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ISSN : 1225-1577(Print)
ISSN : 2384-0900(Online)
The Korean Journal of Oral and Maxillofacial Pathology Vol.46 No.2 pp.25-34
DOI : https://doi.org/10.17779/KAOMP.2022.46.2.002

Association between Catechol-O-Methyltransferase Gene (rs4680) and Fibromyalgia: Updated Meta-Analysis

Gung Hyun Chun1,3), Ju Yeon Ban2), Chong Heon Lee1,3)*
1)Department of Oral Pathology, , Dankook University
2)Department of Dental Pharmacology, Dankook University
3)College of Dentistry, Oral Aging Research Center, Dankook University
*Correspondence: Chong Heon Lee, Department of Oral Pathology, Dental College, Dankook University, Aseodong San 29, Cheonan, Chungnam, 330-714, Korea. Tel: +82-82-41-550-1946 Email: chleeop@naver.com
March 13, 2022 March 25, 2022 April 1, 2022

Abstract


The association between the COMT rs4680 (G>A, Val-158-Met) polymorphism and the risk of fibromyalgia has been investigated in previous studies, but the results are controversial. Therefore, a meta-analysis has been performed to confirm the association between COMT rs4680 (G>A, Val-158-Met) polymorphism and the risk of fibromyalgia in this study. Our study includes eleven case-control studies with 2,909 individuals comprised of 1,365 fibromyalgia patients and 1,544 control subjects. The regression analysis was performed using the random effects model or the fixed effects model and OR with the corresponding 95 % CI was calculated for the allele, recessive, dominant, over-dominant, co-dominant 1, and co-dominant 2 model. No statistical significant associations were observed between COMT rs4680 (G>A, Val-158-Met) polymorphism and risk of fibromyalgia in allele model (P-value = 1.00), recessive model (P-value = 1.00), dominant model (P-value = 0.54), co-dominant 1 model (P-value = 1.00) and co-dominant 2 model (P-value = 1.00). In conclusion, our meta-analysis showed that the COMT rs4680(G>A, Val-158-Met) polymorphism might not be genetic risk factor for the fibromyalgia.


Catechol-O-Methyltransferase Gene(rs4680) , Fibromyalgia

카테콜-O-메틸트랜스퍼아제 유전자(rs4680)와 섬유근육통 사이에 연관성: 최신 메타분석

천 정현1,3), 반 주연2), 이 종헌1,3)*
1)단국대학교 치과대학 구강병리학교실
2)단국대학교 치과대학 치과약리학교실
3)단국대학교 치과대학 구강노화연구소

초록

    Ⅰ. INTRODUCTION

    Fibromyalgia is a disease with symptoms of musculoskeletal pain that can accompany with fatigue, sleep disorders, migraines, emotional problems such as anxiety and depression, and so on1). According to previous studies, it is a common disease with an incidence rate of 1.5 to 3.2%, and most of them occur in female2). Fibromyalgia greatly reduces the quality of life of patients and increase sthe economic burden on society3).The cause of fibromyalgia is uncertain. However, it is presumed that the possible cause is that continuous nerve stimulation causes changes in the brain and spinal cord, which is thought to be caused by abnormal changes in chemical substances. This seems to make them more sensitive to stimul it hat do not cause pain or tomin or pains. Factors affecting fibromyalgia include infection, physical or emotional stress4). A previous study reported that emotional stress such as depression and anxiety have a relationship with the development of fibromyalgia5). A family history of fibromyalgia has also been reported, which suggests that genetic factors may be associated with susceptibility to the disease6).

    There have been many studies to determine the cause of fibromyalgia. Among them, there were many previous studies related to genetic factors. Interleukin-4 70 bp VNTR variations were associated with susceptibility of development of fibromyalgia in Turkish.7) A study in Korean reported that transient receptor potential cation channel 2 and transient receptor potential cation channel 3 were related to the symptoms and development of fibromyalgia8). Brain-derived neurotrophic factor is related to the development and symptom of fibromyalgia9). Serotonin is an important neurotransmitter in the central nerve system, and its abnormalities are known to be associated with the development of fibromyalgia, but T102C polymorphism of the gene was not associated with fibromyalgia10). The genotype of the dopamine D4 receptor gene was associated with novelty seeking and the occurrence of fibromyalgia. This suggests that not only serotonergic but also dopaminergic neurotransmitter pathways are involved in the development of fibromyalgia 11).

