Abstract:
A method and system for classifying subject populations utilizing predictive and diagnostic biomarkers for type I diabetes mellitus. The method including determining the levels of a variety of markers within the serum or plasma of a target organism and correlating this level to general populations as a screen for predisposition or progressive monitoring of disease presence or predisposition.

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application claims priority from Provisional application No. 60/985,333 filed 5 Nov. 2007, incorporated herein in its entirety. 
    
    
     STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY-SPONSORED RESEARCH AND DEVELOPMENT 
     This invention was made with Government support under Contract DE-AC0576RLO1830 awarded by the U.S. Department of Energy, as well as NIH grant DK070146. The Government has certain rights in the invention. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention generally relates to methods and systems for the screening and detection of disease and more particularly to methods and systems for the screening and detection of persons at risk for developing type I diabetes mellitus. 
     2. Background of the Invention 
     Diabetes mellitus is a life changing disease that affects millions of persons. While the disease may be clinically diagnosed and confirmed fairly easily in some cases, earlier detection may lead to the possibility of intervention(s) that would alter or lessen the onset of clinical symptoms or allow other forms of preventative care to be undertaken. Currently, one of the best approaches for predicting who may be at risk for developing diabetes before the onset of clinical symptoms is the measurement of autoantibodies to islet cell antigens. However, for the major autoantibodies predictive of type 1 diabetes, the sensitivities for these antibodies varies considerably. While progress has been made to improve the accuracy and reproducibility of the measurement of islet cell autoantibodies, surrogate biomarkers predictive of those at high risk for developing type 1 diabetes would benefit the clinical community, particularly if such surrogate biomarkers result in higher sensitivity and specificity. 
     Accordingly what is needed is a method and system of screening for persons with increased risk of developing diabetes mellitus that utilizes candidate biomarkers allowing for broad based, reliable screening of large population bases. In addition, effective strategies for characterizing, archiving, and contrasting data from multiple sample types under varying conditions (e.g. control versus disease) are also needed. 
     Additional advantages and novel features of the present invention will be set forth as follows and will be readily apparent from the descriptions and demonstrations set forth herein. Accordingly, the following descriptions of the present invention should be seen as illustrative of the invention and not as limiting in any way. 
     SUMMARY OF THE INVENTION 
     The present application describes novel methods and systems for classifying subject populations and discovering predictive and diagnostic biomarkers for diabetes mellitus. In preliminary studies a variety of markers including alpha-2-glycoprotein 1 (zinc), corticosteroid-binding globulin, and lumican demonstrated serum/plasma concentrations that were 2-fold up-regulated in type 1 diabetic samples relative to nondiabetic control samples, whereas clusterin and serotransferrin were 2-fold up-regulated in control samples relative to type 1 diabetic samples. The observed perturbations in the levels of all five proteins are consistent with the metabolic aberrations found in type 1 diabetes. A complete set of markers that also demonstrated promise in are attached hereto as Appendix 1. 
     The method and system described herein for identifying populations and individuals who may be predisposed to the later development of type I diabetes mellitus includes the steps of obtaining a sample of serum or blood plasma from an individual, this sample having a total mixture of serum or plasma constituents, analyzing the serum or blood plasma to determine the quantity of at least one serum constituent selected from the group described in appendix 1 and comparing the quantity of the at least one serum constituent to a standardized range of levels for this constituent to determine whether the level of the serum constituent when compared to the normal range is indicative of a predisposition for type I diabetes mellitus. A system for performing the method of the present invention is made up of the requisite pieces and parts that would allow such a method to be performed. A flow chart of the general method is shown in  FIG. 1 . 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  shows a flow chart of the general method of the present invention 
     
    
    
