAscan®. The title of each graph shows Gene Symbol:UniProt ID of the target protein. The X axis represents the name of the sample and the Y axis represents the aptamer signal value of the target protein in SOMAscan®.  FIG. 2-1  shows the data on Gene Symbol: BGN and UniProt ID: P21810. 
         FIG. 2-2  shows the data on Gene Symbol: CDH12 and UniProt ID: P55289. 
         FIG. 2-3  shows the data on Gene Symbol: DDX19B and UniProt ID: Q9UMR2. 
         FIG. 2-4  shows the data on Gene Symbol: IL1B and UniProt ID: P01584. 
         FIG. 2-5  shows the data on Gene Symbol: IL2 and UniProt ID: P60568. 
         FIG. 2-6  shows the data on Gene Symbol: LAG3 and UniProt ID: P18627. 
         FIG. 2-7  shows the data on Gene Symbol: MFGE8 and UniProt ID: Q08431. 
         FIG. 2-8  shows the data on Gene Symbol: PDE5A and UniProt ID: 076074. 
         FIG. 2-9  shows the data on Gene Symbol: SERPINE2 and UniProt ID: P07093. 
         FIG. 2-10  shows the data on Gene Symbol: SMPDL3A and UniProt ID: Q92484. 
         FIG. 3  shows the result of analyzing the expression level of a type V collagen degradation product (C5M) in the plasma of healthy individuals/endometriosis patients. The X axis represents the name of the sample and the Y axis represents the concentration of the target degradation product in the plasma (ng/ml). 
     
    
    
     DESCRIPTION OF EMBODIMENTS 
     Markers 
     Markers in the present disclosure can be reworded as biomarkers and refer to specific chemical substances in the body that can be measured and evaluated objectively as indices for normal biological processes, disease development processes, or pharmacological responsiveness to treatment. The markers are useful for evaluating the presence or absence of diseases, progress of diseases, or susceptibility to diseases; evaluating or predicting the effects, the optimal dose, or safety of pharmaceutical agents; predicting prognosis; or such. The markers in the present disclosure are specified by protein names, protein fragment names, or gene names Genes serving as markers are preferably measured as polypeptides or polynucleotides (including the form of DNA and the form of mRNA), and proteins or protein fragments serving as markers are preferably measured as polypeptides. 
     Methods of Measuring the Abundance of Markers 
     The abundance of a marker can be measured by selecting an appropriate method according to the form of the marker or the type of a sample in which the abundance of the marker is to be measured. When the marker is in the form of a polypeptide, it can be measured by immunological methods that use antibodies specifically binding to the polypeptide. Examples of such methods include enzyme immunoassays (ELISA, EIA), fluoroimmunoassays (FIA), radioimmunoassays (RIA), luminescent immunoassays (LIA), electrochemical luminescence (ECL) methods, Western blotting methods, surface plasmon resonance methods, methods that use antibody arrays, immunohistochemical staining methods, fluorescence activated cell sorting (FACS) methods, immunochromatography methods, immunoprecipitation methods, immunonephelometry methods, and latex agglutination methods. When the marker is in the form of a polynucleotide, it can be measured by genetic engineering methods that use oligonucleotides specifically binding to the polynucleotide. Examples of such methods include polymerase chain reaction (PCR) methods, reverse transcription PCR (RT-PCR) methods, real-time quantitative PCR (Q-PCR) methods, northern blotting, and hybridization methods (including methods that use oligonucleotide arrays such as DNA microarrays). 
     When a marker to be measured is a protein expressed from a gene, the abundance can be reworded as expression level. In the present disclosure, the “abundance” includes the expression level of a protein, the expression level of a gene, and the concentration of a protein fragment. 
     In an embodiment of the present disclosure, the abundance of a marker can be a relative abundance. A relative abundance can be measured by comparing the level of a specific marker and the level of other proteins/metabolites in a sample obtained from a subject with a control. A relative abundance can also be measured by LC/MS (liquid chromatography/mass spectrometry). 
     Criteria for the Abundance of Markers 
     In the present disclosure, “the abundance of a marker is high or large” means that the measured value of the marker is higher or larger than a predetermined value (control level) for the marker. “The abundance of a marker is low or small” means that it is lower or smaller than a predetermined value (control level) for the marker or not greater than the control level. 
     The predetermined value in the present disclosure means a value that is predetermined based on a certain scientific basis. It may be any value as long as it can be used as a reference to determine the presence or absence of endometriosis, determine the extent of endometrial fibrosis in a subject, determine the extent of endometrial adhesion in a subject, predict the degree of pain of a subject affected by endometriosis, determine the degree of progression of endometriosis, or monitor pathological conditions of endometriosis. The predetermined value in the present disclosure may be determined for each marker. 
     The predetermined value in the present disclosure can be determined from the measured value of a marker in a sample (control sample) obtained from a healthy subject, for example, a healthy adult. It has been found in the present disclosure that the measured value of a marker in a sample obtained from a subject affected by endometriosis is increased or decreased compared to the measured value of the marker in a sample obtained from a healthy subject. Thus, one possible approach may be to use as a predetermined value the average of the measured values of a marker in samples obtained from multiple healthy subjects. Another possible approach may be to use as a predetermined value the average of the measured values of a marker in samples obtained from multiple healthy subjects plus a value of 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, 2.0, 2.5, or 3.0 times the standard deviation. Accordingly, in one embodiment of the present disclosure, it is shown that determination of whether a test subject is affected by endometriosis, determination of the extent of endometrial fibrosis in a subject, determination of the extent of endometrial adhesion in a subject, prediction of the degree of pain of a subject affected or suspected of being affected by endometriosis, determination of the degree of progression of endometriosis, or monitoring of pathological conditions of endometriosis, is carried out by comparing the abundance of a marker (control level) measured in a sample (control sample) obtained from a healthy individual and the measured value of the marker in a sample obtained from a test subject. 
     In the present disclosure, the measured values and predetermined values of markers in the present disclosure may be measurement results of the abundance of the markers quantified by any method. In the present disclosure, values obtained as a result of measurement (e.g., color development intensity) may be directly used as measured values or predetermined values of markers, or values converted from measurement results (e.g., concentration) by comparing them with a separately prepared positive control sample that contains a known amount of the marker may be used. Alternatively, values given by, for example, grouping the values obtained as described above into certain intervals and scoring them (e.g., grades 1, 2, and 3) may be used. 
     Samples 
     Samples in the present disclosure can be reworded as biological samples and refer to organs, tissues, cells, body fluids, or mixtures thereof contained in living bodies. Specific examples include skin, respiratory tract, intestinal tract, urogenital tract, nerve, tumor, bone marrow, blood cells, blood (whole blood, plasma, serum), lymph, cerebrospinal fluid, intraperitoneal fluid, synovial fluid, intrapulmonary fluid, saliva, sputum, urine, and such. Samples obtained by washing these or obtained by culturing these ex vivo are also included in the samples of the present disclosure. A preferred sample in the present disclosure is blood, and a particularly preferred sample is plasma or serum. 
     In the present disclosure, samples obtained from subjects may be processed by methods such as concentration, purification, extraction, isolation, or physical/chemical treatment before subjected to measurement of the abundance of markers. For example, blood cells or plasma components may be isolated from blood samples, and DNA or RNA may be extracted from tissue/cell samples. Alternatively, unwanted components may be denatured/removed by heating or chemical reagents. Such processing is performed mainly for improving the sensitivity and specificity of measurement of the abundance of markers. 
     In determination of the extent of endometrial fibrosis, determination of the extent of endometrial adhesion, prediction of the degree of pain due to endometriosis, determination of the degree of progression of endometriosis, and monitoring of pathological conditions of endometriosis in the present disclosure, subjects from which samples are obtained may be subjects already diagnosed as being affected by endometriosis or subjects suspected of being affected by endometriosis. Subjects affected by endometriosis may be any subjects as long as they are affected by endometriosis. Subjects may be subjects that have not received, or have already been receiving, treatment for endometriosis. 
     Subjects in the present disclosure are mammals. Mammals include, but are not limited to, domesticated animals (for example, cows, sheep, cats, dogs, and horses), primates (for example, humans and non-human primates like monkeys), rabbits, and rodents (such as mice and rats). In a certain embodiment, subjects are humans. 
     Markers in the Present Disclosure 
     Markers in the present disclosure include type V collagen MMP (matrix metalloproteinase) degradation products (type V collagen-derived polypeptides comprising the amino acid sequence set forth in SEQ ID NO: 4 at its N-terminus and/or comprising the amino acid sequence set forth in SEQ ID NO: 6 at its C-terminus, such as protein fragments set forth in SEQ ID NOs: 2 and 3), the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B. 
     
       
         
           
               
               
               
             
               
                 TABLE 1A 
               
               
                   
               
               
                 UniProt ID 
                 Protein name 
                 Gene name 
               
               
                   
               
             
            
               
                 P02042 
                 Hemoglobin subunit delta 
                 HBD 
               
               
                 P68871 
                 Hemoglobin subunit beta; 
                 HBB 
               
               
                   
                 LVV-hemorphin-7; Spinorphin 
               
               
                 P55072 
                 Transitional endoplasmic reticulum ATPase 
                 VCP 
               
               
                 P50395; P50395-2 
                 Rab GDP dissociation inhibitor beta 
                 GDI2 
               
               
                 O43852-9; O43852-5; O43852-2; 
                 Calumenin 
                 CALU 
               
               
                 O43852; O43852-4; O43852-3; 
               
               
                 O43852-12; O43852-13; O43852-14; 
               
               
                 O43852-7; O43852-15; O43852-11; 
               
               
                 O43852-8; O43852-10; O43852-6 
               
               
                 P04040 
                 Catalase 
                 CAT 
               
               
                 Q06830; Q13162 
                 Peroxiredoxin-1 ; Peroxiredoxin-4 
                 PRDX1; 
               
               
                   
                   
                 PRDX4 
               
               
                 P69905 
                 Hemoglobin subunit alpha 
                 HBA1 
               
               
                 Q13404-8; Q15819; Q13404; 
                 Ubiquitin-conjugating enzyme E2 
                 UBE2V1; 
               
               
                 Q13404-7; Q13404-2; Q13404-1 
                 variant 1; Ubiquitin-conjugating 
                 UBE2V2 
               
               
                   
                 enzyme E2 variant 2 
               
               
                 P06703 
                 Protein S100-A6 
                 S100A6 
               
               
                 P60174-1; P60174; P60174-4 
                 Triosephosphate isomerase 
                 TPI1 
               
               
                 P62937; P62937-2 
                 Peptidyl-prolyl cis-trans 
                 PPIA 
               
               
                   
                 isomerase A; Peptidyl-prolyl 
               
               
                   
                 cis-trans isomerase A, N-terminally 
               
               
                   
                 processed 
               
               
                 P49746-2; P49746 
                 Thrombospondin-3 
                 THBS3 
               
               
                 P09486 
                 SPARC 
                 SPARC 
               
               
                 Q14766-3; Q14766-2; Q14766-5; 
                 Latent-transforming growth factor 
                 LTBP1 
               
               
                 Q14766; Q14766-4 
                 beta-binding protein 1 
               
               
                 P01137 
                 Transforming growth factor beta-1; 
                 TGFB1 
               
               
                   
                 Latency-associated peptide 
               
               
                 P61088; Q5JXB2 
                 Ubiquitin-conjugating enzyme E2 N; 
                 UBE2N; 
               
               
                   
                 Putative ubiquitin-conjugating 
                 UBE2NL 
               
               
                   
                 enzyme E2 N-like 
               
               
                 P00558-2; P00558 
                 Phosphoglycerate kinase 1 
                 PGK1 
               
               
                 P07996; P07996-2 
                 Thrombospondin-1 
                 THBS1 
               
               
                 P02776 
                 Platelet factor 4; Platelet factor 4, 
                 PF4 
               
               
                   
                 short form 
               
               
                 P05067-7; P05067-11; P05067-8; 
                 Amyloid beta A4 protein; N-APP; 
                 APP 
               
               
                 P05067-9; P05067; P05067-10; 
                 Soluble APP-alpha; Soluble APP-beta; 
               
               
                 P05067-3; P05067-4; P05067-5; 
                 C99; Beta-amyloid protein 42; 
               
               
                 P05067-6 
                 Beta-amyloid protein 40; C83; 
               
               
                   
                 P3(42); P3(40); C80; Gamm 
               
               
                   
                 a-secretase C-terminal fragment 59; 
               
               
                   
                 Gamma-secretase C-terminal 
               
               
                   
                 fragment 57; Gamma-secretase 
               
               
                   
                 C-terminal fragment 50; C31 
               
               
                 P00568 
                 Adenylate kinase isoenzyme 1 
                 AK1 
               
               
                 P00918 
                 Carbonic anhydrase 2 
                 CA2 
               
               
                 P32119 
                 Peroxiredoxin-2 
                 PRDX2 
               
               
                 P16070-18; P16070-12; P16070-14; 
                 CD44 antigen 
                 CD44 
               
               
                 P16070-13; P16070-11; P16070-10; 
               
               
                 P16070-16; P16070-8; P16070-17; 
               
               
                 P16070-6; P16070-4; P16070-3; 
               
               
                 P16070-7; P16070-5; P16070; 
               
               
                 P16070-15; P16070-9 
               
               
                 Q13201 
                 Multimerin-1; Platelet glycoprotein 
                 MMRN1 
               
               
                   
                 la*; 155 kDa platelet multimerin 
               
               
                 P27348 
                 14-3-3 protein theta 
                 YWHAQ 
               
               
                 O00592-2; O00592 
                 Podocalyxin 
                 PODXL 
               
               
                 P10599-2; P10599 
                 Thioredoxin 
                 TXN 
               
               
                 P00915 
                 Carbonic anhydrase 1 
                 CA1 
               
               
                 P62158 
                 Calmodulin 
                 CALM1 
               
               
                 P58546 
                 Myotrophin 
                 MTPN 
               
               
                 P62258; P62258-2 
                 14-3-3 protein epsilon 
                 YWHAE 
               
               
                 O94919 
                 Endonuclease domain-containing 
                 ENDOD1 
               
               
                   
                 1 protein 
               
               
                 P37837 
                 Transaldolase 
                 TALDO1 
               
               
                 P07738 
                 Bisphosphoglycerate mutase 
                 BPGM 
               
               
                 P30043 
                 Flavin reductase (NADPH) 
                 BLVRB 
               
               
                 P02775 
                 Platelet basic protein; Connective 
                 PPBP 
               
               
                   
                 tissue-activating peptide III; 
               
               
                   
                 TC-2; Connective tissue-activating 
               
               
                   
                 peptide III(1-81); Beta-thromboglobulin; 
               
               
                   
                 Neutrophil-activating peptide 2(74); 
               
               
                   
                 Neutrophil-activating peptide 2(73); 
               
               
                   
                 Neutrophil-activating peptide 2; TC-1; 
               
               
                   
                 Neutrophil-activating peptide 2(1-66); 
               
               
                   
                 Neutrophil-activating peptide 2(1-63) 
               
               
                 P15311 
                 Ezrin 
                 EZR 
               
               
                 P0DJI8; P0DJI9-2 
                 Serum amyloid A-1 protein; 
                 SAA1; 
               
               
                   
                 Amyloid protein A; 
                 SAA2 
               
               
                   
                 Serum amyloid protein A(2-104); 
               
               
                   
                 Serum amyloid protein A(3-104); 
               
               
                   
                 Serum amyloid protein A(2-103); 
               
               
                   
                 Serum amyloid protein A(2-102); 
               
               
                   
                 Serum amyloid protein A(4-101); 
               
               
                   
                 Serum amyloid A-2 protein 
               
               
                 P10124 
                 Serglycin 
                 SRGN 
               
               
                 P13798 
                 Acylamino-acid-releasing enzyme 
                 APEH 
               
               
                 P23528 
                 Cofilin-1 
                 CFL1 
               
               
                 P30041 
                 Peroxiredoxin-6 
                 PRDX6 
               
               
                 Q8WUM4; Q8WUM4-2 
                 Programmed cell death 
                 PDCD6IP 
               
               
                   
                 6-interacting protein 
               
               
                 P05090 
                 Apolipoprotein D 
                 APOD 
               
               
                 Q99497 
                 Protein deglycase DJ-1 
                 PARK7 
               
               
                 P35579; P35579-2 
                 Myosin-9 
                 MYH9 
               
               
                 Q13228; Q13228-4; 
                 Selenium-binding protein 1 
                 SELENBP1 
               
               
                 Q13228-2; Q13228-3 
               
               
                 P13716; P13716-2 
                 Delta-aminolevulinic acid 
                 ALAD 
               
               
                   
                 dehydratase 
               
               
                 Q9UL13-2; Q9UL13 
                 Protein HEG homolog 1 
                 HEG1 
               
               
                 P07384 
                 Calpain-1 catalytic subunit 
                 CAPN1 
               
               
                 P18065 
                 Insulin-like growth factor-binding 
                 IGFBP2 
               
               
                   
                 protein 2 
               
               
                 P04083 
                 Annexin A1 
                 ANXA1 
               
               
                 P0DMV8-2; P0DMV9; P0DMV8 
                 Heat shock 70 kDa protein 1A; 
                 HSPA1A; 
               
               
                   
                 Heat shock 70 kDa protein 1B 
                 HSPA1B 
               
               
                 P07911-3; P07911; P07911-5; 
                 Uromodulin; Uromodulin, secreted 
                 UMOD 
               
               
                 P07911-4 
                 form 
               
               
                 P15924; P15924-2; P15924-3 
                 Desmoplakin 
                 DSP 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 1B 
               
               
                   
                   
               
               
                   
                 UniProt ID 
                 Protein name 
                 Gene name 
               
               
                   
                   
               
             
            
               
                   