    Catecholamine includes a monoamine-based neurotransmitter or hormone derived from catechol. Catecholamines are secreted from nerve cells and act as neurotransmitters. It also acts as a hormone, and when the sympathetic nervous system is excited by stress, it is released into the blood to induce the body's fight-or-flight response12). Catecholamines are metabolized by two pathways: monoamine oxidase and COMT13). Abnormal catecholamine metabolism causes excessive catecholamine activity and causes diseases such as myocardial ischemia, diabetic cardiomyopathy, postural tachycardia syndrome, and soon14-16).

    COMT is an enzyme discovered by Axelrod in 195717). COMT in activates catecholamines(such as dopamine, epinephrine and norepinephrine), catechol estrogens, various drugs and substances having a catechol structure. Dysfunction of COMT is reported to be associated with the development of various diseases such as schizophrenia, Parkinson's disease, preeclampsia and so on18-20).

    The COMT gene is located in region 22q11.1 to 22q11.2. Among the single-nucleotide polymorphisms (SNP) of COMT, rs4680 is one of the most studied SNPs, and it is a missense mutation occurring at codon 158. This SNP converts guanine (G) to adenine (A), which in turn converts valine (Val) to methionine (Met). The SNP is known to affect the function of enzymes21). It was reported that the A genotype is frequently found in patients with fibromyalgia 22).

    The aim of this study was to evaluate and review the association of the COMT rs4680 (G>A, Val-158-Met) polymorphism and fibromyalgia.

    Ⅱ. MATERIALS and METHODS

    1. Search Strategy

    To collect eligible studies about the COMT rs4680 (G>A, Val-158-Met) polymorphism and fibromyalgia, studies up to July 2021 in Pubmed and google scholar were mined. We searched meta-analysis study about the COMT rs4680 (G>A, Val-158-Met) polymorphism and the case-control association study between the COMT rs4680 SNP (G>A, Val-158-Met) polymorphism and fibromyalgia. The keywords, “Catechol-O-methyltransferase”, or “COMT“, AND “polymorphism”, “polymorphisms”, or “variant” AND “Val-158-Met”, or “rs4680” AND “fibromyalgia”, or “meta analysis” were used to find these studies.

    2. Inclusion Criteria and Data Extraction

    The criteria for judging eligible studies for including in this meta-analysis were as follows; First, case-control study between the COMT rs4680 (G>A, Val-158-Met) polymorphism and fibromyalgia; Second, genotype and allele distributions of COMT rs4680 (G>A, Val-158-Met) polymorphism for genetic analysis were included. We mined the data about first author’s name, year of publication, ethnicity of studied population, sample size of fibromyalgia and control, and allele and genotype frequencies of the COMT rs4680 polymorphism in fibromyalgia and control from the final selected studies.

    3. Statistical analysis

    Hardy-Weinberg equilibrium (HWE) was calculated using the chi-square test in all include studies. The Comprehensive Meta-analysis software was used for meta-analysis. Egger’s test was performed for publication bias. A χ2-test-based Q statistic test and I2 test were performed to assess heterogeneity. When the result of the Q test was p < 0.05 or I2 statistic was >50 %, the random- effects model was adopted, if not, the fixed-effects model. The regression analysis was performed using the random effects model or the fixed effects model. OR with the corresponding 95 % CI was calculated for the allele model (A allele versus. G allele), recessive model (AA genotype versus AG genotype and GG genotypes), dominant model (AA genotype and CG genotypes versus GG genotype), co-dominant1 model (AA genotype versus GG genotype), and co-dominant2 model (AG genotype versus GG genotype), respectively. The adjusted p lower than 0.05 was regarded as statistically significant. To confirm the effect of each paper on the final results, sensitivity analysis was performed in all studies.

