Estrogen Receptor 1 Gene Polymorphism Frequency in Fibromyalgia Syndrome
Condition: Fibromyalgia
MeSH terms: Fibromyalgia; Myofascial Pain Syndromes
Study type: Observational

Summary: 
      Fibromyalgia Syndrome (FMS) is a chronic musculoskeletal disorder accompanied by diffuse body
      pain, increased fatigue and tenderness in specific anatomical regions, and sleep disturbance.
      The higher prevalence of FMS in women and the observation of it from young adulthood suggest
      the effect of sex hormones on the pathophysiology of this condition. Steroid hormones,
      especially estrogen, have effects on both the peripheral and central nervous system receptors
      (estrogen receptor-a [ERa] and estrogen receptor-b [ERb]), on the inflammatory process, and
      on central pain delivery. However, the mechanism of action of these hormonal effects is still
      unknown and is a matter of debate.

      The fact that fibromyalgia syndrome and migraine are more common in women of reproductive age
      and their incidence is higher than other populations suggests that these two diseases may
      have a common genetic basis. Previous studies have shown that ESR-1 594G> A (rs2228480),
      ESR-1 325C> G (rs2295190) polymorphisms significantly increase the risk of migraine
      occurrence. However, there are no studies investigating these polymorphisms in FMS. In this
      study, it was aimed to investigate whether there is a relationship between ESR-1 594G> A
      (rs2228480) and ESR-1 325C> G (rs2295190) polymorphisms and fibromyalgia disease.
    

Detailed description: 
      Objective: The fact that fibromyalgia and migraine are more common in women of reproductive
      age and their incidence are higher than other populations suggests that these three diseases
      may have a common genetic basis. Therefore, we aimed to investigate whether there is a
      relationship between ESR-1 594G> A (rs2228480), ESR-1 325C> G (rs2295190) polymorphisms and
      fibromyalgia disease.

      Introduction: Fibromyalgia syndrome (FMS), diffuse body pain, chronic musculoskeletal disease
      with increased fatigue and tenderness and sleep disorder in specific anatomical regions . The
      FMS diagnosis is based on American College of Rheumatology(ACR) 1990 classification criteria.
      FM frequently affects women between 30 and 50 years of age and its prevalence is between 1%
      and 4% of the whole population, 0-4% in men and 2.5-10.5% in women. Researchers have found
      that the strong familial tendency in FM has a risk of developing FM in first-degree relatives
      of patients with FM, 8 times more than in the general population. Family members of FM
      patients are more susceptible to pain and are more likely to develop conditions such as
      irritable bowel syndrome (IBS), temporomandibular disorder (TMD), headache-migraine, restless
      leg syndrome, and other regional pain syndromes . Several studies have been conducted to
      demonstrate specific genetic polymorphism in FM. To date, polymorphisms in the serotonin
      receptor, serotonin transporter, dopamine D4 receptor and catechol-O-methyltransferase genes
      have been found to be high . All these identified polymorphisms are responsible for the
      metabolism and transport of monoamines; These are compounds that play a critical role in the
      human stress response.

      The more frequent occurrence of FMS in women is observed in young adults, indicating the
      effect of sex hormones on the pathophysiology of this condition. However, the mechanism of
      action of these hormonal effects is still unknown and is a matter of debate. Steroid
      hormones, in particular estrogen, affect both peripheral and central nervous system (CNS)
      receptors (Estrogen Receptor-1; estrogen receptor-a [Era] and Estrogen Receptor-2;estrogen
      receptor-b [ERb]), the inflammatory process and the transmission of central pain. For
      example, estrogen may directly affect monocytes and macrophages to regulate the production of
      cytokines (eg, Interleukin-1 [IL-1], IL-6 and tumor necrosis factor-a [TNF-a]).