                 Q9C0H2-3 
                 Protein tweety homolog 3 
                 TTYH3 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                 TABLE 2A 
               
               
                   
               
               
                   
                   
                 Entrez 
                 Entrez Gene 
               
               
                 Protein name 
                 UniProt ID 
                 Gene ID 
                 Symbol 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 Pulmonary surfactant-associated 
                 P35247 
                 6441 
                 SFTPD 
               
               
                 protein D 
               
               
                 Histone H1.2 
                 P16403 
                 3006 
                 HIST1H1C 
               
               
                 Sialic acid-binding Ig-like 
                 Q9Y336 
                 27180 
                 SIGLEC9 
               
               
                 lectin 9 
               
               
                 Heterogeneous nuclear 
                 P22626 
                 3181 
                 HNRNPA2B1 
               
               
                 ribonucleoproteins A2/B1 
               
               
                 Hexokinase-2 
                 P52789 
                 3099 
                 HK2 
               
               
                 High mobility group protein B1 
                 P09429 
                 3146 
                 HMGB1 
               
               
                 Thrombospondin-1 
                 P07996 
                 7057 
                 THBS1 
               
               
                 3-hydroxy-3-methylglutaryl- 
                 P04035 
                 3156 
                 HMGCR 
               
               
                 coenzyme A reductase 
               
               
                 Platelet factor 4 
                 P02776 
                 5196 
                 PF4 
               
               
                 Protein S100-A9 
                 P06702 
                 6280 
                 S100A9 
               
               
                 40S ribosomal protein S3a 
                 P61247 
                 6189 
                 RPS3A 
               
               
                 Annexin A6 
                 P08133 
                 309 
                 ANXA6 
               
               
                 Inosine-5′-monophosphate 
                 P20839 
                 3614 
                 IMPDH1 
               
               
                 dehydrogenase 1 
               
               
                 Tyrosine-protein kinase Fgr 
                 P09769 
                 2268 
                 FGR 
               
               
                 Serine/threonine-protein 
                 O94768 
                 9262 
                 STK17B 
               
               
                 kinase 17B 
               
               
                 Neutrophil-activating peptide 2 
                 P02775 
                 5473 
                 PPBP 
               
               
                 Estradiol 17-beta-dehydrogenase 1 
                 P14061 
                 3292 
                 HSD17B1 
               
               
                 Connective tissue-activating 
                 P02775 
                 5473 
                 PPBP 
               
               
                 peptide III 
               
               
                 Prostaglandin G/H synthase 2 
                 P35354 
                 5743 
                 PTGS2 
               
               
                 Amyloid beta A4 protein 
                 P05067 
                 351 
                 APP 
               
               
                 GTP-binding nuclear protein Ran 
                 P62826 
                 5901 
                 RAN 
               
               
                 NAD-dependent protein 
                 Q8IXJ6 
                 22933 
                 SIRT2 
               
               
                 deacetylase sirtuin-2 
               
               
                 Protein S100-A12 
                 P80511 
                 6283 
                 S100A12 
               
               
                 Plasminogen activator inhibitor 1 
                 P05121 
                 5054 
                 SERPINE1 
               
               
                 SUMO-conjugating enzyme UBC9 
                 P63279 
                 7329 
                 UBE2I 
               
               
                 Bactericidal permeability-increasing 
                 P17213 
                 671 
                 BPI 
               
               
                 protein 
               
               
                 6-phosphogluconate 
                 P52209 
                 5226 
                 PGD 
               
               
                 dehydrogenase, decarboxylating 
               
               
                 Platelet-derived growth factor 
                 P01127 
                 5155 
                 PDGFB 
               
               
                 subunit B 
               
               
                 Tyrosine-protein phosphatase 
                 P29350 
                 5777 
                 PTPN6 
               
               
                 non-receptor type 6 
               
               
                 Metalloproteinase inhibitor 3 
                 P35625 
                 7078 
                 TIMP3 
               
               
                 NudC domain-containing protein 3 
                 Q8IVD9 
                 23386 
                 NUDCD3 
               
               
                 SPARC 
                 P09486 
                 6678 
                 SPARC 
               
               
                 Protein 4.1 
                 P11171 
                 2035 
                 EPB41 
               
               
                 Sex hormone-binding globulin 
                 P04278 
                 6462 
                 SHBG 
               
               
                 Death-associated protein kinase 2 
                 Q9UIK4 
                 23604 
                 DAPK2 
               
               
                 Hepatoma-derived growth 
                 Q7Z4V5 
                 84717 
                 HDGFRP2 
               
               
                 factor-related protein 2 
               
               
                 Proto-oncogene vav 
                 P15498 
                 7409 
                 VAV1 
               
               
                 Serine/threonine-protein kinase 
                 P11309 
                 5292 
                 PIM1 
               
               
                 pim-1 
               
               
                 Heterogeneous nuclear 
                 Q99729 
                 3182 
                 HNRNPAB 
               
               
                 ribonucleoprotein A/B 
               
               
                 Proliferation-associated 
                 Q9UQ80 
                 5036 
                 PA2G4 
               
               
                 protein 2G4 
               
               
                 Extracellular superoxide 
                 P08294 
                 6649 
                 SOD3 
               
               
                 dismutase [Cu-Zn] 
               
               
                 Angiopoietin-1 
                 Q15389 
                 284 
                 ANGPT1 
               
               
                 Acid sphingomyelinase-like 
                 Q92484 
                 10924 
                 SMPDL3A 
               
               
                 phosphodiesterase 3a 
               
               
                 Peroxiredoxin-6 
                 P30041 
                 9588 
                 PRDX6 
               
               
                 AMP Kinase (alpha1beta1gamma1) 
                 Q13131 
                 5562 
                 PRKAA1 
               
               
                   
                 Q9Y478 
                 5564 
                 PRKAB1 
               
               
                   
                 P54619 
                 5571 
                 PRKAG1 
               
               
                 Serum amyloid A-1 protein 
                 P0DJI8 
                 6288 
                 SAA1 
               
               
                 Insulin-like growth factor-binding 
                 P18065 
                 3485 
                 IGFBP2 
               
               
                 |protein 2 
               
               
                 Histone H2B type 2-E 
                 Q16778 
                 8349 
                 HIST2H2BE 
               
               
                 Fibroblast growth factor 5 
                 P12034 
                 2250 
                 FGF5 
               
               
                 Non-histone chromosomal protein 
                 P05114 
                 3150 
                 HMGN1 
               
               
                 HMG-14 
               
               
                 Calcium/calmodulin-dependent 
                 Q13557 
                 817 
                 CAMK2D 
               
               
                 protein kinase type II subunit delta 
               
               
                 Interstitial collagenase 
                 P03956 
                 4312 
                 MMP1 
               
               
                 ICOS ligand 
                 O75144 
                 23308 
                 ICOSLG 
               
               
                 Calcium/calmodulin-dependent 
                 Q13554 
                 816 
                 CAMK2B 
               
               
                 protein kinase type II subunit beta 
               
               
                 Inosine-5′-monophosphate 
                 P12268 
                 3615 
                 IMPDH2 
               
               
                 dehydrogenase 2 
               
               
                 Dickkopf-related protein 4 
                 Q9UBT3 
                 27121 
                 DKK4 
               
               
                 Glia-derived nexin 
                 P07093 
                 5270 
                 SERPINE2 
               
               
                 14-3-3 protein beta/alpha 
                 P31946 
                 7529 
                 YWHAB 
               
               
                 Macrophage-capping protein 
                 P40121 
                 822 
                 CAPG 
               
               
                 ADP-ribosyl cyclase/cyclic 
                 P28907 
                 952 
                 CD38 
               
               
                 ADP-ribose hydrolase 1 
               
               
                 SH2 domain-containing protein 1A 
                 O60880 
                 4068 
                 SH2D1A 
               
               
                 Vacuolar protein sorting-associated 
                 Q9NP79 
                 51534 
                 VTA1 
               
               
                 protein VTA1 homolog 
               
               
                 Interleukin-1 beta 
                 P01584 
                 3553 
                 IL1B 
               
               
                 Chloride intracellular channel 
                 O00299 
                 1192 
                 CLIC1 
               
               
                 protein 1 
               
               
                 MAP kinase-activated protein 
                 Q16644 
                 7867 
                 MAPKAPK3 
               
               
                 kinase 3 
               
               
                 Mitogen-activated protein kinase 1 
                 P28482 
                 5594 
                 MAPK1 
               
               
                 Choline/ethanolamine kinase 
                 Q9Y259 
                 1120 
                 CHKB 
               
               
                 Creatine kinase B-type 
                 P12277 
                 1152 
                 CKB 
               
               
                 DNA topoisomerase 1 
                 P11387 
                 7150 
                 TOP1 
               
               
                 C-C motif chemokine 5 
                 P13501 
                 6352 
                 CCL5 
               
               
                 C3a anaphylatoxin 
                 P01024 
                 718 
                 C3 
               
               
                 Copine-1 
                 Q99829 
                 8904 
                 CPNE1 
               
               
                 Chymase 
                 P23946 
                 1215 
                 CMA1 
               
               
                 Mitogen-activated protein kinase 
                 O43318 
                 6885 
                 MAP3K7 
               
               
                 kinase kinase 7: TGF-beta-activated 
                 Q15750 
                 10454 
                 TAB1 
               
               
                 kinase 1 and MAP3K7-binding 
               
               
                 protein 1 fusion 
               
               
                 Dickkopf-related protein 1 
                 O94907 
                 22943 
                 DKK1 
               
               
                 Ephrin type-B receptor 4 
                 P54760 
                 2050 
                 EPHB4 
               
               
                 40S ribosomal protein S7 
                 P62081 
                 6201 
                 RPS7 
               
               
                 Intercellular adhesion molecule 1 
                 P05362 
                 3383 
                 ICAM1 
               
               
                 Ubiquitin + 1, truncated mutation 
                 P62979 
                 6233 
                 RPS27A 
               
               
                 for UbB 
               
               
                 Ubiquitin-conjugating enzyme E2 N 
                 P61088 
                 7334 
                 UBE2N 
               
               
                 Moesin 
                 P26038 
                 4478 
                 MSN 
               
               
                 Small ubiquitin-related modifier 3 
                 P55854 
                 6613 
                 SUMO3 
               
               
                 G2/mitotic-specific cyclin-B1 
                 P14635 
                 891 
                 CCNB1 
               
               
                 ATP-dependent RNA helicase 
                 Q9UMR2 
                 11269 
                 DDX19B 
               
               
                 DDX19B 
               
               
                 Tyrosine-protein kinase CSK 
                 P41240 
                 1445 
                 CSK 
               
               
                 Alpha-1-antitrypsin 
                 P01009 
                 5265 
                 SERPINA1 
               
               
                 Adenylate kinase isoenzyme 1 
                 P00568 
                 203 
                 AK1 
               
               
                 Mothers against decapentaplegic 
                 P84022 
                 4088 
                 SMAD3 
               
               
                 homolog 3 
               
               
                 Brain-derived neurotrophic factor 
                 P23560 
                 627 
                 BDNF 
               
               
                 Atrial natriuretic factor 
                 P01160 
                 4878 
                 NPPA 
               
               
                 Annexin A1 
                 P04083 
                 301 
                 ANXA1 
               
               
                 Signal transducer and activator of 
                 P42224 
                 6772 
                 STAT1 
               
               
                 transcription 1-alpha/beta 
               
               
                 Angiopoietin-related protein 4 
                 Q9BY76 
                 51129 
                 ANGPTL4 
               
               
                 Cadherin-12 
                 P55289 
                 1010 
                 CDH12 
               
               
                 Stress-induced-phosphoprotein 1 
                 P31948 
                 10963 
                 STIP1 
               
               
                 Glycylpeptide 
                 P30419 
                 4836 
                 NMT1 
               
               
                 N-tetradecanoyltransferase 1 
               
               
                 Peroxiredoxin-1 
                 Q06830 
                 5052 
                 PRDX1 
               
               
                 Oxidized low-density lipoprotein 
                 P78380 
                 4973 
                 OLR1 
               
               
                 receptor 1 
               
               
                 VPS10 domain-containing receptor 
                 Q96PQ0 
                 57537 
                 SORCS2 
               
               
                 SorCS2 
               
               
                 FACT complex subunit SSRP1 
                 Q08945 
                 6749 
                 SSRP1 
               
               
                 Carbonic anhydrase 1 
                 P00915 
                 759 
                 CA1 
               
               
                 Mitogen-activated protein kinase 11 
                 Q15759 
                 5600 
                 MAPK11 
               
               
                 Triosephosphate isomerase 
                 P60174 
                 7167 
                 TPI1 
               
               
                 Neurexophilin-1 
                 P58417 
                 30010 
                 NXPH1 
               
               
                 Platelet-derived growth factor 
                 P04085 
                 5154 
                 PDGFA 
               
               
                 subunit A 
               
               
                 lnterleukin-22 receptor subunit 
                 Q8N6P7 
                 58985 
                 IL22RA1 
               
               
                 alpha-1 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                 TABLE 2B 
               
               
                   
               
               
                   
                   
                 Entrez 
                 Entrez Gene 
               
               
                 Protein name 
                 UniProt ID 
                 Gene ID 
                 Symbol 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 Cystatin-SN 
                 P01037 
                 1469 
                 CST1 
               
               
                 lnterleukin-22 
                 Q9GZX6 
                 50616 
                 IL22 
               
               
                 Tyrosine-protein kinase Fyn 
                 P06241 
                 2534 
                 FYN 
               
               
                 Biglycan 
                 P21810 
                 633 
                 BGN 
               
               
                 Sonic hedgehog protein 
                 Q15465 
                 6469 
                 SHH 
               
               
                 Cathepsin L2 
                 060911 
                 1515 
                 CTSV 
               
               
                 Interferon alpha/beta receptor 1 
                 P17181 
                 3454 
                 IFNAR1 
               
               
                 Ectodysplasin-A, secreted form 
                 Q92838 
                 1896 
                 EDA 
               
               
                 Dynein light chain 1, cytoplasmic 
                 P63167 
                 8655 
                 DYNLL1 
               
               
                 Cytochrome c 
                 P99999 
                 54205 
                 CYCS 
               
               
                 Lactoperoxidase 
                 P22079 
                 4025 
                 LPO 
               
               
                 Tumor necrosis factor receptor 
                 Q969Z4 
                 84957 
                 RELT 
               
               
                 superfamily member 19L 
               
               
                 Growth factor receptor-bound protein 2 
                 P62993 
                 2885 
                 GRB2 
               
               
                 Ectonucleotide pyrophosphatase/ 
                 Q6UWV6 
                 339221 
                 ENPP7 
               
               
                 phosphodiesterase family member 7 
               
               
                 Glucagon 
                 P01275 
                 2641 
                 GCG 
               
               
                 Eukaryotic translation initiation factor 4 
                 P78344 
                 1982 
                 EIF4G2 
               
               
                 gamma 2 
               
               
                 C-X-C motif chemokine 10 
                 P02778 
                 3627 
                 CXCL10 
               
               
                 Platelet-derived growth factor receptor 
                 P09619 
                 5159 
                 PDGFRB 
               
               
                 beta 
               
               
                 von Willebrand factor 
                 P04275 
                 7450 
                 VWF 
               
               
                 Iduronate 2-sulfatase 
                 P22304 
                 3423 
                 IDS 
               
               
                 cGMP-specific 3′,5′-cyclic 
                 O76074 
                 8654 
                 PDE5A 
               
               
                 phosphodiesterase 
               
               
                 Small glutamine-rich tetratricopeptide 
                 O43765 
                 6449 
                 SGTA 
               
               
                 repeat-containing protein alpha 
               
               
                 Interleukin-25 
                 Q9H293 
                 64806 
                 IL25 
               
               
                 MHC class I polypeptide-related 
                 Q29980 
                 4277 
                 MICB 
               
               
                 sequence B 
               
               
                 C-C motif chemokine 7 
                 P80098 
                 6354 
                 CCL7 
               
               
                 Lactadherin 
                 Q08431 
                 4240 
                 MFGE8 
               
               
                 Macrophage metalloelastase 
                 P39900 
                 4321 
                 MMP12 
               
               
                 Ubiquitin-like protein ISG15 
                 P05161 
                 9636 
                 ISG15 
               
               
                 Fatty acid-binding protein, liver 
                 P07148 
                 2168 
                 FABP1 
               
               
                 Properdin 
                 P27918 
                 5199 
                 CFP 
               
               
                 Stromelysin-2 
                 P09238 
                 4319 
                 MMP10 
               
               
                 Protein FAM107B 
                 Q9H098 
                 83641 
                 FAM107B 
               
               
                 Myosin-binding protein C, slow-type 
                 Q00872 
                 4604 
                 MYBPC1 
               
               
                 Serine/threonine-protein kinase Chk2 
                 O96017 
                 11200 
                 CHEK2 
               
               
                 Xaa-Pro aminopeptidase 1 
                 Q9NQW7 
                 7511 
                 XPNPEP1 
               
               
                 NT-3 growth factor receptor 
                 Q16288 
                 4916 
                 NTRK3 
               
               
                 Interleukin-5 receptor subunit alpha 
                 Q01344 
                 3568 
                 IL5RA 
               
               
                 Ephrin type-A receptor 2 
                 P29317 
                 1969 
                 EPHA2 
               
               
                 Peptidyl-prolyl cis-trans isomerase F, 
                 P30405 
                 10105 
                 PPIF 
               
               
                 mitochondrial 
               
               
                 B-cell lymphoma 6 protein 
                 P41182 
                 604 
                 BCL6 
               
               
                 Cell adhesion molecule 1 
                 Q9BY67 
                 23705 
                 CADM1 
               
               
                 Kinesin-like protein KIF23 
                 Q02241 
                 9493 
                 KIF23 
               