    Ⅲ. RESULTS

    1. Characteristics of Eligible Studies

    In present study, we performed the meta-analysis to assess relationship between the COMT rs4680 (G>A, Val-158-Met) polymorphism and fibromyalgia. Genetic data for the COMT rs4680 (G>A, Val-158-Met) polymorphism and fibromyalgia were retrieved and collected from electronic database, and analyzed. Finally, a total of 11 genetic studies about the COMT rs4680 (G>A, Val-158-Met) polymorphism and fibromyalgia were analyzed for meta-analysis22-31). A total 2, 909 individuals comprised of 1,365 fibromyalgia patients and 1,544 control subjects. Table 1 shows the characteristics and genetic data of eligible studies. Among 11 studies, thes tudies of Garcia-Fructuosoetal(2006), Tanderetal (2008), Barbosa(2012) and Martinez-Jauand(2013) deviate from HWE(P-value lower than 0.05). Therefore, they were excluded from meta-analysis.

    2. Heterogeneity and Model Selection

    Heterogeneity was assessed in allele model, recessive model, dominant model, co-dominant 1 model, and co-dominant 2 model, and heterogeneity was more than 50% in all models; 68.0% in I2 statistic value of allele model, 65.0% in I2 statistic value of recessive model, 55.0% in I2 statistic value of dominant model, 60.0% in I2 statistic value of codominant 1 model, and 70.0% in I2 statistic value of codominant 2 model (Figure 2). Therefore, the random effects model was adopted for all model analyses.

    3. No Publication Bias between Eligible Studies

    In figure 1, forest plot shows that there is no publication bias in all models. The p-value of Egger's test is p = 0.7034 in the allele model, 0.7162 in recessive model, 0.3067 in dominant model, 0.4402 in co-dominant 1 model, and 0.7997 in co-dominant 2 model. These results imply that there was no publication bias among these studies.

    4. No Association between COMT rs4680 (G>A, Val-158-Met) Polymorphism and Fibromyalgia

    However, we did not find any significant results in the regression analysis. No statistical significant associations were observed between COMT rs4680 (G>A, Val-158-Met) polymorphism and risk of fibromyalgia in allele model (OR=1.18, 95% CI=0.91-1.56, adjusted P-value = 1.00), recessive model (OR=1.11, 95% CI=0.71-1.74, adjusted P-value = 1.00), dominant model (OR=1.32, 95% CI=0.90-1.95, adjusted P-value = 1.00), co-dominant 1 model (OR=1.00, 95% CI=0.64-1.56, adjusted P-value = 1.00) and co-dominant 2 model (OR=1.27, 95% CI=0.68-2.38, adjusted P-value = 1.00). These results suggest that COMT rs4680 (G>A, Val-158-Met) polymorphism might not be related to the development of fibromyalgia.

    Ⅳ. DISCUSSION

    In patients with fibromyalgia, a change in the pain threshold is observed, and the sensitivity to heat, cold, and pressure increases32). Patients with fibromyalgia experience pain even with stimuli that are not felt by normal healthy people. This process is related to noradrenergic transmission in the central nervous system, and central pain processing is disordered. It is also known that such pain hypersensitivity is related to central augmentation of sensory input33). Abnormalities in the pain inhibition pathway could cause fibromyalgia. Neurotransmitters such as norepinephrine and serotonin activate pain related fibers which can inhibit the transmission of sensory input to the brain34). However, decreased levels of the seneurotransmitters are observed in patients with fibromyalgia35). In patients with fibromyalgia, not only sympathetic hyporeactivity but also sympathetic hyperactivity is observed. Pain was reduced by sympathetic blockage and reoccurred by injection of norepinephrine 36).The main neurotransmitters that act on the sympathetic nerve has a catecholamine, such as epinephrine, norepinephrine and dopamine37).