     DETAILED DESCRIPTION 
     In one embodiment of the present invention, the method for determining whether a persons has an increased risk of developing diabetes mellitus involves the steps of obtaining plasma or serum from an individual and then testing this plasma or serum for the presence of at least of the following serum constituent biomarkers: alpha-2-glycoprotein 1 (zinc), corticosteroid-binding globulin, lumican, clusterin and serotransferrin present in said sample. The results of this test are then compared to a standardized range to determine whether the level of the particular serum constituent is within a preselected range indicative of type I diabetes mellitus. 
     The following description of one set of experiments related to one embodiment of the present invention provides a description related to particular experiments that demonstrate the application of the present invention, and the identification of the bio markers described above. While the following description is provided, it is to be distinctly understood that the invention is not limited thereto but may be variously embodied according to the needs and necessities of the user. 
     To identify candidate biomarkers, a label-free quantitation strategy based on LC-FTICR analyses of individual samples from control and patient subjects was utilized. Peptides, and later proteins, were identified by matching detected LC-FTICR features to the plasma AMT tag database using the AMT tag approach. In this study, 9116±710 (mean±standard deviation) features from 59 LC-FTICR datasets (one dataset for control individual 5 was excluded as an outlier, see below) were matched to 1517±199 AMT tags, representing ˜16% of data identified. A total of 1930 unique peptides were identified during this quantitative study, corresponding to 120 unique proteins (≧2 unique peptides per protein), based on stringent filtering. The total number of unique peptide identifications across all 20 individuals was also quite consistent given the expected biological variations between samples. Following the application of statistical t-test at the protein level, 30 out of a total 120 proteins were shown to have significant abundance differences (p&lt;0.05) between control and patient individuals. These proteins were further examined at the peptide level where we required the average peptide p-value to be &lt;0.1. Nine proteins showing statistically significant abundance differences based on both the peptide- and protein-level t-tests were identified. Of these 9 proteins, only 5 were identified with ≧2 unique peptides in at least 8 of 10 control and patient individuals; therefore, emphasis will be placed on alpha-2-glycoprotein 1 (zinc), clusterin (apolipoprotein J), corticosteroid-binding globulin, lumican, and serotransferrin. 
     Alpha-2-glycoprotein 1 (zinc). Relative levels of alpha-2-glycoprotein 1 (zinc) were determined in all individuals using three unique peptides. This protein was consistently up-regulated in patient samples versus controls; however, control individuals 2 and 3 exhibited relatively higher levels compared to the other eight control individuals. Alpha-2-glycoprotein 1 (zinc) is a member of the immunoglobulin superfamily and displays lipid mobilization activity. The patient samples collected as part of the DASP study correspond to recently diagnosed individuals, several of whom may have been ketotic; therefore, increased levels of alpha-2-glycoprotein 1 (zinc) in patient relative to control samples may be an indication of a system-wide mobilization of fats for energy production. Indeed, the patient samples were suspected to be hyperlipidemic relative to control samples during sample preparation for proteomic analysis, based on observed opaqueness and increased viscosity (also possibly due to hyperglycemia) of the plasma and serum. In addition, several isoforms of alpha-2-glycoprotein 1 (zinc) have been shown to exist in human plasma and human serum, leaving open the possibility of genetic differences in the expression or isoforms of this protein in patients relative to controls. 
     Clusterin. Fourteen unique peptides were used to determine relative levels of clusterin in patient and control samples, although detection of peptides was variable among individuals. Clusterin, or apolipoprotein J, demonstrates a nearly ubiquitous tissue distribution and is produced in two immunologically distinct forms by alternative splicing. A glycosylated form is secreted and displays cytoprotective effects, whereas a non-glycosylated, cytoplasmic/nuclear form displays apoptotic properties. In this study, 7 control individuals exhibited relatively high levels of clusterin, whereas 5 patients exhibited relatively low levels of this protein. It is possible that low levels of clusterin in patient samples indicate poor cytoprotective capability, which may facilitate autoimmune destruction of pancreatic beta cells leading to development of type 1 diabetes mellitus. 