               
                 Netrin receptor UNC5D 
                 Q6UXZ4 
                 137970 
                 UNC5D 
               
               
                 Lymphocyte activation gene 3 protein 
                 P18627 
                 3902 
                 LAG3 
               
               
                 Serine protease HTRA2, mitochondrial 
                 O43464 
                 27429 
                 HTRA2 
               
               
                 lnterleukin-22 receptor subunit alpha-2 
                 Q969J5 
                 116379 
                 IL22RA2 
               
               
                 Caspase-3 
                 P42574 
                 836 
                 CASP3 
               
               
                 Platelet-derived growth factor receptor 
                 P16234 
                 5156 
                 PDGFRA 
               
               
                 alpha 
               
               
                 Interleukin-20 
                 Q9NYY1 
                 50604 
                 IL20 
               
               
                 Ferritin 
                 P02794 
                 2495 
                 FTH1 
               
               
                   
                 P02792 
                 2512 
                 FTL 
               
               
                 Ephrin-A5 
                 P52803 
                 1946 
                 EFNA5 
               
               
                 Amphoterin-induced protein 2 
                 Q86SJ2 
                 347902 
                 AMIGO2 
               
               
                 Interleukin-2 
                 P60568 
                 3558 
                 IL2 
               
               
                 Phospholipase A2 
                 P04054 
                 5319 
                 PLA2G1B 
               
               
                 Protein kinase C alpha type 
                 P17252 
                 5578 
                 PRKCA 
               
               
                 Tumor necrosis factor ligand 
                 P32971 
                 944 
                 TNFSF8 
               
               
                 superfamily member 8 
               
               
                 Endoglin 
                 P17813 
                 2022 
                 ENG 
               
               
                 Gamma-enolase 
                 P09104 
                 2026 
                 ENO2 
               
               
                 C-X-C motif chemokine 9 
                 Q07325 
                 4283 
                 CXCL9 
               
               
                 beta-nerve growth factor 
                 P01138 
                 4803 
                 NGF 
               
               
                 Hepcidin 
                 P81172 
                 57817 
                 HAMP 
               
               
                 Inorganic pyrophosphatase 
                 Q15181 
                 5464 
                 PPA1 
               
               
                 Kallikrein-8 
                 O60269 
                 11202 
                 KLK8 
               
               
                 Semaphorin-6B 
                 Q9H3T3 
                 10501 
                 SEMA6B 
               
               
                 Adapter molecule crk 
                 P46108 
                 1398 
                 CRK 
               
               
                 Phosphoglycerate mutase 1 
                 P18669 
                 5223 
                 PGAM1 
               
               
                 Proprotein convertase subtilisin/kexin 
                 Q16549 
                 9159 
                 PCSK7 
               
               
                 type 7 
               
               
                 Pancreatic hormone 
                 P01298 
                 5539 
                 PPY 
               
               
                 Interleukin-1 receptor type 1 
                 P14778 
                 3554 
                 IL1R1 
               
               
                 C-X-C motif chemokine 11 
                 O14625 
                 6373 
                 CXCL11 
               
               
                 Secreted frizzled-related protein 1 
                 Q8N474 
                 6422 
                 SFRP1 
               
               
                 Inhibin beta A chain 
                 P08476 
                 3624 
                 INHBA 
               
               
                 Immunoglobulin D 
                 P01880 
                 3495 
                 IGHD 
               
               
                   
                   
                 50802 
                 IGK@ 
               
               
                   
                   
                 3535 
                 IGL@ 
               
               
                 Complement C3b 
                 P01024 
                 718 
                 C3 
               
               
                 Teratocarcinoma-derived growth factor 1 
                 P13385 
                 6997 
                 TDGF1 
               
               
                 Brother of CDO 
                 Q9BWV1 
                 91653 
                 BOC 
               
               
                 CD109 antigen 
                 Q6YHK3 
                 135228 
                 CD109 
               
               
                 Aminoacylase-1 
                 Q03154 
                 95 
                 ACY1 
               
               
                 60 kDa heat shock protein, 
                 P10809 
                 3329 
                 HSPD1 
               
               
                 mitochondrial 
               
               
                 Importin subunit beta-1 
                 Q14974 
                 3837 
                 KPNB1 
               
               
                 C-reactive protein 
                 P02741 
                 1401 
                 CRP 
               
               
                 Ephrin type-A receptor 1 
                 P21709 
                 2041 
                 EPHA1 
               
               
                 Semaphorin-6A 
                 Q9H2E6 
                 57556 
                 SEMA6A 
               
               
                 SLIT and NTRK-like protein 5 
                 O94991 
                 26050 
                 SLITRK5 
               
               
                 Leucine-rich repeat transmembrane 
                 Q9NZU0 
                 23767 
                 FLRT3 
               
               
                 protein FLRT3 
               
               
                 dCTP pyrophosphatase 1 
                 Q9H773 
                 79077 
                 DCTPP1 
               
               
                 Osteopontin 
                 P10451 
                 6696 
                 SPP1 
               
               
                 Formimidoyltransferase-cyclodeaminase 
                 O95954 
                 10841 
                 FTCD 
               
               
                 Ephrin-B2 
                 P52799 
                 1948 
                 EFNB2 
               
               
                 T-lymphocyte surface antigen Ly-9 
                 Q9HBG7 
                 4063 
                 LY9 
               
               
                 Sialic acid-binding Ig-like lectin 14 
                 Q08ET2 
                 100049587 
                 SIGLEC14 
               
               
                 N-acylethanolamine-hydrolyzing acid 
                 Q02083 
                 27163 
                 NAAA 
               
               
                 amidase 
               
               
                 Endoplasmic reticulum aminopeptidase 1 
                 Q9NZ08 
                 51752 
                 ERAP1 
               
               
                 Low affinity immunoglobulin gamma Fc 
                 P12318 
                 2212 
                 FCGR2A 
               
               
                 region receptor II-a 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
             
               
                 TABLE 5A 
               
               
                   
               
               
                 UniProt ID 
                 Protein name 
                 Gene name 
               
               
                   
               
             
            
               
                 Q15389 
                 Angiopoietin-1 (ANG-1) 
                 ANGPT1 
               
               
                 P23560 
                 Brain-Derived Neurotrophic Factor (BDNF) 
                 BDNF 
               
               
                 O94907 
                 Dickkopf-related protein 1 (DKK-1) 
                 DKK1 
               
               
                 P80511 
                 S100-A12 
                 S100A12 
               
               
                 P42830 
                 Epithelial-Derived Neutrophil-Activating 
                 CXCL5 
               
               
                   
                 Protein 78 (ENA-78) 
               
               
                 P02794 
                 Ferritin (FRTN) 
                 FTH1 
               
               
                 P09341 
                 Growth-Regulated alpha protein (GRO-alpha) 
                 CXCL1 
               
               
                 P01137 
                 Latency-Associated Peptide of Transforming 
                 TGFB1 
               
               
                   
                 Growth Factor beta 1 (LAP TGF-b1) 
               
               
                 Q8WXL0 
                 Luteinizing Hormone (LH) 
                 LHB 
               
               
                 G3CBL7 
                 MHC class I chain-related protein A (MICA) 
                 MICA 
               
               
                 P02775 
                 Platelet basic protein 
                 PPBP 
               
               
                 P01127 
                 Platelet-Derived Growth Factor BB (PDGF-BB) 
                 PDGFB 
               
               
                 P01236 
                 Prolactin (PRL) 
                 PRL 
               
               
                 PODJI8; 
                 Serum amyloid A-1 protein; Amyloid protein A; 
                 SAA1; SAA2 
               
               
                 PODJI9-2 
                 Serum amyloid protein A(2-104); Serum amyloid 
               
               
                   
                 protein A(3-104); Serum amyloid protein 
               
               
                   
                 A(2-103); Serum amyloid protein A(2-102); 
               
               
                   
                 Serum amyloid protein A(4-101); Serum 
               
               
                   
                 amyloid A-2 protein 
               
               
                 P13501 
                 T-Cell-Specific Protein RANTES (RANTES) 
                 CCL5 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
             
               
                 TABLE 5B 
               
               
                   
               
               
                 UniProt ID 
                 Protein name 
                 Gene name 
               
               
                   
               
             
            
               
                 P10645 
                 Chromogranin-A (CgA) 
                 CHGA 
               
               
                 Q9GZV9 
                 Fibroblast growth factor 23 (FGF-23) 
                 FGF23 
               
               
                 P01266 
                 Thyroglobul in (TG) 
                 TG 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
             
               
                 TABLE 6A 
               
               
                   
               
               
                 UniProt ID 
                 Protein name 
                 Gene name 
               
               
                   
               
             
            
               
                 P07996 
                 Thrombospondin-1 0S =  Homo sapiens  0X = 9606 
                 THBS1 
               
               
                   
                 GN = THBS1 PE = 1 SV = 2 
               
               
                 P69905 
                 Hemoglobin subunit alpha 0S =  Homo sapiens  0X = 9606 
                 HBA1 
               
               
                   
                 GN = HBA1 PE = 1 SV = 2 
               
               
                 P32119 
                 Peroxiredoxin-2 0S =  Homo sapiens  0X = 9606 GN = PRDX2 
                 PRDX2 
               
               
                   
                 PE = 1 SV = 5 
               
               
                 P00918 
                 Carbonic anhydrase 2 0S =  Homo sapiens  0X = 9606 
                 CA2 
               
               
                   
                 GN = CA2 PE = 1 SV = 2 
               
               
                 P30043 
                 Flavin reductase (NADPH) 0S =  Homo sapiens  0X = 9606 
                 BLVRB 
               
               
                   
                 GN = BLVRB PE = 1 SV = 3 
               
               
                 O76011 
                 Keratin, type I cuticular Ha4 0S =  Homo sapiens   
                 KRT34 
               
               
                   
                 0X = 9606 GN = KRT34 PE = 1 SV = 2 
               
               
                 P13716 
                 Delta-aminolevulinic acid dehydratase 0S = 
                 ALAD 
               
               
                   
                   Homo sapiens  0X = 9606 GN = ALAD PE = 1 SV = 1 
               
               
                 P00568 
                 Adenylate kinase isoenzyme 1 0S =  Homo sapiens   
                 AK1 
               
               
                   
                 0X = 9606 GN = AK1 PE = 1 SV = 3 
               
               
                 P07738 
                 Bisphosphoglycerate mutase 0S =  Homo sapiens   
                 BPGM 
               
               
                   
                 0X = 9606 GN = BPGM PE = 1 SV = 2 
               
               
                 P02775 
                 Platelet basic protein 0S =  Homo sapiens  0X = 
                 PPBP 
               
               
                   
                 9606 GN = PPBP PE = 1 SV = 3 
               
               
                 P22392 
                 Nucleoside diphosphate kinase B 0S =  Homo sapiens   
                 NME2 
               
               
                   
                 0X = 9606 GN = NME2 PE = 1 SV = 1 
               
               
                 P10124 
                 Serglycin 0S =  Homo sapiens  0X = 9606 GN = SRGN 
                 SRGN 
               
               
                   
                 PE = 1 SV = 3 
               
               
                 A0A0C4DH67 
                 Immunoglobulin kappa variable 1-8 0S = 
                 IGKV1-8 
               
               
                   
                   Homo sapiens  0X = 9606 GN = IGKV1-8 PE = 3 SV = 1 
               
               
                 P63241 
                 Eukaryotic translation initiation factor 5A-1 
                 EIF5A 
               
               
                   
                 0S =  Homo sapiens  0X = 9606 GN = EIF5A PE = 1 SV = 2 
               
               
                 P02776 
                 Platelet factor 4 0S =  Homo sapiens  0X = 9606 
                 PF4 
               
               
                   
                 GN = PF4 PE = 1 SV = 2 
               
               
                 A0A075B6S2 
                 Immunoglobulin kappa variable 2D-29 0S = 
                 IGKV2D-29 
               
               
                   
                   Homo sapiens  0X = 9606 GN = IGKV2D-29 PE = 3 SV = 1 
               
               
                 Q9UKU6 
                 Thyrotropin-releasing hormone-degrading ectoenzyme 
                 TRHDE 
               
               
                   
                 0S =  Homo sapiens  0X = 9606 GN = TRHDE PE = 2 SV = 1 
               
               
                 Q8WUM4 
                 Programmed cell death 6-interacting protein 0S = 
                 PDCD6IP 
               
               
                   
                   Homo sapiens  0X = 9606 GN = PDCD6IP PE = 1 SV = 1 
               
               
                 P00441 
                 Superoxide dismutase [Cu-Zn] 0S =  Homo sapiens   
                 SOD1 
               
               
                   
                 0X = 9606 GN = SOD1 PE = 1 SV = 2 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
             
               
                 TABLE 6B 
               
               
                   
               
               
                 UniProt ID 
                 Protein name 
                 Gene name 
               
               
                   
               
             
            
               
                 P36980 
                 Complement factor H-related protein 2 0S = 
                 CFHR2 
               
               
                   
                   Homo sapiens  0X = 9606 GN = CFHR2 PE = 1 SV = 1 
               
               
                 PODOX3 
                 Immunoglobulin delta heavy chain 0S =  Homo sapiens   
                 N/A 
               
               
                   
                 0X = 9606 PE = 1 SV = 1 
               
               
                 P01880 
                 Immunoglobulin heavy constant delta 0S = 
                 IGHD 
               
               
                   
                   Homo sapiens  0X = 9606 GN = IGHD PE = 1 SV = 3 
               
               
                 Q8N6C8 
                 Leukocyte immunoglobulin-like receptor subfamily A 
                 LILRA3 
               
               
                   
                 member 3 0S =  Homo sapiens  0X = 9606 GN = LILRA3 
               
               
                   
                 PE = 1 SV = 3 
               
               
                 P47929 
                 Galectin-7 0S =  Homo sapiens  0X = 9606 GN = LGALS7 
                 LGALS7 
               
               
                   
                 PE = 1 SV = 2 
               
               
                 O75339 
                 Cartilage intermediate layer protein 1 0S =  Homo sapiens   
                 CILP 
               
               
                   
                 0X = 9606 GN = CILP PE = 1 SV = 4 
               
               
                 O15389 
                 Sialic acid-binding Ig-like lectin 5 0S =  Homo sapiens   
                 SIGLEC5 
               
               
                   
                 0X = 9606 GN = SIGLEC5 PE = 1 SV = 1 
               
               
                 P35247 
                 Pulmonary surfactant-associated protein D 0S = 
                 SFTPD 
               
               
                   
                   Homo sapiens  0X = 9606 GN = SFTPD PE = 1 SV = 3 
               
               
                   
               
            
           
         
       
     