    Catecholamine can induce sympathetically maintained pain by activating nociceptive nerve endings38). There are many reports supporting the association between catecholamine and pain. An association between increased catecholamine and Exaggerated NE responses and increased heart rate in patients with fibromyalgia has been reported39). Pindolol, a β-adrenergic receptor antagonist, was effective in the treatment of fibromyalgia40).COMT is an enzyme that inactivates catecholamines. The COMT genotype is related to pain, and the pain sensitivity differs according to the COMT haplotype41). The most well-known SNP in COMT is rs4680, which changes G to A and the amino acid Val to Met..21) Therefore, there have been many studies on this SNP and pain. Individuals with Met/Met had reduced regional mu-opioid system responses to pain and were more sensitive to pain than individuals with Val/Val42).

    According to the ACTTION-APS Pain Taxonomy, COMT polymorphism may or may not be associated with fibromyalgia 43). Therefore, we performed a meta-analysis and found a lack of association between the polymorphism of COMT and the occurrence of fibromyalgia.

    In the present study, we have performed meta-analysis for five previous studies to investigate the relationship between COMT rs4680(G>A, Val-158-Met) polymorphism and the risk of fibromyalgia. Our study includes eleven case-control studies with 2,909 individuals comprised of 1,365 fibromyalgia patients and 1,544 control subjects. There was no publication bias in the included studies, and sensitivity analysis did not find any evidence that each study affected the final results. However, our meta-analysis failed to show an association between COMT rs4680(G>A, Val-158-Met) polymorphism and the risk of fibromyalgia. No statistical significance was observed in any analysis model (P > 0.05). Our results suggest that COMT rs4680 (G>A, Val-158-Met) polymorphism is not associated with the development of fibromyalgia.

    Our study has tried to determine whether there is an association between COMT rs4680(G>A, Val-158-Met) polymorphism and the risk of fibromyalgia.; however, our study has limitations. We could not investigate the various ethnic distributions because most of the studies were conducted in Caucasians, and only one study was conducted in Asians. In addition, fibromyalgia is a disease with a very complex pathophysiology and multifactorial, and catecholamine-related sympathetic hyporeactivity and sympathetic hyperactivity occur simultaneously. However, in this meta-analysis, only the effect of the gene, the polymorphism of COMT rs4680 (G>A, Val-158-Met) was considered.

    Ⅴ. CONCLUSION

    In this study, we performed a meta-analysis to clarify the association between the COMT rs4680 (G>A, Val-158-Met) polymorphism and the development of fibromyalgia. Despite some limitations, we have shown here that the COMT rs4680 (G>A, Val-158-Met) polymorphism might not be associated with the development of fibromyalgia. If further studies in more ethnicities might be made, the relationship between the COMT rs4680 (G>A, Val-158-Met) polymorphism and the development of fibromyalgia would be clarified. And that would improve our knowledge for pathogenesis of fibromyalgia, clinical prognosis and treatment.

    Figure

    KAOMP-46-2-25_F1.gif

    Publication bias in genetic models between COMT polymorphism [G>A, Val-158-Met (rs4680)] and susceptibility of fibromyalgia; A: Allele model (A allele versus G allele), B: Recessive model (AA genotype versus AG genotype and GG genotype), C: Dominant model (AA genotype and AG genotype versus GG genotype), D: Co-Dominant 1 model (AA genotype versus GG genotype) and E: Co-Dominant 2 model (AG genotype versus GG genotype).

    KAOMP-46-2-25_F2.gif

    Forest plots in genetic models between COMT polymorphism [G>A, Val-158-Met (rs4680)] and susceptibility of fibromyalgia; A: Allele model (A allele versus G allele), B: Recessive model (AA genotype versus AG genotype and GG genotype), C: Dominant model (AA genotype and AG genotype versus GG genotype), D: Co-Dominant 1 model (AA genotype versus GG genotype) and E: Co-Dominant 2 model (AG genotype versus GG genotype).

    Table

    Characteristics of eligible studies included in the meta-analysis

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