     Corticosteroid-binding globulin. Relative levels of corticosteroid-binding globulin were determined in control and patient individuals using up to three unique peptides (at least 2 unique peptides mapping to this protein were detected in all individuals). This protein was consistently up-regulated in patient samples versus controls; however, control individuals 2 and 9 exhibited relatively higher levels compared to the other eight control individuals. Insulin and insulin-like growth factor I have been reported to inhibit secretion of corticosteroid-binding globulin by a human hepatoma cell line, and plasma corticosteroid-binding globulin was recently shown to correlate positively with fasting glucose and hemoglobin A1c but negatively with insulin response to intravenous and oral glucose administration in obese individuals with glucose intolerance. In the current study, the observation of relatively high levels of corticosteroid-binding globulin in patients relative to controls likely reflects the absence or lower circulating levels of insulin in the plasma and serum of patients. 
     Lumican. Up to nine unique peptides were used to determine relative levels of lumican in patient and control samples, although detection of peptides was variable among individuals. This protein was consistently and strongly up-regulated in patient samples versus controls, with the exception of patients 1 (no up-regulation), 7, and 8 (moderate up-regulation). In addition, the LC-MS/MS data for this protein, while semi-quantitative, strongly support these results. Lumican is a member of the small leucine-rich proteoglycan family and is a component of the extracellular matrix (ECM) and binding partner of TGF-β, a key mediator of fibrotic diseases. This protein was reported to be expressed in the cornea, dermis, cartilage, heart, lung, and kidney of developing mouse embryos, thus it is difficult to speculate on the specific tissue source of plasma/serum lumican in patient samples. However, lumican has been shown to be up-regulated in the tubulointerstitium and glomeruli of diabetic patients with nephropathy. In addition, lumican (as well as other proteoglycans) has been reported to be up-regulated in kidneys of rats experiencing unilateral ureteral obstruction. These studies suggest that increased thickening of the ECM and possibly glomerulosclerosis may be accompanied by up-regulation of select proteoglycans, including lumican. Because the samples involved in the DASP study are from recently diagnosed patients, it is difficult to estimate the degree to which plasma hyperglycemia affects the morphology and function of the kidney. However, it is possible that increased plasma lumican in patient samples reflects an acute response of the kidney to high levels of plasma glucose. 
     Serotransferrin. Relative levels of serotransferrin were determined in control and patient individuals using up to twenty-nine unique peptides, although detection of these peptides was highly variable among individuals. This protein was strongly up-regulated in four control individuals and moderately up-regulated in six control individuals relative to patients. In addition, the LC-MS/MS data for this protein, while semi-quantitative, strongly support these results. Increased urinary transferrin excretion rates have been reported in type 1 diabetic patients with normal urinary albumin excretion rates, suggesting that transferrin might be released preferentially from the diabetic kidney leading to lower levels in plasma. Indeed, van Campenhout and colleagues found lower levels of transferrin and total iron-binding capacity in serum of type 1 diabetic subjects relative to controls. 
     Five candidate protein biomarkers for type 1 diabetes have been identified. It is believed that serum or plasma testing for any or all of these five proteins discussed may serve as a predictive or diagnostic screen or test for type 1 diabetes. 
     The purpose of the foregoing abstract is to enable the United States Patent and Trademark Office and the public generally, especially the scientists, engineers, and practitioners in the art who are not familiar with patent or legal terms or phraseology, to determine quickly from a cursory inspection the nature and essence of the technical disclosure of the application. The abstract is neither intended to define the invention of the application, which is measured by the claims, nor is it intended to be limiting as to the scope of the invention in any way. 
     Various advantages and novel features of the present invention are described herein and will become further readily apparent to those skilled in this art. As will be realized, the invention is capable of modification in various respects without departing from the invention. While various preferred embodiments of the invention are shown and described, it is to be distinctly understood that this invention is not limited thereto but may be variously embodied to practice within the scope of the following claims. From the foregoing description, it will be apparent that various changes may be made without departing from the spirit and scope of the invention as defined by the following claims. 
     