     The sequences of the markers (mRNA and protein) listed in these tables can be easily retrieved from the database known to those skilled in the art (Uniprot: https://www.uniprot.org/) on the basis of the Uniprot IDs shown in the above tables. Specifically, a Uniprot ID can be used to search for the corresponding Uniprot entry to retrieve sequences provided in the “sequences” section. It is also possible to obtain IDs/accession numbers for other databases (for example, RefSeq, EMBL, GenBank, DDBJ, CCDS, PIR, UniGene, Ensemble, GeneID, KEGG, and USCS) from the description of the “sequences” section, and retrieve more sequences from those databases. In the present disclosure, the sequence of each marker refers to a sequence and an ID/accession number provided in the latest version of the corresponding Uniprot entry with a release number earlier than 2018-09 (for example, 2018-08; if 2018-08 does not exist, then 2018_07; if neither 2018_08 nor 2018_07 exists, then 2018_06; the same applies to numbers earlier than 2018_06). 
     Furthermore, in the FTP where the archives of Uniprot release data are stored (ftp://ftp.uniprot.org/pub/databases/uniprot/previous_releases/), the amino acid sequences of the markers in the above tables can also be retrieved from the data included in directory “release-2018_08/knowledgebase” (the “knowledgebase” directory included in “release-2018_08”) by using the Uniprot IDs shown in the tables. 
     The groups of markers listed in the above tables include markers indicating fibrosis (TGFB1, SPARC, etc.). Furthermore, the groups of markers listed in the above tables include many molecules considered to be derived from platelets. For example, uniprot says that PPBP, THBS1, PF4, SERPINA1, TIMP3, APP, CALU, CASP3, MMRN1, SAA1, SRGN, VWF, and others are involved in platelet degranulation and such. Zhang et al. demonstrated in an in vitro experimental system using endometrial-derived cells that TGFb1 released from activated platelets induced epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT), increased collagen production, and induced fibrosis (Molecular and Cellular Endocrinology, 428, 1-16, 2016). This is consistent with the fact that TGFb1 and platelet-derived proteins were selected as markers in the present disclosure, suggesting that changes in these proteins may reflect changes in platelet activation and such. 
     Type V collagen MMP degradation products are also called MMP mediated type V collagen degradation and are products resulting from degradation of the alpha 3 chain (Refseq: NP_056534.2, SEQ ID NO: 1) of type V collagen by MMP. Specifically, the type V collagen MMP degradation products are type V collagen degradation products produced by cleaving type V collagen shown in SEQ ID NO: 1 between amino acids 1316 (G) and 1317 (H) (Clin Biochem. 2012 May;45(7-8):541-6). Specifically, any polypeptides are included in the type V collagen MMP degradation products as long as they are derived from type V collagen and comprise the amino acid sequence set forth in SEQ ID NO: 4 at the N-terminus and/or comprise the amino acid sequence set forth in SEQ ID NO: 6 at the C-terminus. Examples of the type V collagen MMP degradation products include protein fragments shown in SEQ ID NO: 2 or 3. Among the type V collagen MMP degradation products, the peptide fragment of SEQ ID NO: 4 (HMGREGREGE) is sometimes referred to as C5M. 
     The presence of a type V collagen MMP degradation product is detected by any method that can detect a type V collagen fragment after cleavage between amino acids 1316 (G) and 1317 (H) set forth in SEQ ID NO: 1. In a certain embodiment, an antibody that specifically recognizes peptide HMGREGREGE (SEQ ID NO: 4) located at the N-terminus of the type V collagen fragment shown in SEQ ID NO: 2 can be used to detect the abundance of a type V collagen MMP degradation product. In a more specific embodiment, an antibody that can recognize peptide HMGREGREGE (SEQ ID NO: 4) located at the N-terminus of the type V collagen fragment shown in SEQ ID NO: 2 and that does not recognize GHMGREGREGE (SEQ ID NO: 5) can be used to detect the abundance of a type V collagen MMP degradation product (an ELISA detection method that uses such an antibody was established in Clin Biochem. 2012 May;45(7-8):541-6.). In another embodiment, an antibody that specifically recognizes peptide GPPGKRGPSG (SEQ ID NO: 6) located at the C-terminus of the type V collagen fragment set forth in SEQ ID NO: 3 can be used to detect the abundance of a type V collagen MMP degradation product. In a more specific embodiment, an antibody that can recognize peptide GPPGKRGPSG (SEQ ID NO: 6) located at the C-terminus of the type V collagen fragment shown in SEQ ID NO: 3 and that does not recognize GPPGKRGPSGH (SEQ ID NO: 7) can be used to detect the abundance of a type V collagen MMP degradation product. 
     In the present disclosure, a protein selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B may be used alone as a marker, or a combination of selected proteins may be used as markers. When more than one protein is used as markers, each of the markers may be measured individually and then the results may be combined, or the markers may be measured together. 
     The abundance of the markers of the present disclosure can be measured using the measuring methods described in the present disclosure or using commercially available measuring reagents. Specific measured values and predetermined values of each marker described herein can be construed as values measured using the above-mentioned measuring reagents. 
     The predetermined values (control levels) determined for the markers of the present disclosure can vary depending on the type of a sample of a subject for which the abundance of each marker is measured, but can be determined, for example, from the range of 0.1 to 100 ng/mL. Alternatively, it can be determined from the range of 0.2 to 90 ng/mL, 0.3 to 80 ng/mL, 0.4 to 70 ng/mL, 0.5 to 60 ng/mL, 1.0 to 50 ng/mL, 1.5 to 40 ng/mL, 2.0 to 30 ng/mL, 2.5 to 20 ng/mL, 3.0 to 10 ng/mL, and so on, but is not limited thereto. 
     The predetermined value determined for each marker of the present disclosure can be determined from values such as 0.1 ng/mL, 0.2 ng/mL, 0.3 ng/mL, 0.4 ng/mL, 0.5 ng/mL, 0.6 ng/mL, 0.7 ng/mL, 0.8 ng/mL, 0.9 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 5.5 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10 ng/mL, 15 ng/mL, 20 ng/mL, 25 ng/mL, 30 ng/mL, 35 ng/mL, 40 ng/mL, 45 ng/mL, 50 ng/mL, 60 ng/mL, 70 ng/mL, 80 ng/mL, 90 ng/mL, and 100 ng/mL, but is not limited thereto. 
     In the present disclosure, when the abundance of each marker of the present disclosure is greater than the predetermined value (control level), it can be decided that “the abundance is high” or “the abundance is large.” For example, in the present disclosure, it can be decided that “the abundance is high” or “the abundance is large” when, without limitation, the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, and the markers shown in Table 5A is, for example, 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more, 1.6 times or more, 1.7 times or more, 1.8 times or more, 1.9 times or more, 2.0 times or more, 2.1 times or more, 2.2 times or more, 2.3 times or more, 2.4 times or more, 2.5 times or more, 2.6 times or more, 2.7 times or more, 2.8 times or more, 2.9 times or more, or 3.0 times or more the abundance of the same marker in a sample obtained from a healthy individual, or more. Alternatively, in the present disclosure, it can be decided that “the abundance is high” or “the abundance is large” when, without limitation, the abundance of at least one marker selected from the markers shown in Table 6A is, for example, 1.10 times or more, 1.15 times or more, 1.20 times or more, 1.25 times or more, 1.30 times or more, 1.35 times or more, 1.40 times or more, 1.45 times or more, 1.50 times or more, 1.55 times or more, 1.60 times or more, 1.65 times or more, 1.70 times or more, 1.75 times or more, 1.80 times or more, 1.85 times or more, 1.90 times or more, 1.95 times or more, or 2.00 times or more the abundance of the same marker in a sample obtained from a healthy individual, or more. 
     In the present disclosure, when the abundance of each marker of the present disclosure is less than the predetermined value (control level), it can be decided that “the abundance is low” or “the abundance is small.” For example, in the present disclosure, it can be decided that “the abundance is low” or “the abundance is small” when, without limitation, the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1B, the markers shown in Table 2B, and the markers shown in Table 5B is, for example, 0.9 times or less, 0.8 times or less, 0.7 times or less, 0.6 times or less, 0.5 times or less, 0.4 times or less, 0.3 times or less, 0.2 times or less, or 0.1 times or less the abundance of the same marker in a sample obtained from a healthy individual, or less. Alternatively, in the present disclosure, it can be decided that “the abundance is low” or “the abundance is small” when, without limitation, the abundance of at least one marker selected from the markers shown in Table 6B is, for example, 0.9 times or less, 0.8 times or less, 0.7 times or less, 0.6 times or less, 0.5 times or less, 0.4 times or less, 0.3 times or less, 0.2 times or less, or 0.1 times or less the abundance of the same marker in a sample obtained from a healthy individual, or less. 
     Diagnosis of Endometriosis and Determination of Whether or Not a Subject is Affected by Endometriosis 
     One aspect of the present disclosure relates to methods of diagnosing endometriosis or methods of determining whether or not a subject is affected by endometriosis. One aspect of the present disclosure also relates to methods of detecting endometriosis or markers thereof. One aspect of the present disclosure also relates to methods of assisting the diagnosis or determination. One aspect of the present disclosure also relates to methods of providing instructions for the diagnosis or determination. One aspect of the present disclosure relates to reagents and kits for use in these methods. 
     The above respective methods comprise measuring the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject. The methods can also comprise comparing the abundance with a predetermined value (control level). 
     The above reagents are reagents for measuring the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B. The above kits contain such reagents. 
     The above respective methods may comprise a step in which if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A in the sample obtained from the subject is higher than a predetermined value (control level) or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B in the sample obtained from the subject is lower than a predetermined value (control level), the subject that the sample is derived from is shown to be affected or potentially affected by endometriosis. 
     The above respective methods can be performed both in vivo and in vitro, but are preferably performed in vitro. 
     Furthermore, the above respective methods may also comprise obtaining a sample from the subject. 
     Moreover, the above respective methods may also comprise treating a subject that has been shown to be affected or potentially affected by endometriosis. The above respective methods may also comprise administering a known therapeutic agent for endometriosis to a subject that has been shown to be affected or potentially affected by endometriosis. Thus, the present invention relates to methods of treating endometriosis in a subject that has been shown to be affected or potentially affected by endometriosis by each of the above methods. Various therapeutic agents for endometriosis are known to those skilled in the art, and examples thereof include, but are not limited to, estrogen/progesterone mixtures, progesterone preparations, GnRH agonists, GnRH antagonists, and danazol. 
     The above-mentioned kits may further comprise instructions stating that if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A in the sample obtained from the subject is higher than a predetermined value (control level) or if the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is lower than a predetermined value (control level), the subject that the sample is derived from is shown to be affected or potentially affected by endometriosis. 
     Determination of the Extent of Endometrial Fibrosis in a Subject 
     One aspect of the present disclosure relates to methods of determining the extent of endometrial fibrosis in a subject, methods of assisting the determination, methods of providing instructions for the determination, and reagents and kits for use in these. 
     The above respective methods comprise measuring the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject. The methods can also comprise comparing the abundance with a predetermined value (control level). 
     The above reagents are reagents for measuring the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B. The above-mentioned kits contain such reagents. 
     The above respective methods may comprise a step in which if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A in the sample obtained from the subject is higher than a predetermined value (control level) or if the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B in the sample obtained from the subject is lower than a predetermined value (control level), it is shown that endometrial fibrosis is occurring or potentially occurring in the subject that the sample is derived from. 
     The above respective methods can be performed both in vivo and in vitro, but is preferably performed in vitro. 
     Furthermore, the above respective methods may comprise obtaining a sample from the subject. 
     Moreover, the above respective methods may also comprise treating a subject in whom or which it has been shown that endometrial fibrosis has occurred or potentially occurred. The above respective methods may also comprise administering a known therapeutic agent for suppressing endometrial fibrosis to a subject in whom or which it has been shown that endometrial fibrosis has occurred or potentially occurred. Thus, the present invention relates to methods of suppressing fibrosis in a subject in whom or which it has been shown by the above respective methods that endometrial fibrosis has occurred or potentially occurred. Examples of therapeutic agents for suppressing endometrial fibrosis include the above-mentioned therapeutic agents for endometriosis. 
     The above kits may further comprise instructions stating that if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is higher than a predetermined value (control level) or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is lower than a predetermined value (control level) in a sample obtained from the subject, it is shown that endometrial fibrosis has occurred or potentially occurred in the subject that the sample is derived from. 
     Determination of the Extent of Endometrial Adhesion in a Subject 
     One aspect of the present disclosure relates to methods of determining the extent of endometrial adhesion in a subject, methods of assisting the determination, methods of providing instructions for the determination, and reagents and kits for use in these methods. 
     The above respective methods comprise measuring the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject. The methods can also comprise comparing the abundance with a predetermined value (control level). 
     The above reagents are reagents for measuring the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B. The above kits contain such reagents. 
     The above respective methods may comprise a step in which if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A in a sample obtained from the subject is higher than a predetermined value (control level) or if the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject is lower than a predetermined value (control level), it is shown that endometrial adhesion has occurred or potentially occurred in the subject that the sample is derived from. 
     The above respective methods can be performed both in vivo and in vitro, but are preferably performed in vitro. 
     Furthermore, The above respective methods may comprise obtaining a sample from the subject. 
     Moreover, the above respective methods may also comprise treating a subject in whom or which it has been shown that endometrial adhesion has occurred or potentially occurred. Each of the above methods may also comprise administering a known therapeutic agent for suppressing endometrial adhesion to a subject in whom or which it has been shown that endometrial adhesion has occurred or potentially occurred. Thus, the present invention relates to methods of suppressing endometrial adhesion in a subject in whom or which it has been shown by the above respective methods that endometrial adhesion has occurred or potentially occurred. Examples of therapeutic agents for suppressing endometrial adhesion include the above-mentioned therapeutic agents for endometriosis. 
     The above kits may further comprise instructions stating that if the abundance of at least one marker selected from the group consisting of the concentration of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is higher than a predetermined value (control level) or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is lower than a predetermined value (control level) in a sample obtained from the subject, it is shown that endometrial adhesion has occurred or potentially occurred in the subject that the sample is derived from. 
     Prediction of the Degree of Pain Due to Endometriosis in a Subject Affected or Suspected of Being Affected by Endometriosis 
     One aspect of the present disclosure relates to methods of predicting the degree of pain due to endometriosis in a subject affected or suspected of being affected by endometriosis, methods of assisting the prediction, methods of providing instructions for the prediction, and reagents and kits for use in these methods. 
     The above respective methods comprise measuring the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject. The methods can also comprise comparing the abundance with a predetermined value (control level). 
     The above reagents are reagents for measuring the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B. The above kits contain such reagents. 
     The above respective methods may comprise a step in which if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A in a sample obtained from the subject is higher than a predetermined value (control level) or if the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject is lower than a predetermined value (control level), the subject that the sample is derived from is shown to develop or potentially develop pain due to endometriosis. 
     The above respective methods can be performed both in vivo and in vitro, but is preferably performed in vitro. 
     Furthermore, the above respective methods may comprise obtaining a sample from the subject. 
     Moreover, the above respective methods may also comprise alleviating pain due to endometriosis in a subject that has been shown to develop or potentially develop pain due to endometriosis. The above respective methods may also comprise administering a known therapeutic agent for suppressing pain due to endometriosis to a subject that has been shown to develop or potentially develop pain due to endometriosis. Thus, the present invention relates to methods of suppressing pain due to endometriosis in a subject that has been shown to develop or potentially develop pain due to endometriosis by the above respective methods. Examples of therapeutic agents for suppressing pain due to endometriosis include the above-mentioned therapeutic agents for endometriosis. 
     The above kits may further comprise instructions stating that if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is higher than a predetermined value (control level) or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is lower than a predetermined value (control level) in a sample obtained from the subject, the subject that the sample is derived from is shown to develop or potentially develop pain due to endometriosis. 
     Determination of the Degree of Progression of Endometriosis 
     One aspect of the present disclosure relates to methods of determining the degree of progression of endometriosis in a subject affected or suspected of being affected by endometriosis, methods of assisting the determination, methods of providing instructions for the determination, and reagents and kits for use in these methods. 
     The above respective methods comprise measuring the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject. The methods can also comprise comparing the abundance with a predetermined value (control level). 
     The above reagents are reagents for measuring the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B. The above kits contain such reagents. 
     The above respective methods may comprise a step in which if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A in a sample obtained from the subject is higher than a predetermined value (control level) or if the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject is lower than a predetermined value (control level), it is shown that endometriosis is progressing or potentially progressing in the subject that the sample is derived from. 
     The above respective methods can be performed both in vivo and in vitro, but are preferably performed in vitro. 
     Furthermore, the above respective methods may comprise obtaining a sample from the subject. 
     Moreover, the above respective methods may also comprise treating a subject in whom or which it has been shown that endometriosis is progressing or potentially progressing. The above respective methods may also comprise administering a known therapeutic agent for suppressing progression of endometriosis to a subject in whom or which it has been shown that endometriosis is progressing or potentially progressing. Thus, the present invention relates to methods of suppressing progression of endometriosis in a subject in whom or which it has been shown by the above respective methods that endometriosis is progressing or potentially progressing. Examples of therapeutic agents for suppressing progression of endometriosis include the above-mentioned therapeutic agents for endometriosis. 
     The above kits may further comprise instructions stating that if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A is higher than a predetermined value (control level) or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B is lower than a predetermined value (control level) in a sample obtained from the subject, it is shown that endometriosis is progressing or potentially progressing in the subject that the sample is derived from. 
     Monitoring of Pathological Conditions of Endometriosis 
     One aspect of the present disclosure relates to methods of monitoring pathological conditions of endometriosis in a subject affected or suspected of being affected by endometriosis, methods of assisting the monitoring, methods of providing instructions for the monitoring, and reagents and kits for use in these methods. The monitoring in the present disclosure includes evaluating a therapeutic effect and/or providing information on a future therapeutic regimen or therapeutic policy. 
     The above respective methods comprise measuring the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from the subject. 
     The above reagents are reagents for measuring the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B. The above kits contain such reagents. 
     The above respective methods may comprise measuring each of the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in each of a plurality of samples collected from a subject at different points of time. The methods may also comprise comparing the abundance of the marker in each sample in a plurality of samples collected at different points of time. In the present disclosure, the timing and number of times of collecting samples are not limited, and samples can be collected at various points of time before treatment, during treatment, and after treatment as necessary. Samples can also be collected at various timings within each period of before treatment, during treatment, and after treatment. In the present disclosure, “plurality” is not particularly limited, and examples thereof include 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times. The above kits may comprise instructions stating that the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in each of a plurality of samples obtained from a subject collected at different points of time is compared. 
     The above respective methods may comprise a step in which if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A decreased over time or if the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B increased over time, it is shown that the pathological conditions of endometriosis are improving or potentially improving in the subject that the sample is derived from. 
     The above respective methods may comprise a step in which if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A increased over time or if the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B decreased over time, it is shown that the pathological conditions of endometriosis are worsening or potentially worsening in the subject the sample is derived from. 
     The above respective methods can be performed both in vivo and in vitro, but are preferably performed in vitro. 
     Furthermore, the above respective methods may comprise obtaining a sample from the subject. 
     Moreover, the above respective methods may comprise treating a subject in whom or which it has been shown that the pathological conditions of endometriosis are worsening or potentially worsening. The above respective methods may also comprise administering a known therapeutic agent for endometriosis to a subject in whom or which it has been shown that the pathological conditions of endometriosis are worsening or potentially worsening. Thus, the present invention relates to methods of treating endometriosis in a subject in whom or which it has been indicated by each of the above methods that the pathological conditions of endometriosis are worsening or potentially worsening. The above-mentioned agents can be used as therapeutic agents for endometriosis. 
     The above kits may comprise instructions stating that if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A decreased over time or if the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B increased over time, it is shown that the pathological conditions of endometriosis are improving or potentially improving in the subject that the sample is derived from. 
     The above kits may comprise instructions stating that if the abundance of at least one marker selected from the group consisting of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 5A, and the markers shown in Table 6A increased over time or if the abundance of at least one marker selected from the group consisting of the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5B, and the markers shown in Table 6B decreased over time, it is shown that the pathological conditions of endometriosis are worsening or potentially worsening in the subject that the sample is derived from. 
     Reagents/Kits 
     Reagents contained in the kits of the present disclosure are not particularly limited as long as the abundance of markers can be measured. Reagents can be appropriately selected depending on the form of markers. When the form of a marker is a polypeptide, reagents comprising an antibody that specifically binds to the polypeptide are preferable. When the form of a marker is a polynucleotide, reagents comprising an oligonucleotide that specifically binds to the polynucleotide are preferable. In the present disclosure, the antibody or the polynucleotide itself may be a reagent. Polynucleotides in the present disclosure include those in the form of DNA and in the form of mRNA. 
     Antibodies in the present disclosure may be chimeric antibodies, humanized antibodies, or human antibodies. In some embodiments, antibodies may be multispecific antibodies, e.g., bispecific antibodies. Alternatively, antibodies in the present disclosure may be antibody fragments or modified products thereof. For example, antibody fragments include Fab, F (ab′)2, Fv, or single chain Fv (scFv) in which an H chain Fv and an L chain Fv are linked with an appropriate linker. These antibodies can be obtained by methods well known to those skilled in the art. 
     Antibodies can be labeled by commonly known methods. Labeling substances known to those skilled in the art, such as fluorescent dyes, enzymes, coenzymes, chemiluminescent substances, and radioactive substances, can be used. 
     Oligonucleotides in the present disclosure can be any oligonucleotide that specifically hybridizes to at least a portion of a polynucleotide that is a marker in the present disclosure or a complementary strand thereof. The nucleotide sequence of such an oligonucleotide for detecting a polynucleotide is selected from the nucleotide sequence complementary to the sense strand of a marker in the present disclosure. Oligonucleotides typically have a length of at least 15 bp or more. 
     Oligonucleotides in the present disclosure can also be used after being labeled by commonly known methods. Oligonucleotides in the present disclosure can be produced, for example, by commercially available oligonucleotide synthesizers. 
     Kits of the present disclosure preferably contain a positive control sample as a reference for measuring the abundance of markers. The positive control sample is not particularly limited as long as the amount of the markers contained therein has been determined in advance, and can be appropriately prepared depending on the form of markers measured by the kits. For example, when the form of a marker is a polypeptide, a positive control sample is preferably a sample comprising a polypeptide prepared by isolating, purifying, and quantifying the same polypeptide as the marker. 
     In addition to the above, kits of the present invention may include, for example, sterile water, saline, vegetable oil, surfactant, lipid, solubilizer, buffer, protein stabilizer (such as BSA and gelatin), preservative, blocking solution, reaction solution, reaction stop solution, and reagents for treating samples as necessary. 
     Sets of type V collagen MMP degradation products, the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B are also included in the present disclosure. Such sets can be used for diagnosing endometriosis, determining the presence or absence of endometriosis, determining the extent of endometrial fibrosis or adhesion in patients affected by endometriosis, predicting pain of patients affected by endometriosis, monitoring pathological conditions of patients affected by endometriosis, and such. 
     All prior art documents cited herein are incorporated herein by reference. 
     EXAMPLES 
     The present disclosure will be further illustrated by the Examples below but is not limited thereto. 
     (Example 1) Search for Biomarkers by LC-MS Analysis Using Plasma of Healthy Human Individuals and Patients with Endometriosis 
     (1-1) Obtainment of Human Plasma Samples 
     Plasma from healthy individuals and endometriosis patients was purchased from Proteogenex. 
     (1-2) LC-MS Analysis of Plasma Proteins 
     With the Seppro IgY14 column (Sigma aldrich), highly abundant proteins in each plasma sample were bound to the column and removed by the method recommended by the manufacturer. The proteins in the flow-through fraction that did not bind to the column were precipitated by the methanol/chloroform method and dissolved in 8 M urea/400 mM ammonium bicarbonate solution. The dissolved proteins were reduced and alkylated, and then digested into peptides with lysyl endopeptidase and trypsin. The peptide solution was demineralized with Monospin C18 (GL Science) by the method recommended by the manufacturer. 
     The peptides were labeled with TMT10plex Mass Tag Labeling Kits and Reagents (ThermoFisher Scientific) (hereinafter, referred to as TMT 10-plex) by the method recommended by the manufacturer. The labeled peptides were fractionated with Pierce™ High pH Reversed-Phase Peptide Fractionation Kit (ThermoFisher Scientific) by the method recommended by the manufacturer. Each fraction was analyzed by the LC-MS analysis system in which Orbitrap fusion Lumos (ThermoFisher scientific) was coupled to the nano-LC system (Ultimate3000, Dionex). The analysis samples included seven samples: the peptides obtained from the plasma of each of three healthy individuals and three endometriosis patients, and a sample (control) prepared by mixing an equal amount of these six peptide solutions. Each sample was analyzed three times, and an independent data set in each analysis was then analyzed (N=3, hereinafter, data set TMT1, 2, and 3). 
     The proteins in the samples were identified from the raw data of the LC-MS analysis by the MaxQuant software (http://www.biochem.mpg.de/5111795/maxquant), and their relative expression levels were analyzed. The database search for protein identification was performed with the following parameters. Taxonomy: uniprot human, Fixed modification: carbamidomethylation (C), Variable modification: oxidation (M); deamidation (NQ), Acetyl (protein N-term), and FDR (protein, peptide)&lt;1%. The relative expression levels were calculated by the following formula: 
     
