Association of catechol-O-methyltransferase single nucleotide polymorphisms, ethnicity, and sex in a large cohort of fibromyalgia patients

Abstract

Background: Fibromyalgia (FM) is a complex, centralized pain condition that is often difficult to diagnose and treat. FM is considered to have a genetic background due to its familial aggregation and due to findings from multiple candidate-gene studies implicating catecholaminergic and serotonergic neurotransmitter systems in chronic pain. However, a multi-factorial analysis of both genetic and environmental risk factors is lacking. A better characterization of the interplay of risk factors may assist in understanding the pathophysiology of FM, its clinical course, and assist in early diagnosis and treatment of the disorder. Methods: This retrospective study included 60,367 total participants from 237 clinics across the USA. Of those, 2713 had been diagnosed with fibromyalgia, as indicated by ICD code. Logistic regression was used to test for associations of diagnosed FM in study subjects with COMT SNPs and COMT haplotypes, which were previously found to be linked with pain sensitivity, as well as demographics such as age, sex, and ethnicity. The minor allele frequencies of COMT SNPs in the FM population were compared with 1000 Genomes data using a χ2 test to determine significant deviations from the estimated population allelic frequencies. Results: FM diagnosis was strongly associated with sex, age, and ethnicity. Females, those between 49 and 63 years, and non-Caucasians were at higher risk of FM. Females had 1.72 increased odds of FM (p =1.17×10− 30). African-Americans were 1.52 times more likely to have a diagnosis of FM compared to Caucasians (p =3.11×10− 12). Hispanics were less likely to have a diagnosis of FM compared to Caucasians (p =3.95×10− 7). After adjusting for sex and ethnicity, those in the low age group and mid age group had 1.29 (p =1.02×10− 5) and 1.60 (p =1.93×10− 18) increased odds of FM, respectively, compared to the high age group, where age was categorized by tertile (low (< 49), mid (49–63), and high (> 63)). The COMT haplotypes associated with pain sensitivity were not associated with FM, but African-Americans were 11.3 times more likely to have a high pain sensitivity COMT diplotype, regardless of FM diagnosis. However, the minor alleles of COMT SNPs rs4680, rs4818, rs4633 and rs6269 were overrepresented in the FM population overall, and varied when compared with ethnically-similar populations from 1000 Genomes. Conclusions: This is the largest study, to date, that examines demographic and genetic associations of FM in a diverse population. While pain sensitivity-associated COMT haplotypes were not found to be directly associated with FM diagnosis, the minor alleles that make up the COMT haplotypes were overrepresented in the FM population, suggesting a role of COMT in FM. Future studies are needed to elucidate the exact role of COMT variation in widespread pain conditions, such as FM. Clinically, this information can be used to provide insight into the pathways underlying FM and to identify those at greater risk of developing FM.