      Migraine is a neurological disorder characterized by episodes of hemicranial pain
      characterized by attacks. one-year prevalence of migraine in the general population in Turkey
      16.4%, while the proportion of patients with FM were significantly lower (9). The incidence
      of headache increased in patients with fibromyalgia syndrome. Migraine and non-migraine
      headaches have been reported in patients with FM between 28% and 58% . Similarly, in a study
      conducted on 33 FM patients, the current migraine was present at 45% and the lifetime
      migraine history was 55% . The prevalence of migraine has been reported to be approximately
      2-fold (reproductive period) and the severity of migraine attacks in women compared to men .
      Studies investigating the relationship between sex hormone levels and polymorphisms due to
      more frequent reproductive states have shown that they are associated with estrogen
      receptor-alpha (ERa 594G> A (rs2228480), ERa 325C> G (rs2295190) polymorphisms.

      Methods: Establishment of study groups: 100 patients diagnosed as Fibromyalgia syndrome
      according to the criteria of ACR 1990, 18-65 years old, and having similar sociodemographic
      characteristics. 100 control patients will be taken. As the inclusion criteria for the
      patients; Being between 18 and 60 years of age, taking the diagnosis of primary FMS according
      to ACR 1990 diagnostic criteria, accepting to participate in the study, lack of any sex
      hormone disease. The control group will be composed of volunteers with similar age and gender
      characteristics. The volunteers taken into the control group will have no sex hormone. The
      participants will be informed about the subject before being taken into the study and the
      necessary permits will be taken.

      Semi-structured sociodemographic information form prepared by us will be used in accordance
      with the clinical experience and the information obtained from the scanned sources and the
      aims of the study (ANNEX-1) Age, gender, education level, marital status, BMI, family history
      of fibromyalgia diseases and accompanying symptoms. Accompanied by the symptoms; TMD symptoms
      such as migraine type headache, jaw pain and locking, sleep disorder, dry mouth, dry eyes,
      irritable bowel symptoms, restless leg symptoms, soft tissue swelling, fatigue, depressive
      symptoms or depression history will be questioned. Patients with headache will be evaluated
      by a neurologist in terms of the diagnosis of migraine. Pain evaluation of the cases will be
      done by Visual Analog Scale (VAS). A 10 cm ruler will be used for this. Patients will be
      evaluated once and the appropriate amount of blood samples will be collected from the
      patients after the evaluation.

      Collection of Blood Samples: 5 mL blood samples from the control and patient groups will be
      taken into sterile, citrate tubes. The blood in the tubes will be stored at -80 ° C until
      isolation of the DNA.

      Isolation of Genomic DNA: Genomic DNA will be isolated from the blood using a DNA isolation
      kit. DNA purity will be determined by spectrophotometric method.

      Genotyping: Genotyping of ESR-1 325 C> G and 594 G> A polymorphisms in the study group will
      be performed by using single nucleotide polymorphism analysis kit and sequence-specific
      double-dye hydrolysis probes and allelic segregation analysis in real-time polimerase chain
      reaction (RT-PCR) using primers. Genotyping of each patient and control will be repeated 3
      times to ensure the reliability of the analysis results.

      Statistical methods: The number of individuals to be included in the study was determined by
      Statistical Power Analysis. In this study, when α = 0.05, β = 0.10, 1- β = 0.90, it was
      decided to take 100 individuals to each patient and control groups, and the strength of the
      test was found to be p = 0.9072. All data obtained from the study will be evaluated with SPSS
      18 program. The χ2 test and Student-t and Mann-Whitney tests will be used to evaluate the
      suitability of nominal and continuous variables.
    

Intervention name(s): ACR 1990 fibromyalgia critters
Intervention type(s): Diagnostic Test
Intervention description(s): ACR 1990 fibromyalgia critters
Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        Fibromyalgia: 100 person, Control: 100 person.
      
Biospecimen description: 
      Estrogen receptor alpha polymorphism
    
Keywords: Fibromyalgia; Migraine; estrogen receptor alpha; polymorphism