       
         
           
             
               Relative 
               ⁢ 
               
                   
               
               ⁢ 
               expression 
               ⁢ 
               
                   
               
               ⁢ 
               level 
             
             = 
             
               
                 
                   
                     
                       Target 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       protein 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       signal 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       in 
                       ⁢ 
                       
                         
                             
                         
                         ⁢ 
                         
                             
                         
                       
                       ⁢ 
                       plasma 
                       ⁢ 
                       
                         
                             
                         
                         ⁢ 
                         
                             
                         
                       
                       ⁢ 
                       samples 
                     
                   
                 
                 
                   
                     
                       ( 
                       
                         from 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         patients 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         with 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         endometriosis 
                         ⁢ 
                         
                           
                               
                           
                           ⁢ 
                           
                               
                           
                         
                         ⁢ 
                         or 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         healthy 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         individuals 
                       
                       ) 
                     
                   
                 
               
               
                 Target 
                 ⁢ 
                 
                     
                 
                 ⁢ 
                 protein 
                 ⁢ 
                 
                     
                 
                 ⁢ 
                 signal 
                 ⁢ 
                 
                     
                 
                 ⁢ 
                 in 
                 ⁢ 
                 
                   
                       
                   
                   ⁢ 
                   
                       
                   
                 
                 ⁢ 
                 the 
                 ⁢ 
                 
                     
                 
                 ⁢ 
                 control 
                 ⁢ 
                 
                   
                       
                   
                   ⁢ 
                   
                       
                   
                 
                 ⁢ 
                 sample 
               
             
           
         
       
     
     The target protein signal value used in the above formula was calculated using the column of “Reporter intensity corrected” in Protein groups.txt, which is one of the output files of MaxQunat, where for each label of TMT 10-plex, the sum of the intensity was divided by the sum of the intensity of the control sample and multiplied by 1×10 11  using pipeline pilot (BIOVIA). 
     (1-3) Selection of Biomarker Candidate Molecules 
     The LC-MS result data were analyzed for each data set of TMT1, 2, and 3 by statistical programming environment R and Microsoft Excel. From the relative expression level of each protein in each of the samples (three healthy individuals and three endometriosis patients), 58 proteins for which altered expression was found in endometriosis patients were selected according to the following criteria for each data set (Table 3A and Table 3B). 
     
       
         
           
             
               - 
               
                 
                   
                     
                       
                         The 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         average 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         value 
                         ⁢ 
                         
                           
                               
                           
                           ⁢ 
                           
                               
                           
                         
                         ⁢ 
                         of 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         the 
                         ⁢ 
                         
                           
                               
                           
                           ⁢ 
                           
                               
                           
                         
                         ⁢ 
                         relative 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         expression 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         level 
                       
                     
                   
                   
                     
                       
                         of 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         the 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         protein 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         in 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         three 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         patients 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         with 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         endometriosis 
                       
                     
                   
                 
                 
                   
                     
                       
                         The 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         average 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         value 
                         ⁢ 
                         
                           
                               
                           
                           ⁢ 
                           
                               
                           
                         
                         ⁢ 
                         of 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         the 
                         ⁢ 
                         
                           
                               
                           
                           ⁢ 
                           
                               
                           
                         
                         ⁢ 
                         relative 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         expression 
                       
                     
                   
                   
                     
                       
                         level 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         of 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         the 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         protein 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         in 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         three 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         healthy 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         individuals 
                       
                     
                   
                 
               
             
             ≧ 
             
               2 
               ⁢ 
               
                   
               
               ⁢ 
               or 
             
             ≦ 
             0.5 
           
         
       
         
         
           
             The relative expression level of the protein in three healthy individuals and three endometriosis patients was p&lt;0.05 in the Welch t-test. 
           
         
       
    
     
       
         
           
               
               
             
               
                   
                 TABLE 3A 
               
             
            
               
                   
                   
               
               
                   
                 Relative expression level of protein: 
               
               
                   
                 Average value of 3 patients/ 
               
               
                   
                 Average value of 3 healthy individuals 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 Data set 
                 Data set 
                 Data set 
               
               
                 UniProt ID 
                 Protein name 
                 Gene name 
                 TMT1 
                 TMT2 
                 TMT3 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 P02042 
                 Hemoglobin subunit delta 
                 HBD 
                 4.848 
                 4.12 
                 4.27 
               
               
                 P68871 
                 Hemoglobin subunit beta; 
                 HBB 
                 3.662 
                 4.58 
                 4.153 
               
               
                   
                 LVV-hemorphin-7; Spinorphin 
               
               
                 P55072 
                 Transitional endoplasmic reticulum ATPase 
                 VCP 
                 2.915 
                 3 
                 2.306 
               
               
                 P50395; P50395-2 
                 Rab GDP dissociation inhibitor beta 
                 GDI2 
                 2.06 
                 2.19 
                 1.784 
               
               
                 O43852-9; O43852-5; O43852-2; 
                 Calumenin 
                 CALU 
                 6.081 
                 5.24 
                 4.619 
               
               
                 O43852; O43852-4; O43852-3; 
               
               
                 O43852-12; O43852-13; O43852-14; 
               
               
                 O43852-7; O43852-15; O43852-11; 
               
               
                 O43852-8; O43852-10; O43852-6 
               
               
                 P04040 
                 Catalase 
                 CAT 
                 3.085 
                 3.36 
                 3.258 
               
               
                 Q06830; Q13162 
                 Peroxiredoxin-1 ; Peroxiredoxin-4 
                 PRDX1; 
                 3.006 
                 2.87 
                 3.052 
               
               
                   
                   
                 PRDX4 
               
               
                 P69905 
                 Hemoglobin subunit alpha 
                 HBA1 
                 4.877 
                 5.88 
                 5.135 
               
               
                 Q13404-8; Q15819; Q13404; 
                 Ubiquitin-conjugating enzyme E2 
                 UBE2V1; 
                 3.279 
                 2.76 
                 2.538 
               
               
                 Q13404-7; Q13404-2; Q13404-1 
                 variant 1; Ubiquitin-conjugating 
                 UBE2V2 
               
               
                   
                 enzyme E2 variant 2 
               
               
                 P06703 
                 Protein S100-A6 
                 S100A6 
                 4.041 
                 4.37 
                 4.052 
               
               
                 P60174-1; P60174; P60174-4 
                 Triosephosphate isomerase 
                 TPI1 
                 2.433 
                 2.71 
                 2.574 
               
               
                 P62937; P62937-2 
                 Peptidyl-prolyl cis-trans 
                 PPIA 
                 2.957 
                 2.84 
                 2.631 
               
               
                   
                 isomerase A; Peptidyl-prolyl 
               
               
                   
                 cis-trans isomerase A, N-terminally 
               
               
                   
                 processed 
               
               
                 P49746-2; P49746 
                 Thrombospondin-3 
                 THBS3 
                 3.863 
                 1.19 
                 1.208 
               
               
                 P09486 
                 SPARC 
                 SPARC 
                 4.177 
                 5.05 
                 4.681 
               
               
                 Q14766-3; Q14766-2; Q14766-5; 
                 Latent-transforming growth factor 
                 LTBP1 
                 6.967 
                 2.71 
                 6.079 
               
               
                 Q14766; Q14766-4 
                 beta-binding protein 1 
               
               
                 P01137 
                 Transforming growth factor beta-1; 
                 TGFB1 
                 4.8 
                 5.77 
                 2.667 
               
               
                   
                 Latency-associated peptide 
               
               
                 P61088; Q5JXB2 
                 Ubiquitin-conjugating enzyme 
                 UBE2N; 
                 2.742 
                 2.92 
                 3.356 
               
               
                   
                 E2 N; Putative ubiquitin-conjugating 
                 UBE2NL 
               
               
                   
                 enzyme E2 N-like 
               
               
                 P00558-2; P00558 
                 Phosphoglycerate kinase 1 
                 PGK1 
                 2.278 
                 2.02 
                 2.685 
               
               
                 P07996; P07996-2 
                 Thrombospondin-1 
                 THBS1 
                 8.012 
                 8.27 
                 6.402 
               
               
                 P02776 
                 Platelet factor 4; Platelet factor 4, 
                 PF4 
                 6.872 
                 7.55 
                 7.134 
               
               
                   
                 short form 
               
               
                 P05067-7; P05067-11 ; P05067-8; 
                 Amyloid beta A4 protein; N-APP; 
                 APP 
                 5.951 
                 3.84 
                 5.453 
               
               
                 P05067-9; P05067; P05067-10; 
                 Soluble APP-alpha; Soluble 
               
               
                 P05067-3; P05067-4; P05067-5; 
                 APP-beta; C99; Beta-amyloid 
               
               
                 P05067-6 
                 protein 42; Beta-amyloid protein 
               
               
                   
                 40; C83; P3(42); P3(40); C80; 
               
               
                   
                 Gamm a-secretase C-terminal 
               
               
                   
                 fragment 59; Gamma-secretase 
               
               
                   
                 C-terminal fragment 57; 
               
               
                   
                 Gamma-secretase C-terminal 
               
               
                   
                 fragment 50; C31 
               
               
                 P00568 
                 Adenylate kinase isoenzyme 1 
                 AK1 
                 2.762 
                 3.62 
                 2.942 
               
               
                 P00918 
                 Carbonic anhydrase 2 
                 CA2 
                 2.721 
                 2.78 
                 3.387 
               
               
                 P32119 
                 Peroxiredoxin-2 
                 PRDX2 
                 3.697 
                 3.66 
                 3.939 
               
               
                 P16070-18; P16070-12; P16070-14; 
                 CD44 antigen 
                 CD44 
                 2.047 
                 1.83 
                 1.814 
               
               
                 P16070-13; P16070-11; P16070-10; 
               
               
                 P16070-16; P16070-8; P16070-17; 
               
               
                 P16070-6; P16070-4; P16070-3; 
               
               
                 P16070-7; P16070-5; P16070; 
               
               
                 P16070-15; P16070-9 
               
               
                 Q13201 
                 Multimerin-1 ; Platelet glycoprotein 
                 MMRN1 
                 4.569 
                 4.27 
                 3.898 
               
               
                   
                 la*; 155 kDa platelet multimerin 
               
               
                 P27348 
                 14-3-3 protein theta 
                 YWHAQ 
                 1.983 
                 2.65 
                 1.942 
               
               
                 O00592-2; O00592 
                 Podocalyxin 
                 PODXL 
                 1.953 
                 2.03 
                 2.009 
               
               
                 P10599-2; P10599 
                 Thioredoxin 
                 TXN 
                 2.744 
                 1.94 
                 2.597 
               
               
                 P00915 
                 Carbonic anhydrase 1 
                 CA1 
                 3.741 
                 3.62 
                 4.046 
               
               
                 P62158 
                 Calmodulin 
                 CALM1 
                 2.102 
                 3.05 
                 2.229 
               
               
                 P58546 
                 Myotrophin 
                 MTPN 
                 1.836 
                 2.09 
                 1.787 
               
               
                 P62258; P62258-2 
                 14-3-3 protein epsilon 
                 YWHAE 
                 2.002 
                 1.16 
                 1.448 
               
               
                 O94919 
                 Endonuclease domain-containing 
                 ENDOD1 
                 3.075 
                 2.53 
                 3.181 
               
               
                   
                 1 protein 
               
               
                 P37837 
                 Transaldolase 
                 TALDO1 
                 2.995 
                 1.02 
                 0.806 
               
               
                 P07738 
                 Bisphosphoglycerate mutase 
                 BPGM 
                 2.761 
                 3.14 
                 2.939 
               
               
                 P30043 
                 Flavin reductase (NADPH) 
                 BLVRB 
                 2.985 
                 3.09 
                 2.68 
               
               
                 P02775 
                 Platelet basic protein; Connective 
                 PPBP 
                 12.41 
                 9.69 
                 11.867 
               
               
                   
                 tissue-activating peptide III; TC-2; 
               
               
                   
                 Connective tissue-activating 
               
               
                   
                 peptide III(1-81); Beta-thromboglobulin; 
               
               
                   
                 Neutrophil-activating peptide 2(74); 
               
               
                   
                 Neutrophil-activating peptide 2(73); 
               
               
                   
                 Neutrophil-activating peptide 2; 
               
               
                   
                 TC-1; Neutrophil-activating peptide 
               
               
                   
                 2(1-66); Neutrophil-activating 
               
               
                   
                 peptide 2(1-63) 
               
               
                 P15311 
                 Ezrin 
                 EZR 
                 2.116 
                 2.1 
                 2.294 
               
               
                 P0DJI8; P0DJI9-2 
                 Serum amyloid A-1 protein; 
                 SAA1; SAA2 
                 3.374 
                 4.17 
                 3.645 
               
               
                   
                 Amyloid protein A; Serum amyloid 
               
               
                   
                 protein A(2-104); Serum amyloid protein 
               
               
                   
                 A(3-104); Serum amyloid protein 
               
               
                   
                 A(2-103); Serum amyloid protein 
               
               
                   
                 A(2-102); Serum amyloid protein 
               
               
                   
                 A(4-101); Serum amyloid A-2 protein 
               
               
                 P10124 
                 Serglycin 
                 SRGN 
                 3.41 
                 5.68 
                 4.664 
               
               
                 P13798 
                 Acylamino-acid-releasing enzyme 
                 APEH 
                 4.068 
                 4.14 
                 4.786 
               