       
         
               
               
               
             
           
               
                 APPENDIX 1 
               
               
                   
               
               
                 International 
                   
                   
               
               
                 Protein Index (IPI) 
                 Protein Description 
                 SEQ ID NOs: 
               
               
                   
               
             
             
               
                 IPI:IPI00879551.1 
                 12 kDa protein 
                 1 
               
               
                 IPI:IPI00790473.1 
                 12 kDa protein 
                 2-5 
               
               
                 IPI:IPI00879551.1 
                 12 kDa protein 
                  6-10 
               
               
                 IPI:IPI00642045.1 
                 14 kDa protein 
                 11-13 
               
               
                 IPI:IPI00879915.1 
                 15 kDa protein 
                 14-17 
               
               
                 IPI:IPI00879984.1 
                 16 kDa protein 
                 18-24 
               
               
                 IPI:IPI00879718.1 
                 17 kDa protein 
                 25-32 
               
               
                 IPI:IPI00877698.1 
                 18 kDa protein 
                 33-35 
               
               
                 IPI:IPI00879608.1 
                 19 kDa protein 
                 36-37 
               
               
                 IPI:IPI00793626.1 
                 22 kDa protein 
                 38-41 
               
               
                 IPI:IPI00796279.1 
                 25 kDa protein 
                 42-53 
               
               
                 IPI:IPI00791901.1 
                 26 kDa protein 
                 54-55 
               
               
                 IPI:IPI00879937.1 
                 28 kDa protein 
                 56-62 
               
               
                 IPI:IPI00795830.1 
                 29 kDa protein 
                 63-69 
               
               
                 IPI:IPI00795257.1 
                 32 kDa protein 
                 70-71 
               
               
                 IPI:IPI00749466.1 
                 35 kDa protein 
                 72-75 
               
               
                 IPI:IPI00788737.1 
                 39 kDa protein 
                 76-77 
               
               
                 IPI:IPI00795153.2 
                 43 kDa protein 
                 78-94 
               
               
                 IPI:IPI00793848.1 
                 54 kDa protein 
                  95-109 
               
               
                 IPI:IPI00798006.1 
                 7 kDa protein 
                 110-111 
               
               
                 IPI:IPI00871139.1 
                 92 kDa protein 
                 112-114 
               
               
                 IPI:IPI00019943.1 
                 Afamin precursor 
                 115-127 
               
               
                 IPI:IPI00550991.3 
                 Alpha-1-antichymotrypsin precursor 
                 128-152 
               
               
                 IPI:IPI00879231.1 
                 Alpha-2-antiplasmin precursor 
                 153-167 
               
               
                 IPI:IPI00166729.4 
                 alpha-2-glycoprotein 1; zinc 
                 168-181 
               
               
                 IPI:IPI00022431.1 
                 Alpha-2-HS-glycoprotein precursor 
                 182-192 
               
               
                 IPI:IPI00022229.1 
                 Apolipoprotein B-100 precursor 
                 193-194 
               
               
                 IPI:IPI00797309.1 
                 BCHE protein 
                 195-196 
               
               
                 IPI:IPI00064667.4 
                 Beta-Ala-His dipeptidase precursor 
                 197-205 
               
               
                 IPI:IPI00639937.1 
                 B-factor; properdin 
                 206-259 
               
               
                 IPI:IPI00385045.1 
                 C1 inhibitor mutant (Fragment) 
                 260-262 
               
               
                 IPI:IPI00418163.3 
                 C4B1 
                 263-365 
               
               
                 IPI:IPI00442286.1 
                 CDNA FLJ16195 fis; clone 
                 366-367 
               
               
                   
                 BRTHA3000296 
                   
               
               
                 IPI:IPI00871960.2 
                 cDNA FLJ75203; highly similar to  Homo   
                 368-370 
               
               
                   
                   sapiens  mannan-binding lectin serine 
                   
               
               
                   
                 protease 1 (C4/C2activating component 
                   
               
               
                   
                 of Ra-reactive factor) (MASP1); 
                   
               
               
                   
                 transcriptvariant 2; mRNA 
                   
               
               
                 IPI:IPI00879931.1 
                 cDNA FLJ78023; highly similar to  Homo   
                 371-387 
               
               
                   
                   sapiens  serine (or cysteine) proteinase 
                   
               
               
                   
                 inhibitor; clade G (C1inhibitor); member 1; 
                   
               
               
                   
                 (angioedema; hereditary) (SERPING1); 
                   
               
               
                   
                 mRNA 
                   
               
               
                 IPI:IPI00794070.1 
                 CFI protein 
                 388-404 
               
               
                 IPI:IPI00025864.5 
                 Cholinesterase precursor 
                 405-418 
               
               
                 IPI:IPI00795633.1 
                 CLU 
                 419-437 
               
               
                 IPI:IPI00400826.1 
                 clusterin isoform 1 
                 438-456 
               
               
                 IPI:IPI00291262.3 
                 Clusterin precursor 
                 457-481 
               
               
                 IPI:IPI00296176.2 
                 Coagulation factor IX precursor 
                 482-485 
               
               
                 IPI:IPI00296165.5 
                 Complement C1r subcomponent 
                 486-498 
               
               
                   
                 precursor 
                   
               
               
                 IPI:IPI00783987.2 
                 Complement C3 precursor (Fragment) 
                 499-542 
               
               
                 IPI:IPI00032258.4 
                 Complement C4-A precursor 
                 543-642 
               
               
                 IPI:IPI00654875.1 
                 Complement C4-B precursor 
                 643-742 
               
               
                 IPI:IPI00515098.1 
                 Complement component 2 (Fragment) 
                 743-747 
               
               
                 IPI:IPI00643525.1 
                 Complement component 4A 
                 748-850 
               
               
                 IPI:IPI00294395.1 
                 Complement component C8 beta chain 
                 851-877 
               
               
                   
                 precursor 
                   
               
               