               
                 P23528 
                 Cofilin-1 
                 CFL1 
                 2.704 
                 2.79 
                 2.566 
               
               
                 P30041 
                 Peroxiredoxin-6 
                 PRDX6 
                 2.111 
                 2.01 
                 1.81 
               
               
                 Q8WUM4; Q8WUM4-2 
                 Programmed cell death 
                 PDCD6IP 
                 2.152 
                 2.36 
                 2.291 
               
               
                   
                 6-interacting protein 
               
               
                 P05090 
                 Apolipoprotein D 
                 APOD 
                 2.213 
                 2.51 
                 2.381 
               
               
                 Q99497 
                 Protein deglycase DJ-1 
                 PARK7 
                 3.668 
                 2.22 
                 2.939 
               
               
                 P35579; P35579-2 
                 Myosin-9 
                 MYH9 
                 2.97 
                 2.8 
                 2.504 
               
               
                 Q13228; Q13228-4; Q13228-2; 
                 Selenium-binding protein 1 
                 SELENBP1 
                 2.032 
                 2.33 
                 1.843 
               
               
                 Q13228-3 
               
               
                 P13716; P13716-2 
                 Delta-aminolevulinic acid 
                 ALAD 
                 1.983 
                 2.28 
                 2.524 
               
               
                   
                 dehydratase 
               
               
                 Q9ULI3-2; Q9ULI3 
                 Protein HEG homolog 1 
                 HEG1 
                 2.16 
                 1.95 
                 2.819 
               
               
                 P07384 
                 Calpain-1 catalytic subunit 
                 CAPN1 
                 1.752 
                 0.97 
                 2.358 
               
               
                 P18065 
                 Insulin-like growth factor-binding 
                 IGFBP2 
                 2.507 
                 2.87 
                 2.833 
               
               
                   
                 protein 2 
               
               
                 P04083 
                 Annexin A1 
                 ANXA1 
                 2.684 
                 8.03 
                 3.645 
               
               
                 P0DMV8-2; P0DMV9; P0DMV8 
                 Heat shock 70 kDa protein 1A; 
                 HSPA1A; HSPA 1B 
                 2.188 
                 2.3 
                 2.203 
               
               
                   
                 Heat shock 70 kDa protein 1B 
               
               
                 P07911-3; P07911; P07911-5; 
                 Uromodulin; Uromodulin, secreted form 
                 UMOD 
                 1.565 
                 1.85 
                 2.121 
               
               
                 P07911-4 
               
               
                 P15924; P15924-2; P15924-3 
                 Desmoplakin 
                 DSP 
                 1.636 
                 3.38 
                 1.968 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 3B 
               
             
            
               
                   
                   
               
               
                   
                 Relative expression level of protein: 
               
               
                   
                 Average value of 3 patients/ 
               
               
                   
                 Average value of 3 healthy individuals 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 Data set 
                 Data set 
                 Data set 
               
               
                 UniProt ID 
                 Protein name 
                 Gene name 
                 TMT1 
                 TMT2 
                 TMT3 
               
               
                   
               
               
                 Q9C0H2-3 
                 Protein tweety homolog 3 
                 TTYH3 
                 0.511 
                 0.619 
                 0.5 
               
               
                   
               
            
           
         
       
     
     The selected proteins are promising as biomarkers for diagnosing endometriosis.  FIGS. 1-1 to 1-10  show the graphs of relative expression levels of representative proteins among them. 
     (Example 2) Search for Biomarkers by Aptamer-Binding Protein Analysis (SOMAscan®) Using Plasma of Healthy Human Individuals and Patients with Endometriosis 
     (2-1) Obtainment of Human Plasma Samples 
     Plasma from healthy individuals and endometriosis patients was purchased from Proteogenex. 
     (2-2) SOMAscan® Analysis of Plasma Proteins 
     Low-expressed proteins in plasma samples (three healthy individuals and three endometriosis patients) were analyzed by SOMAscan (registered trademark, Somalogic). Specifically, aptamers that each specifically binds to 1310 proteins were prepared, mixed with plasma, and allowed to bind to proteins in the plasma. The proteins bound to the aptamers were then biotinylated, and the aptamer-protein complexes were purified with streptavidin beads. Next, the aptamers were eluted and detected by a microarray, thereby the expression levels of the proteins bound to the aptamers in the plasma were analyzed. 
     (2-3) Selection of Biomarker Candidates 
     The aptamer signal data of SOMAscan® were analyzed by statistical programming environment R and Microsoft Excel. According to the following criterion, 200 proteins for which altered expression was found in endometriosis patients were selected (Table 4A and Table 4B). 
     
       
         
           
             
               - 
               
                 
                   
                     
                       
                         The 
                         ⁢ 
                         
                           
                               
                           
                           ⁢ 
                           
                               
                           
                         
                         ⁢ 
                         average 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         value 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         of 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         the 
                         ⁢ 
                         
                           
                               
                           
                           ⁢ 
                           
                               
                           
                         
                         ⁢ 
                         aptamer 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         signal 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         of 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         the 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         target 
                       
                     
                   
                   
                     
                       
                         protein 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         in 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         three 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         patients 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         with 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         endometriosis 
                       
                     
                   
                 
                 
                   
                     
                       
                         The 
                         ⁢ 
                         
                           
                               
                           
                           ⁢ 
                           
                               
                           
                         
                         ⁢ 
                         average 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         value 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         of 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         the 
                         ⁢ 
                         
                           
                               
                           
                           ⁢ 
                           
                               
                           
                         
                         ⁢ 
                         aptamer 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         signal 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         of 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         the 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         target 
                       
                     
                   
                   
                     
                       
                         protein 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         in 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         three 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         healthy 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         individuals 
                       
                     
                   
                 
               
             
             ≧ 
             
               2 
               ⁢ 
               
                   
               
               ⁢ 
               or 
             
             ≦ 
             0.5 
           
         
       
     
     In the above calculation, proteins with a maximum aptamer signal value of less than 1000 were considered to be below the detection limit and excluded from analysis. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 4A 
               
               
                   
               
               
                   
                   
                   
                   
                 Aptamer signal: 
               
               
                   
                   
                 Entrez 
                 Entrez Gene 
                 Average value of 3 patients/ 
               
               
                 Protein name 
                 UniProt ID 
                 Gene ID 
                 Symbol 
                 Average value of 3 healthy individuals 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Pulmonary surfactant-associated 
                 P35247 
                 6441 
                 SFTPD 
                 12.382 
               
               
                 protein D 
               
               
                 Histone H1.2 
                 P16403 
                 3006 
                 HIST1H1C 
                 11.014 
               
               
                 Sialic acid-binding Ig-like lectin 9 
                 Q9Y336 
                 27180 
                 SIGLEC9 
                 9.473 
               
               
                 Heterogeneous nuclear 
                 P22626 
                 3181 
                 HNRNPA2B1 
                 7.516 
               
               
                 ribonucleoproteins A2/B1 
               
               
                 Hexokinase-2 
                 P52789 
                 3099 
                 HK2 
                 6.671 
               
               
                 High mobility group protein B1 
                 P09429 
                 3146 
                 HMGB1 
                 5.584 
               
               
                 Thrombospondin-1 
                 P07996 
                 7057 
                 THBS1 
                 5.365 
               
               
                 3-hydroxy-3-methylglutaryl- 
                 P04035 
                 3156 
                 HMGCR 
                 4.718 
               
               
                 coenzyme A reductase 
               
               
                 Platelet factor 4 
                 P02776 
                 5196 
                 PF4 
                 4.686 
               
               
                 Protein S100-A9 
                 P06702 
                 6280 
                 S100A9 
                 4.681 
               
               
                 40S ribosomal protein S3a 
                 P61247 
                 6189 
                 RPS3A 
                 4.5 
               
               
                 Annexin A6 
                 P08133 
                 309 
                 ANXA6 
                 4.484 
               
               
                 Inosine-5′-monophosphate 
                 P20839 
                 3614 
                 IMPDH1 
                 4.417 
               
               
                 dehydrogenase 1 
               
               
                 Tyrosine-protein kinase Fgr 
                 P09769 
                 2268 
                 FGR 
                 4.238 
               
               
                 Serine/threonine-protein kinase 17B 
                 O94768 
                 9262 
                 STK17B 
                 3.957 
               
               
                 Neutrophil-activating peptide 2 
                 P02775 
                 5473 
                 PPBP 
                 3.826 
               
               
                 Estradiol 17-beta-dehydrogenase 1 
                 P14061 
                 3292 
                 HSD17B1 
                 3.787 
               
               
                 Connective tissue-activating 
                 P02775 
                 5473 
                 PPBP 
                 3.746 
               
               
                 peptide III 
               
               
                 Prostaglandin G/H synthase 2 
                 P35354 
                 5743 
                 PTGS2 
                 3.686 
               
               
                 Amyloid beta A4 protein 
                 P05067 
                 351 
                 APP 
                 3.667 
               
               
                 GTP-binding nuclear protein Ran 
                 P62826 
                 5901 
                 RAN 
                 3.605 
               
               
                 NAD-dependent protein 
                 Q8IXJ6 
                 22933 
                 SIRT2 
                 3.54 
               
               
                 deacetylase sirtuin-2 
               
               
                 Protein S100-A12 
                 P80511 
                 6283 
                 S100A12 
                 3.498 
               
               
                 Plasminogen activator inhibitor 1 
                 P05121 
                 5054 
                 SERPINE1 
                 3.367 
               
               
                 SUMO-conjugating enzyme UBC9 
                 P63279 
                 7329 
                 UBE2I 
                 3.336 
               
               
                 Bactericidal permeability-increasing 
                 P17213 
                 671 
                 BPI 
                 3.321 
               
               
                 protein 
               
               
                 6-phosphogluconate 
                 P52209 
                 5226 
                 PGD 
                 3.204 
               
               
                 dehydrogenase, decarboxylating 
               
               
                 Platelet-derived growth factor 
                 P01127 
                 5155 
                 PDGFB 
                 3.158 
               
               
                 subunit B 
               
               
                 Tyrosine-protein phosphatase 
                 P29350 
                 5777 
                 PTPN6 
                 3.117 
               
               
                 non-receptor type 6 
               
               
                 Metalloproteinase inhibitor 3 
                 P35625 
                 7078 
                 TIMP3 
                 3.113 
               
               
                 NudC domain-containing protein 3 
                 Q8IVD9 
                 23386 
                 NUDCD3 
                 3.112 
               
               
                 SPARC 
                 P09486 
                 6678 
                 SPARC 
                 3.046 
               
               
                 Protein 4.1 
                 P11171 
                 2035 
                 EPB41 
                 2.967 
               
               
                 Sex hormone-binding globulin 
                 P04278 
                 6462 
                 SHBG 
                 2.905 
               
               
                 Death-associated protein kinase 2 
                 Q9UIK4 
                 23604 
                 DAPK2 
                 2.834 
               
               
                 Hepatoma-derived growth 
                 Q7Z4V5 
                 84717 
                 HDGFRP2 
                 2.777 
               
               
                 factor-related protein 2 
               
               
                 Proto-oncogene vav 
                 P15498 
                 7409 
                 VAV1 
                 2.723 
               
               
                 Serine/threonine-protein kinase 
                 P11309 
                 5292 
                 PIM1 
                 2.694 
               
               
                 pim-1 
               
               
                 Heterogeneous nuclear 
                 Q99729 
                 3182 
                 HNRNPAB 
                 2.685 
               
               
                 ribonucleoprotein A/B 
               
               
                 Proliferation-associated 
                 Q9UQ80 
                 5036 
                 PA2G4 
                 2.654 
               
               
                 protein 2G4 
               
               
                 Extracellular superoxide 
                 P08294 
                 6649 
                 SOD3 
                 2.654 
               
               
                 dismutase [Cu-Zn] 
               
               
                 Angiopoietin-1 
                 Q15389 
                 284 
                 ANGPT1 
                 2.643 
               
               
                 Acid sphingomyelinase-like 
                 Q92484 
                 10924 
                 SMPDL3A 
                 2.631 
               
               
                 phosphodiesterase 3a 
               
               
                 Peroxiredoxin-6 
                 P30041 
                 9588 
                 PRDX6 
                 2.624 
               
               
                 AMP Kinase (alpha1beta1gamma1) 
                 Q13131 
                 5562 
                 PRKAA1 
                 2.577 
               
               
                   
                 Q9Y478 
                 5564 
                 PRKAB1 
               
               
                   
                 P54619 
                 5571 
                 PRKAG1 
               
               
                 Serum amyloid A-1 protein 
                 P0DJI8 
                 6288 
                 SAA1 
                 2.556 
               
               
                 Insulin-like growth factor-binding 
                 P18065 
                 3485 
                 IGFBP2 
                 2.52 
               
               
                 protein 2 
               
               
                 Histone H2B type 2-E 
                 Q16778 
                 8349 
                 HIST2H2BE 
                 2.491 
               
               
                 Fibroblast growth factor 5 
                 P12034 
                 2250 
                 FGF5 
                 2.491 
               
               
                 Non-histone chromosomal protein 
                 P05114 
                 3150 
                 HMGN1 
                 2.467 
               
               
                 HMG-14 
               
               
                 Calcium/calmodulin-dependent 
                 Q13557 
                 817 
                 CAMK2D 
                 2.464 
               
               
                 protein kinase type II subunit delta 
               
               
                 Interstitial collagenase 
                 P03956 
                 4312 
                 MMP1 
                 2.454 
               
               
                 ICOS ligand 
                 O75144 
                 23308 
                 ICOSLG 
                 2.444 
               
               
                 Calcium/calmodulin-dependent 
                 Q13554 
                 816 
                 CAMK2B 
                 2.425 
               
               
                 protein kinase type II subunit beta 
               
               
                 Inosine-5′-monophosphate dehydrogenase 2 
                 P12268 
                 3615 
                 IMPDH2 
                 2.398 
               
               
                 Dickkopf-related protein 4 
                 Q9UBT3 
                 27121 
                 DKK4 
                 2.375 
               
               
                 Glia-derived nexin 
                 P07093 
                 5270 
                 SERPINE2 
                 2.365 
               
               
                 14-3-3 protein beta/alpha 
                 P31946 
                 7529 
                 YWHAB 
                 2.357 
               
               
                 Macrophage-capping protein 
                 P40121 
                 822 
                 CAPG 
                 2.352 
               
               
                 ADP-ribosyl cyclase/cyclic 
                 P28907 
                 952 
                 CD38 
                 2.349 
               
               
                 ADP-ribose hydrolase 1 
               
               
                 SH2 domain-containing protein 1A 
                 O60880 
                 4068 
                 SH2D1A 
                 2.324 
               
               
                 Vacuolar protein sorting-associated 
                 Q9NP79 
                 51534 
                 VTA1 
                 2.319 
               
               
                 protein VTA1 homolog 
               
               
                 Interleukin-1 beta 
                 P01584 
                 3553 
                 IL1B 
                 2.312 
               
               
                 Chloride intracellular channel 
                 O00299 
                 1192 
                 CLIC1 
                 2.306 
               
               
                 protein 1 
               
               
                 MAP kinase-activated protein 
                 Q16644 
                 7867 
                 MAPKAPK3 
                 2.298 
               
               
                 kinase 3 
               
               
                 Mitogen-activated protein kinase 1 
                 P28482 
                 5594 
                 MAPK1 
                 2.295 
               
               
                 Choline/ethanolamine kinase 
                 Q9Y259 
                 1120 
                 CHKB 
                 2.293 
               
               
                 Creatine kinase B-type 
                 P12277 
                 1152 
                 CKB 
                 2.287 
               
               
                 DNA topoisomerase 1 
                 P11387 
                 7150 
                 TOP1 
                 2.286 
               
               
                 C-C motif chemokine 5 
                 P13501 
                 6352 
                 CCL5 
                 2.28 
               
               
                 C3a anaphylatoxin 
                 P01024 
                 718 
                 C3 
                 2.276 
               
               
                 Copine-1 
                 Q99829 
                 8904 
                 CPNE1 
                 2.274 
               
               
                 Chymase 
                 P23946 
                 1215 
                 CMA1 
                 2.27 
               
               
                 Mitogen-activated protein kinase 
                 O43318 
                 6885 
                 MAP3K7 
                 2.27 
               
               
                 kinase kinase 7: TGF-beta-activated 
                 Q15750 
                 10454 
                 TAB1 
               
               
                 kinase 1 and MAP3K7-binding 
               
               
                 protein 1 fusion 
               
               
                 Dickkopf-related protein 1 
                 O94907 
                 22943 
                 DKK1 
                 2.266 
               
               
                 Ephrin type-B receptor 4 
                 P54760 
                 2050 
                 EPHB4 
                 2.261 
               
               
                 40S ribosomal protein S7 
                 P62081 
                 6201 
                 RPS7 
                 2.253 
               
               
                 Intercellular adhesion molecule 1 
                 P05362 
                 3383 
                 ICAM1 
                 2.248 
               
               
                 Ubiquitin + 1, truncated mutation 
                 P62979 
                 6233 
                 RPS27A 
                 2.222 
               
               
                 for UbB 
               
               
                 Ubiquitin-conjugating enzyme E2 N 
                 P61088 
                 7334 
                 UBE2N 
                 2.219 
               
               
                 Moesin 
                 P26038 
                 4478 
                 MSN 
                 2.201 
               
               
                 Small ubiquitin-related modifier 3 
                 P55854 
                 6613 
                 SUMO3 
                 2.196 
               
               
                 G2/mitotic-specific cyclin-B1 
                 P14635 
                 891 
                 CCNB1 
                 2.19 
               
               
                 ATP-dependent RNA helicase 
                 Q9UMR2 
                 11269 
                 DDX19B 
                 2.178 
               
               
                 DDX19B 
               
               
                 Tyrosine-protein kinase CSK 
                 P41240 
                 1445 
                 CSK 
                 2.17 
               
               
                 Alpha-1-antitrypsin 
                 P01009 
                 5265 
                 SERPINA1 
                 2.162 
               
               
                 Adenylate kinase isoenzyme 1 
                 P00568 
                 203 
                 AK1 
                 2.145 
               
               
                 Mothers against decapentaplegic 
                 P84022 
                 4088 
                 SMAD3 
                 2.137 
               
               
                 homolog 3 
               
               
                 Brain-derived neurotrophic factor 
                 P23560 
                 627 
                 BDNF 
                 2.136 
               
               
                 Atrial natriuretic factor 
                 P01160 
                 4878 
                 NPPA 
                 2.131 
               
               
                 Annexin A1 
                 P04083 
                 301 
                 ANXA1 
                 2.13 
               
               
                 Signal transducer and activator of 
                 P42224 
                 6772 
                 STAT1 
                 2.12 
               
               
                 transcription 1-alpha/beta 
               
               
                 Angiopoietin-related protein 4 
                 Q9BY76 
                 51129 
                 ANGPTL4 
                 2.104 
               
               
                 Cadherin-12 
                 P55289 
                 1010 
                 CDH12 
                 2.098 
               
               
                 Stress-induced-phosphoprotein 1 
                 P31948 
                 10963 
                 STIP1 
                 2.096 
               
               
                 Glycylpeptide 
                 P30419 
                 4836 
                 NMT1 
                 2.091 
               
               
                 N-tetradecanoyltransferase 1 
               
               
                 Peroxiredoxin-1 
                 Q06830 
                 5052 
                 PRDX1 
                 2.077 
               
               
                 Oxidized low-density lipoprotein 
                 P78380 
                 4973 
                 OLR1 
                 2.075 
               
               
                 receptor 1 
               
               
                 VPS10 domain-containing receptor 
                 Q96PQ0 
                 57537 
                 SORCS2 
                 2.059 
               
               
                 SorCS2 
               
               
                 FACT complex subunit SSRP1 
                 Q08945 
                 6749 
                 SSRP1 
                 2.049 
               
               
                 Carbonic anhydrase 1 
                 P00915 
                 759 
                 CA1 
                 2.035 
               
               
                 Mitogen-activated protein kinase 11 
                 Q15759 
                 5600 
                 MAPK11 
                 2.034 
               
               
                 Triosephosphate isomerase 
                 P60174 
                 7167 
                 TPI1 
                 2.029 
               
               
                 Neurexophilin-1 
                 P58417 
                 30010 
                 NXPH1 
                 2.018 
               
               
                 Platelet-derived growth factor 
                 P04085 
                 5154 
                 PDGFA 
                 2.017 
               
               
                 subunit A 
               
               
                 Interleukin-22 receptor subunit 
                 Q8N6P7 
                 58985 
                 IL22RA1 
                 2.004 
               
               
                 alpha-1 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 4B 
               
               
                   
               
               
                   
                   
                   
                   
                 Aptamer signal: 
               
               
                   
                   
                   
                   
                 Average value of 
               
               
                   
                   
                   
                   
                 3 patients/Average 
               
               
                   
                   
                 Entrez 
                 Entrez 
                 value of 3 healthy 
               
               
                 Protein name 
                 UniProt ID 
                 Gene ID 
                 Gene Symbol 
                 individuals 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Cystatin-SN 
                 P01037 
                 1469 
                 CST1 
                 0.499 
               
               
                 Interleukin-22 
                 Q9GZX6 
                 50616 
                 IL22 
                 0.497 
               
               
                 Tyrosine-protein kinase Fyn 
                 P06241 
                 2534 
                 FYN 
                 0.497 
               
               
                 Biglycan 
                 P21810 
                 633 
                 BGN 
                 0.495 
               
               
                 Sonic hedgehog protein 
                 Q15465 
                 6469 
                 SHH 
                 0.492 
               
               
                 Cathepsin L2 
                 O60911 
                 1515 
                 CTSV 
                 0.49 
               
               
                 Interferon alpha/beta receptor 1 
                 P17181 
                 3454 
                 IFNAR1 
                 0.486 
               
               
                 Ectodysplasin-A, secreted form 
                 Q92838 
                 1896 
                 EDA 
                 0.485 
               
               
                 Dynein light chain 1, cytoplasmic 
                 P63167 
                 8655 
                 DYNLL1 
                 0.483 
               
               
                 Cytochrome c 
                 P99999 
                 54205 
                 CYCS 
                 0.482 
               
               
                 Lactoperoxidase 
                 P22079 
                 4025 
                 LPO 
                 0.48 
               
               
                 Tumor necrosis factor receptor 
                 Q969Z4 
                 84957 
                 RELT 
                 0.48 
               
               
                 superfamily member 19L 
               
               
                 Growth factor receptor-bound protein 2 
                 P62993 
                 2885 
                 GRB2 
                 0.467 
               
               
                 Ectonucleotide pyrophosphatase/ 
                 Q6UWV6 
                 339221 
                 ENPP7 
                 0.466 
               
               
                 phosphodiesterase family member 7 
               
               
                 Glucagon 
                 P01275 
                 2641 
                 GCG 
                 0.466 
               
               
                 Eukaryotic translation initiation factor 4 
                 P78344 
                 1982 
                 EIF4G2 
                 0.465 
               
               
                 gamma 2 
               
               
                 C-X-C motif chemokine 10 
                 P02778 
                 3627 
                 CXCL10 
                 0.457 
               
               
                 Platelet-derived growth factor receptor 
                 P09619 
                 5159 
                 PDGFRB 
                 0.453 
               
               
                 beta 
               
               
                 von Willebrand factor 
                 P04275 
                 7450 
                 VWF 
                 0.452 
               
               
                 Iduronate 2-sulfatase 
                 P22304 
                 3423 
                 IDS 
                 0.443 
               
               
                 cGMP-specific 3′,5′-cyclic 
                 O76074 
                 8654 
                 PDE5A 
                 0.443 
               
               
                 phosphodiesterase 
               
               
                 Small glutamine-rich tetratricopeptide 
                 O43765 
                 6449 
                 SGTA 
                 0.441 
               
               
                 repeat-containing protein alpha 
               
               
                 Interleukin-25 
                 Q9H293 
                 64806 
                 IL25 
                 0.433 
               
               
                 MHC class I polypeptide-related 
                 Q29980 
                 4277 
                 MICB 
                 0.433 
               
               
                 sequence B 
               
               
                 C-C motif chemokine 7 
                 P80098 
                 6354 
                 CCL7 
                 0.429 
               
               
                 Lactadherin 
                 Q08431 
                 4240 
                 MFGE8 
                 0.427 
               
               
                 Macrophage metalloelastase 
                 P39900 
                 4321 
                 MMP12 
                 0.425 
               
               
                 Ubiquitin-like protein ISG15 
                 P05161 
                 9636 
                 ISG15 
                 0.423 
               
               
                 Fatty acid-binding protein, liver 
                 P07148 
                 2168 
                 FABP1 
                 0.418 
               
               
                 Properdin 
                 P27918 
                 5199 
                 CFP 
                 0.417 
               
               
                 Stromelysin-2 
                 P09238 
                 4319 
                 MMP10 
                 0.415 
               
               
                 Protein FAM107B 
                 Q9H098 
                 83641 
                 FAM107B 
                 0.413 
               
               
                 Myosin-binding protein C, slow-type 
                 Q00872 
                 4604 
                 MYBPC1 
                 0.413 
               
               
                 Serine/threonine-protein kinase Chk2 
                 O96017 
                 11200 
                 CHEK2 
                 0.41 
               
               
                 Xaa-Pro aminopeptidase 1 
                 Q9NQW7 
                 7511 
                 XPNPEP1 
                 0.395 
               
               
                 NT-3 growth factor receptor 
                 Q16288 
                 4916 
                 NTRK3 
                 0.394 
               
               
                 Interleukin-5 receptor subunit alpha 
                 Q01344 
                 3568 
                 IL5RA 
                 0.392 
               
               
                 Ephrin type-A receptor 2 
                 P29317 
                 1969 
                 EPHA2 
                 0.391 
               
               
                 Peptidyl-prolyl cis-trans isomerase F, 
                 P30405 
                 10105 
                 PPIF 
                 0.387 
               
               
                 mitochondrial 
               
               
                 B-cell lymphoma 6 protein 
                 P41182 
                 604 
                 BCL6 
                 0.384 
               
               
                 Cell adhesion molecule 1 
                 Q9BY67 
                 23705 
                 CADM1 
                 0.384 
               
               
                 Kinesin-like protein KIF23 
                 Q02241 
                 9493 
                 KIF23 
                 0.383 
               
               
                 Netrin receptor UNC5D 
                 Q6UXZ4 
                 137970 
                 UNC5D 
                 0.381 
               
               
                 Lymphocyte activation gene 3 protein 
                 P18627 
                 3902 
                 LAG3 
                 0.377 
               
               
                 Serine protease HTRA2, mitochondrial 
                 O43464 
                 27429 
                 HTRA2 
                 0.376 
               
               
                 Interleukin-22 receptor subunit alpha-2 
                 Q969J5 
                 116379 
                 IL22RA2 
                 0.375 
               
               
                 Caspase-3 
                 P42574 
                 836 
                 CASP3 
                 0.374 
               
               
                 Platelet-derived growth factor receptor 
                 P16234 
                 5156 
                 PDGFRA 
                 0.372 
               
               
                 alpha 
               
               
                 Interleukin-20 
                 Q9NYY1 
                 50604 
                 IL20 
                 0.368 
               
               
                 Ferritin 
                 P02794 P02792 
                 2495 2512 
                 FTH1 FTL 
                 0.367 
               
               
                 Ephrin-A5 
                 P52803 
                 1946 
                 EFNA5 
                 0.361 
               
               
                 Amphoterin-induced protein 2 
                 Q86SJ2 
                 347902 
                 AMIGO2 
                 0.353 
               
               
                 Interleukin-2 
                 P60568 
                 3558 
                 IL2 
                 0.351 
               
               
                 Phospholipase A2 
                 P04054 
                 5319 
                 PLA2G1B 
                 0.346 
               
               
                 Protein kinase C alpha type 
                 P17252 
                 5578 
                 PRKCA 
                 0.345 
               
               
                 Tumor necrosis factor ligand 
                 P32971 
                 944 
                 TNFSF8 
                 0.343 
               
               
                 superfamily member 8 
               
               
                 Endoglin 
                 P17813 
                 2022 
                 ENG 
                 0.342 
               
               
                 Gamma-enolase 
                 P09104 
                 2026 
                 ENO2 
                 0.332 
               
               
                 C-X-C motif chemokine 9 
                 Q07325 
                 4283 
                 CXCL9 
                 0.329 
               
               
                 beta-nerve growth factor 
                 P01138 
                 4803 
                 NGF 
                 0.327 
               
               
                 Hepcidin 
                 P81172 
                 57817 
                 HAMP 
                 0.323 
               
               
                 Inorganic pyrophosphatase 
                 Q15181 
                 5464 
                 PPA1 
                 0.319 
               
               
                 Kallikrein-8 
                 O60259 
                 11202 
                 KLK8 
                 0.314 
               
               
                 Semaphorin-6B 
                 Q9H3T3 
                 10501 
                 SEMA6B 
                 0.312 
               
               
                 Adapter molecule crk 
                 P46108 
                 1398 
                 CRK 
                 0.307 
               
               
                 Phosphoglycerate mutase 1 
                 P18669 
                 5223 
                 PGAM1 
                 0.298 
               
               
                 Proprotein convertase subtilisin/ 
                 Q16549 
                 9159 
                 PCSK7 
                 0.298 
               
               
                 kexin type 7 
               
               
                 Pancreatic hormone 
                 P01298 
                 5539 
                 PPY 
                 0.297 
               
               
                 Interleukin-1 receptor type 1 
                 P14778 
                 3554 
                 IL1R1 
                 0.296 
               
               
                 C-X-C motif chemokine 11 
                 O14625 
                 6373 
                 CXCL11 
                 0.293 
               
               
                 Secreted frizzled-related protein 1 
                 Q8N474 
                 6422 
                 SFRP1 
                 0.288 
               
               
                 Inhibin beta A chain 
                 P08476 
                 3624 
                 INHBA 
                 0.284 
               
               
                 Immunoglobulin D 
                 P01880 
                 3495 50802 3535 
                 IGHD IGK@ 
                 0.277 
               
               
                   
                   
                   
                 IGL@ 
               
               
                 Complement C3b 
                 P01024 
                 718 
                 C3 
                 0.272 
               
               
                 Teratocarcinoma-derived growth 
                 P13385 
                 6997 
                 TDGF1 
                 0.27 
               
               
                 factor 1 
               
               
                 Brother of CDO 
                 Q9BWV1 
                 91653 
                 BOC 
                 0.269 
               
               
                 CD109 antigen 
                 Q6YHK3 
                 135228 
                 CD109 
                 0.26 
               
               
                 Aminoacylase-1 
                 Q03154 
                 95 
                 ACY1 
                 0.259 
               
               
                 60 kDa heat shock protein, 
                 P10809 
                 3329 
                 HSPD1 
                 0.255 
               
               
                 mitochondrial 
               
               
                 Importin subunit beta-1 
                 Q14974 
                 3837 
                 KPNB1 
                 0.253 
               
               
                 C-reactive protein 
                 P02741 
                 1401 
                 CRP 
                 0.251 
               
               
                 Ephrin type-A receptor 1 
                 P21709 
                 2041 
                 EPHA1 
                 0.242 
               
               
                 Semaphorin-6A 
                 Q9H2E6 
                 57556 
                 SEMA6A 
                 0.24 
               
               
                 SLIT and NTRK-like protein 5 
                 O94991 
                 26050 
                 SLITRK5 
                 0.233 
               
               
                 Leucine-rich repeat transmembrane 
                 Q9NZU0 
                 23767 
                 FLRT3 
                 0.217 
               
               
                 protein FLRT3 
               
               
                 dCTP pyrophosphatase 1 
                 Q9H773 
                 79077 
                 DCTPP1 
                 0.21 
               
               
                 Osteopontin 
                 P10451 
                 6696 
                 SPP1 
                 0.206 
               
               
                 Formimidoyltransferase-cyclodeaminase 
                 O95954 
                 10841 
                 FTCD 
                 0.191 
               
               
                 Ephrin-B2 
                 P52799 
                 1948 
                 EFNB2 
                 0.175 
               
               
                 T-lymphocyte surface antigen Ly-9 
                 Q9HBG7 
                 4063 
                 LY9 
                 0.17 
               
               
                 Sialic acid-binding Ig-like lectin 14 
                 Q08ET2 
                 100049587 
                 SIGLEC14 
                 0.157 
               
               
                 N-acylethanolamine-hydrolyzing acid 
                 Q02083 
                 27163 
                 NAAA 
                 0.146 
               
               
                 amidase 
               
               
                 Endoplasmic reticulum aminopeptidase 1 
                 Q9NZ08 
                 51752 
                 ERAP1 
                 0.118 
               
               
                 Low affinity immunoglobulin gamma Fc 
                 P12318 
                 2212 
                 FCGR2A 
                 0.053 
               
               
                 region receptor II-a 
               
               
                   
               
            
           
         
       
     
     The selected proteins are promising as biomarkers for diagnosing endometriosis.  FIGS. 2-1 to 2-10  show the graphs of expression levels of representative proteins among them. 
     (Example 3) Search for Biomarkers by Extracellular Matrix Degradation Product Analysis Using Plasma of Healthy Human Individuals and Patients with Endometriosis 
     (3-1) Obtainment of Human Plasma Samples 
     Plasma from healthy individuals and endometriosis patients was purchased from Proteogenex. 
     (3-2) Extracellular Matrix Measurement of Plasma Proteins 
     Plasma samples (three healthy individuals and three endometriosis patients) were analyzed by the ELISA system with an antibody specific to the cleavage site of the extracellular matrix, and the total amount of extracellular matrix and the degradation/synthesis state of extracellular matrix in the samples were analyzed (Nordic Bioscience). Specifically, with antibodies against the cleavage site contained in degradation products when type III, IV, V, or VI collagen, decorin, or nidogen was degraded, the expression level of each degradation product was analyzed. The result showed that the type V collagen MMP degradation product (C5M) was remarkably increased in two of the three patients (the C5M concentration was 10.2 ng/ml and 11.8 ng/ml in the plasma of the two patients with increased C5M), while the plasma C5M concentration was below the detection limit in all healthy individuals. Thus, it was suggested that C5M is promising as a biomarker for endometriosis.  FIG. 3  shows the graph of the plasma concentration of the type V collagen MMP degradation product (C5M). 
     (Example 4) Search for Biomarkers by Luminex xMAP™ Technology Using Plasma of Healthy Human Individuals and Patients with Endometriosis 
     (4-1) Obtainment of Human Plasma Samples 
     Plasma of healthy individuals (five plasma samples at secretory stage and five plasma samples at proliferative stage) was purchased from Proteogenex. As plasma of endometriosis patients, a total of 111 plasma samples were obtained from 37 endometriosis patients, each before surgery, at 3 days after surgery, and at 1 month after surgery. 
     (4-2) Analysis of Plasma Proteins by Luminex xMAP™ Technology 
     Proteins in plasma samples were analyzed by Luminex xMAP™ (a trademark of Luminex). The Luminex xMAP™ technology is a technology of staining macrobeads with two fluorescent dyes combined at various concentrations and immobilizing onto each bead a substance that binds to each analysis target, whereby multiple items can be simultaneously analyzed with a small amount of samples using the content of the fluorescent dyes as an identification code. 
     In this Example, 152 proteins were selected and analyzed using protein measurement panels. Specifically, an antibody that binds to a target protein was immobilized on beads for each panel, a plasma sample was reacted with the antibody on the beads, a reporter antibody (labeled with a fluorescent dye) against the target protein was further reacted, and the expression level of the target protein was analyzed by measuring the fluorescence intensity with two types of lasers by flow cytometry technology (using the Luminex100 device). 
     (4-3) Selection of Biomarker Candidates 
     The plasma concentrations of the obtained various proteins were analyzed by Microsoft Excel. According to the following criterion, 24 proteins for which altered expression was found in endometriosis patients were selected (Table 7A and Table 7B). 
     