                 IPI:IPI00165972.3 
                 Complement factor D preproprotein 
                 878-884 
               
               
                 IPI:IPI00299307.4 
                 Complement-activating component of Ra- 
                 885-887 
               
               
                   
                 reactive factor precursor 
                   
               
               
                 IPI:IPI00027482.1 
                 Corticosteroid-binding globulin precursor 
                 888-890 
               
               
                 IPI:IPI00642842.1 
                 C-reactive protein; pentraxin-related 
                 891-892 
               
               
                 IPI:IPI00333770.6 
                 dedicator of cytokinesis 10 
                 893-894 
               
               
                 IPI:IPI00645849.1 
                 Extracellular matrix protein 1 
                 895-907 
               
               
                 IPI:IPI00003351.2 
                 Extracellular matrix protein 1 precursor 
                 908-921 
               
               
                 IPI:IPI00743766.2 
                 Fetuin-B precursor 
                 922-933 
               
               
                 IPI:IPI00377087.4 
                 Gelsolin 
                 934-953 
               
               
                 IPI:IPI00789134.1 
                 Glyceraldehyde 3-phosphate 
                 954-955 
               
               
                   
                 dehydrogenase 
                   
               
               
                 IPI:IPI00219018.7 
                 Glyceraldehyde-3-pho 
                 956-957 
               
               
                 IPI:IPI00552199.3 
                 GUGU beta form 
                 958-967 
               
               
                 IPI:IPI00553061.1 
                 GUGU gamma form 
                 968-976 
               
               
                 IPI:IPI00879573.1 
                 Heparin cofactor 2 precursor 
                 977-982 
               
               
                 IPI:IPI00029193.1 
                 Hepatocyte growth factor activator 
                 983-986 
               
               
                   
                 precursor 
                   
               
               
                 IPI:IPI00292218.4 
                 Hepatocyte growth factor-like protein 
                 987-990 
               
               
                   
                 precursor 
                   
               
               
                 IPI:IPI00022371.1 
                 Histidine-rich glycoprotein precursor 
                  991-1008 
               
               
                 IPI:IPI00385264.1 
                 Ig mu heavy chain disease protein 
                 1009-1012 
               
               
                 IPI:IPI00477090.6 
                 IGHM protein 
                 1013-1014 
               
               
                 IPI:IPI00479708.5 
                 IGHM protein 
                 1015-1016 
               
               
                 IPI:IPI00549291.4 
                 IGHM protein 
                 1017-1018 
               
               
                 IPI:IPI00828205.1 
                 IGHM protein 
                 1019-1020 
               
               
                 IPI:IPI00883614.1 
                 IGHM protein 
                 1021-1022 
               
               
                 IPI:IPI00884141.1 
                 IGHM protein 
                 1023-1024 
               
               
                 IPI:IPI00884180.1 
                 IGHM protein 
                 1025-1026 
               
               
                 IPI:IPI00884293.1 
                 IGHM protein 
                 1027-1028 
               
               
                 IPI:IPI00884452.1 
                 IGHM protein 
                 1029-1030 
               
               
                 IPI:IPI00292530.1 
                 Inter-alpha-trypsin inhibitor heavy chain 
                 1031-1061 
               
               
                   
                 H1 precursor 
                   
               
               
                 IPI:IPI00847635.1 
                 Isoform 1 of Alpha-1-antichymotrypsin 
                 1062-1086 
               
               
                   
                 precursor 
                   
               
               
                 IPI:IPI00329775.7 
                 Isoform 1 of Carboxypeptidase B2 
                 1087-1099 
               
               
                   
                 precursor 
                   
               
               
                 IPI:IPI00019591.1 
                 Isoform 1 of Complement 
                 1100-1055 
               
               
                 IPI:IPI00029739.5 
                 Isoform 1 of Complement factor H 
                 1156-1225 
               
               
                   
                 precursor 
                   
               
               
                 IPI:IPI00022389.1 
                 Isoform 1 of C-reactive protein precursor 
                 1226-1227 
               
               
                 IPI:IPI00026314.1 
                 Isoform 1 of Gelsolin precursor 
                 1228-1246 
               
               
                 IPI:IPI00028413.8 
                 Isoform 1 of Inter-alpha-trypsin inhibitor 
                 1247-1262 
               
               
                   
                 heavy chain H3 precursor 
                   
               
               
                 IPI:IPI00163207.1 
                 Isoform 1 of N-acetylmuramoyl-L-alanine 
                 1263-1282 
               