       
         
           
             
               
                 
                   
                     
                       The 
                       ⁢ 
                       
                         
                             
                         
                         ⁢ 
                         
                             
                         
                       
                       ⁢ 
                       average 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       value 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       of 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       the 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       plasma 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       concentration 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       of 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       the 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       protein 
                     
                   
                 
                 
                   
                     
                       in 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       37 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       patients 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       with 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       endometriosis 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       before 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       surgery 
                     
                   
                 
               
               
                 
                   
                     
                       
                         
                           
                             The 
                             ⁢ 
                             
                               
                                   
                               
                               ⁢ 
                               
                                   
                               
                             
                             ⁢ 
                             average 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             value 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             of 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             the 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             plasma 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             concentration 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             of 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             the 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             protein 
                           
                         
                       
                       
                         
                           
                             
                               in 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               10 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               samples 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               from 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               5 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               healthy 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               individuals 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               at 
                             
                             ⁢ 
                             
                                 
                             
                           
                         
                       
                     
                   
                 
                 
                   
                     
                       secretory 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       and 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       proliferative 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       stages 
                     
                   
                 
               
             
             ≧ 
             
               2 
               ⁢ 
               
                   
               
               ⁢ 
               or 
             
             ≦ 
             0.5 
           
         
       
     
     Of the 24 proteins selected, 12 proteins showed the highest value in endometriosis patients at the time of surgery and a decreased value one month after surgery, and also showed the lowest value in healthy individuals. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 7A 
               
               
                   
               
               
                   
                   
                   
                   
                 Patients with endometriosis 
               
               
                   
                   
                   
                   
                 (before surgery) &gt; Patients 
               
               
                   
                   
                   
                   
                 with endometriosis (1 
               
               
                   
                   
                   
                 Abundance 
                 month after surgery) &gt; 
               
               
                 UniProt ID 
                 Protein name 
                 Gene name 
                 ratio 
                 Healthy individuals 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Q15389 
                 Angiopoietin-1 (ANG-1) 
                 ANGPT1 
                 2.96 
                 ∘ 
               
               
                 P23560 
                 Brain-Derived Neurotrophic Factor (BDNF) 
                 BDNF 
                 4.03 
                 ∘ 
               
               
                 O94907 
                 Dickkopf-related protein 1 (DKK-1) 
                 DKK1 
                 2.11 
                 ∘ 
               
               
                 P80511 
                 S100-A12 
                 S100A12 
                 4.67 
                 ∘ 
               
               
                 P42830 
                 Epithelial-Derived Neutrophil-Activating 
                 CXCL5 
                 2.52 
                 ∘ 
               
               
                   
                 Protein 78 (ENA-78) 
               
               
                 P02794 
                 Ferritin (FRTN) 
                 FTH1 
                 2.99 
               
               
                 P09341 
                 Growth-Regulated alpha protein (GRO-alpha) 
                 CXCL1 
                 2.23 
                 ∘ 
               
               
                 P01137 
                 Latency-Associated Peptide of Transforming 
                 TGFB1 
                 2.55 
                 ∘ 
               
               
                   
                 Growth Factor beta 1 (LAPTGF-b1) 
               
               
                 Q8WXL0 
                 Luteinizing Hormone (LH) 
                 LHB 
                 2.26 
                 ∘ 
               
               
                 G3CBL7 
                 MHC class I chain-related protein A (MICA) 
                 MICA 
                 2.29 
               
               
                 P02775 
                 Platelet basic protein 
                 PPBP 
                 2.92 
                 ∘ 
               
               
                 P01127 
                 Platelet-Derived Growth Factor BB (PDGF-BB) 
                 PDGFB 
                 4.25 
                 ∘ 
               
               
                 P01236 
                 Prolactin (PRL) 
                 PRL 
                 3.76 
                 ∘ 
               
               
                 P0DJI8; P0DJI9-2 
                 Serum amyloid A-1 protein; Amyloid protein 
                 SAA1; SAA2 
                 3.01 
               
               
                   
                 A; Serum amyloid protein A(2-104); Serum 
               
               
                   
                 amyloid protein A(3-104); Serum amyloid 
               
               
                   
                 protein A(2-103); Serum amyloid protein 
               
               
                   
                 A(2-102); Serum amyloid protein A(4- 
               
               
                   
                 101); Serum amyloid A-2 protein 
               
               
                 P13501 
                 T-Cell-Specific Protein RANTES (RANTES) 
                 CCL5 
                 2.18 
                 ∘ 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                 TABLE 7B 
               
               
                   
               
               
                 UniProt ID 
                 Protein name 
                 Gene name 
                 Abundance ratio 
               
               
                   
               
             
            
               
                 P10645 
                 Chromogranin-A (CgA) 
                 CHGA 
                 0.38 
               
               
                 Q9GZV9 
                 Fibroblast growth factor 23 (FGF-23) 
                 FGF23 
                 0.22 
               
               
                 P01266 
                 Thyroglobulin (TG) 
                 TG 
                 0.47 
               
               
                   
               
            
           
         
       
     
     (Example 5) Search for Biomarkers by LC-MS Analysis Using Plasma of Healthy Human Individuals and Patients with Endometriosis 
     (5-1) Obtainment of Human Plasma Samples 
     Plasma of healthy individuals (five plasma samples at secretory stage and five plasma samples at proliferative stage) was purchased from Proteogenex. As plasma of endometriosis patients, a total of 125 plasma samples were obtained from 39 endometriosis patients, each before surgery, at 3 days after surgery, and at 1 month after surgery. 
     (5-2) LC-MS Analysis of Plasma Proteins 
     With High Select™ Top14 Abundant Protein Depletion Mini Spin Columns (Thermo), highly abundant proteins in each plasma sample were bound to the column and removed by the method recommended by the manufacturer. The proteins in the flow-through fraction that did not bind to the column were precipitated by the methanol/chloroform method and dissolved in 8 M urea/400 mM ammonium bicarbonate solution. The dissolved proteins were reduced and alkylated, and then digested into peptides with lysyl endopeptidase and trypsin. The peptide solution was demineralized with Monospin C18 (GL Science) by the method recommended by the manufacturer. 
     The peptides were labeled with TMT10plex by the method recommended by the manufacturer. With AssayMAP reversed phase (RP-S) cartridges (Agilent technologies), the labeled peptides were fractionated by the High pH Reversed-Phase method with triethylamine Each fraction was analyzed by the LC-MS analysis system in which Orbitrap Fusion Lumos (ThermoFisher scientific) was coupled to the nano-LC system (EASY-nLC™ 1200 system, ThermoFisher Scientific). The analysis samples were peptides obtained from the plasma of each of five healthy individuals (each at secretory stage and proliferative stage; a total of 10 samples) and 39 endometriosis patients (before surgery, at 3 days after surgery, and at 1 month after surgery; a total of 125 samples). The sample prepared by mixing an equal amount of seven samples from healthy individuals and seven samples from endometriosis patients, which were purchased for correction between measurements, was used as a control in each analysis, and 10 samples were used for each analysis. Each sample was analyzed three times, and they were integrated during analysis. 
     The proteins in the samples were identified from the raw data of the LC-MS analysis by Thermo Scientific™ Proteome Discoverer™, and their relative expression levels were analyzed. The database search for protein identification was performed with the following parameters. 
     Taxonomy: uniprot human
 
Static modifications: TMT6plex/+229.163 Da (Any N-Terminus), Carbamidomethyl/+57.021 Da (C, C-Terminus), TMT6plex /+229.163 Da (K, C-Terminus)
 
     Dynamic Modifications: Oxidation/+15.995 Da (M), Acetyl/+42.011 Da (N-Terminus) 
     FDR: Target FDR (Strict)/0.01, Target FDR (Relaxed)/0.05 
     The relative expression levels of the target proteins in the plasma samples from endometriosis patients before surgery relative to the target proteins in the plasma samples from healthy individuals were calculated by the analysis software (Proteome Discoverer). 
     (5-3) Selection of Biomarker Candidate Molecules 
     The LC-MS result data were analyzed by Proteome Discoverer. From the relative expression level of each protein in the samples (10 samples from five healthy individuals at secretory stage and proliferative stage and samples from 39 endometriosis patients before surgery), 27 proteins for which altered expression was found in endometriosis patients were selected according to the following criteria (Table 8A and Table 8B).
         For the abundance ratio, P-Value≤0.5 in ANOVA and tukey HSD post hoc; and   Abundance ratios≤0.6250 or ≥1.6000       

     
       
         
           
             
               Abundance 
               ⁢ 
               
                   
               
               ⁢ 
               ratio 
             
             = 
             
               
                 
                   
                     
                       The 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       median 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       value 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       of 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       the 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       relative 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       expression 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       level 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       of 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       the 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       protein 
                     
                   
                 
                 
                   
                     
                       in 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       39 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       patients 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       with 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       edometriosis 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       before 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       surgery 
                     
                   
                 
               
               
                 
                   
                     
                       The 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       median 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       value 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       of 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       the 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       relative 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       expression 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       level 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       of 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       the 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       protein 
                     
                   
                 
                 
                   
                     
                       in 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       10 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       samples 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       from 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       5 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       healthy 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       individuals 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       at 
                     
                   
                 
                 
                   
                     
                       secretory 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       and 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       proliferative 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       stages 
                     
                   
                 
               
             
           
         
       
     
     Of the 27 proteins selected, 16 proteins showed the highest value in endometriosis patients at the time of surgery and a decreased value one month after surgery, and also showed the lowest value in healthy individuals. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 8A 
               
               
                   
               
               
                   
                   
                   
                   
                 Patients with endometriosis 
               
               
                   
                   
                   
                   
                 (before surgery) &gt; Patients 
               
               
                   
                   
                   
                   
                 with endometriosis (1 
               
               
                   
                   
                   
                 Abundance 
                 month after surgery) &gt; 
               
               
                 UniProt ID 
                 Protein name 
                 Gene name 
                 ratio 
                 Healthy individuals 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 P07996 
                 Thrombospondin-1 OS =  Homo sapiens   
                 THBS1 
                 3.149 
                 ∘ 
               
               
                   
                 OX = 9606 GN = THBS1 PE = 1 SV = 2 
               
               
                 P69905 
                 Hemoglobin subunit alpha OS =  Homo sapiens   
                 HBA1 
                 1.717 
                 ∘ 
               
               
                   
                 OX = 9606 GN = HBA1 PE = 1 SV = 2 
               
               
                 P32119 
                 Peroxiredoxin-2 OS =  Homo sapiens   
                 PRDX2 
                 1.772 
                 ∘ 
               
               
                   
                 OX = 9606 GN = PRDX2 PE = 1 SV = 5 
               
               
                 P00918 
                 Carbonic anhydrase 2 OS =  Homo sapiens   
                 CA2 
                 1.821 
                 ∘ 
               
               
                   
                 OX = 9606 GN = CA2 PE = 1 SV = 2 
               
               
                 P30043 
                 Flavin reductase (NADPH) OS =  Homo sapiens   
                 BLVRB 
                 1.787 
                 ∘ 
               
               
                   
                 OX = 9606 GN = BLVRB PE = 1 SV = 3 
               
               
                 O76011 
                 Keratin, type I cuticular Ha4 OS =  Homo sapiens   
                 KRT34 
                 2.091 
                 ∘ 
               
               
                   
                 OX = 9606 GN = KRT34 PE = 1 SV = 2 
               
               
                 P13716 
                 Delta-aminolevulinic acid dehydratase OS = 
                 ALAD 
                 1.867 
                 ∘ 
               
               
                   
                   Homo sapiens  OX = 9606 GN = ALAD PE = 1 SV = 1 
               
               
                 P00568 
                 Adenylate kinase isoenzyme 1 OS =  Homo sapiens   
                 AK1 
                 1.786 
                 ∘ 
               
               
                   
                 OX = 9606 GN = AK1 PE = 1 SV = 3 
               
               
                 P07738 
                 Bisphosphoglycerate mutase OS =  Homo sapiens   
                 BPGM 
                 1.735 
                 ∘ 
               
               
                   
                 OX = 9606 GN = BPGM PE = 1 SV = 2 
               
               
                 P02775 
                 Platelet basic protein OS =  Homo sapiens   
                 PPBP 
                 3.628 
                 ∘ 
               
               
                   
                 OX = 9606 GN = PPBP PE = 1 SV = 3 
               
               
                 P22392 
                 Nucleoside diphosphate kinase B OS = 
                 NME2 
                 1.779 
                 ∘ 
               
               
                   
                   Homo sapiens  OX = 9606 GN = NME2 PE = 1 SV = 1 
               
               
                 P10124 
                 Serglycin OS =  Homo sapiens   
                 SRGN 
                 3.181 
                 ∘ 
               
               
                   
                 OX = 9606 GN = SRGN PE = 1 SV = 3 
               
               
                 A0A0C4DH67 
                 Immunoglobulin kappa variable 1-8 OS = 
                 IGKV1-8 
                 1.615 
                 x 
               
               
                   
                   Homo sapiens  OX = 9606 GN = IGKV1-8 PE = 3 SV = 1 
               
               
                 P63241 
                 Eukaryotic translation initiation factor 5A-1 OS = 
                 EIF5A 
                 1.874 
                 ∘ 
               
               
                   
                   Homo sapiens  OX = 9606 GN = EIF5A PE = 1 SV = 2 
               
               
                 P02776 
                 Platelet factor 4 OS =  Homo sapiens   
                 PF4 
                 3.438 
                 ∘ 
               
               
                   
                 OX = 9606 GN = PF4 PE = 1 SV = 2 
               
               
                 A0A075B6S2 
                 Immunoglobulin kappa variable 2D-29 OS = 
                 IGKV2D-29 
                 2.174 
                 x 
               
               
                   
                   Homo sapiens  OX = 9606 GN = IGKV2D-29 PE = 3 SV = 1 
               
               
                 Q9UKU6 
                 Thyrotropin-releasing hormone-degrading ectoenzyme 
                 TRHDE 
                 1.879 
                 ∘ 
               
               
                   
                 OS =  Homo sapiens  OX = 9606 GN = TRHDE PE = 2 SV = 1 
               
               
                 Q8WUM4 
                 Programmed cell death 6-interacting protein OS = 
                 PDCD6IP 
                 1.644 
                 x 
               
               
                   
                   Homo sapiens  OX = 9606 GN = PDCD6IP PE = 1 SV = 1 
               
               
                 P00441 
                 Superoxide dismutase [Cu—Zn] OS =  Homo sapiens   
                 SOD1 
                 2.01 
                 ∘ 
               
               
                   
                 OX = 9606 GN = SOD1 PE = 1 SV = 2 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                 TABLE 8B 
               
               
                   
               
               
                 UniProt ID 
                 Protein name 
                 Gene name 
                 Abundance ratio 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 P36980 
                 Complement factor H-related protein 2 OS =  Homo sapiens   
                 CFHR2 
                 0.443 
               
               
                   
                 OX = 9606 GN = CFHR2 PE = 1 SV = 1 
               
               
                 P0D0X3 
                 Immunoglobulin delta heavy chain OS =  Homo sapiens   
                 N/A 
                 0.518 
               
               
                   
                 OX = 9606 PE = 1 SV = 1 
               
               
                 P01880 
                 Immunoglobulin heavy constant delta OS =  Homo sapiens   
                 IGHD 
                 0.456 
               
               
                   
                 OX = 9606 GN = IGHD PE = 1 SV = 3 
               
               
                 Q8N6C8 
                 Leukocyte immunoglobulin-like receptor subfamily A member 
                 LILRA3 
                 0.318 
               
               
                   
                 3 OS =  Homo sapiens  OX = 9606 GN = LILRA3 PE = 1 SV = 3 
               
               
                 P47929 
                 Galectin-7 OS =  Homo sapiens   
                 LGALS7 
                 0.533 
               
               
                   
                 OX = 9606 GN = LGALS7 PE = 1 SV = 2 
               
               
                 O75339 
                 Cartilage intermediate layer protein 1 OS =  Homo sapiens   
                 CILP 
                 0.614 
               
               
                   
                 OX = 9606 GN = CILP PE = 1 SV = 4 
               
               
                 O15389 
                 Sialic acid-binding Ig-like lectin 5 OS =  Homo sapiens   
                 SIGLEC5 
                 0.546 
               
               
                   
                 OX = 9606 GN = SIGLEC5 PE = 1 SV = 1 
               
               
                 P35247 
                 Pulmonary surfactant-associated protein D OS = 
                 SFTPD 
                 0.605 
               
               
                   
                   Homo sapiens  OX = 9606 GN = SFTPD PE = 1 SV = 3 
               
               
                   
               
            
           
         
       
     
     INDUSTRIAL APPLICABILITY 
     The present disclosure proved that by measuring the concentration of a type V collagen MMP degradation product or the abundance of at least one marker selected from the group consisting of the markers shown in Table 1A, the markers shown in Table 2A, the markers shown in Table 1B, the markers shown in Table 2B, the markers shown in Table 5A, and the markers shown in Table 6A, the markers shown in Table 5B, and the markers shown in Table 6B in a sample obtained from a subject, whether or not the subject is affected by endometriosis can be diagnosed. The invention of the present disclosure allows for the diagnosis of endometriosis by non-invasive means and is highly useful in the diagnosis and treatment of the disease.