               
                   
                 amidase precursor 
                   
               
               
                 IPI:IPI00293057.5 
                 Isoform 2 of Carboxypeptidase B2 
                 1283-1292 
               
               
                   
                 precursor 
                   
               
               
                 IPI:IPI00218999.2 
                 Isoform 2 of Complement factor H 
                 1293-1322 
               
               
                   
                 precursor 
                   
               
               
                 IPI:IPI00218876.3 
                 Isoform 2 of C-reactive protein precursor 
                 1323-1324 
               
               
                 IPI:IPI00375113.2 
                 Isoform 2 of Dedicator of cytokinesis 
                 1325-1326 
               
               
                   
                 protein 10 
                   
               
               
                 IPI:IPI00646773.2 
                 Isoform 2 of Gelsolin precursor 
                 1327-1344 
               
               
                 IPI:IPI00876950.1 
                 Isoform 2 of Inter-alpha-trypsin inhibitor 
                 1345-1360 
               
               
                   
                 heavy chain H3 precursor 
                   
               
               
                 IPI:IPI00394992.1 
                 Isoform 2 of N-acetylmuramoyl-L-alanine 
                 1361-1379 
               
               
                   
                 amidase precursor 
                   
               
               
                 IPI:IPI00020986.2 
                 Lumican precursor 
                 1380-1388 
               
               
                 IPI:IPI00290283.6 
                 mannan-binding lectin serine protease 1 
                 1389-1391 
               
               
                   
                 isoform 2 precursor 
                   
               
               
                 IPI:IPI00216882.4 
                 mannan-binding lectin serine protease 1 
                 1392-1394 
               
               
                   
                 isoform 3 
                   
               
               
                 IPI:IPI00006114.4 
                 Pigment epithelium-derived factor 
                 1395-1419 
               
               
                   
                 precursor 
                   
               
               
                 IPI:IPI00654888.4 
                 Plasma kallikrein precursor 
                 1420-1446 
               
               
                 IPI:IPI00291866.5 
                 Plasma protease C1 inhibitor precursor 
                 1447-1465 
               
               
                 IPI:IPI00156243.1 
                 Plasminogen-related protein A precursor 
                 1466-1468 
               
               
                 IPI:IPI00022445.1 
                 Platelet basic protein precursor 
                 1469-1473 
               
               
                 IPI:IPI00877925.1 
                 Pre-alpha 2-plasmin inhibitor 
                 1474-1480 
               
               
                 IPI:IPI00383338.1 
                 PRO2769 
                 1481-1492 
               
               
                 IPI:IPI00021364.1 
                 Properdin precursor 
                 1493-1497 
               
               
                 IPI:IPI00019568.1 
                 Prothrombin precursor (Fragment) 
                 1498-1530 
               
               
                 IPI:IPI00873401.1 
                 Putative uncharacterized protein 
                 1531-1533 
               
               
                   
                 DKFZp686101199 
                   
               
               
                 IPI:IPI00556459.1 
                 Serine/cysteine proteinase inhibitor clade 
                 1534-1547 
               
               
                   
                 G member 1 splice variant 2 (Fragment) 
                   
               
               
                 IPI:IPI00022463.1 
                 Serotransferrin precursor 
                 1548-1575 
               
               
                 IPI:IPI00292950.4 
                 Serpin peptidase inhibitor; clade D 
                 1576-1581 
               
               
                   
                 (Heparin cofactor); member 1 
                   
               
               
                 IPI:IPI00029863.4 
                 SERPINF2 protein 
                 1582-1596 
               
               
                 IPI:IPI00855916.1 
                 Transthyretin 
                 1597-1604 
               
               
                 IPI:IPI00022432.1 
                 Transthyretin precursor 
                 1605-1612 
               
               
                 IPI:IPI00871596.1 
                 Uncharacterized protein AZGP1 
                 1613-1618 
               
               
                   
                 (Fragment) 
                   
               
               
                 IPI:IPI00515041.5 
                 Uncharacterized protein CFH 
                 1619-1638 
               
               
                 IPI:IPI00871622.1 
                 Uncharacterized protein 
                 1639-1641 
               
               
                   
                 ENSP00000381161 
                   
               
               
                 IPI:IPI00873416.1 
                 Uncharacterized protein ITIH3 
                 1642-1657 
               
               
                 IPI:IPI00843913.2 
                 ZA protein 
                 1658-1661