Genetic variation in catechol‐O‐methyltransferase is associated with individual differences in conditioned pain modulation in healthy subjects

Abstract

Background Genetic variation in the catechol‐O‐methyltransferase (COMT) gene is associated with sensitivity to both acute experimental pain and chronic pain conditions. Four single nucleotide polymorphisms (SNPs) have traditionally been used to infer three common haplotypes designated as low, average and high pain sensitivity and are reported to affect both COMT enzymatic activity and pain sensitivity. One mechanism that may partly explain individual differences in sensitivity to pain is conditioned pain modulation (CPM). We hypothesized that variation in CPM may have a genetic basis. Methods We evaluated CPM in 77 healthy pain‐free Caucasian subjects by applying repeated mechanical stimuli to the dominant forearm using 26‐g von Frey filament as the test stimulus with immersion of the non‐dominant hand in hot water as the conditioning stimulus. We assayed COMT SNP genotypes by the TaqMan method using DNA extracted from saliva. Results SNP rs4680 (val158met) was not associated with individual differences in CPM. However, CPM was associated with COMT low pain sensitivity haplotypes under an additive model (p = 0.004) and the effect was independent of gender. Conclusions We show that, although four SNPs are used to infer COMT haplotypes, the low pain sensitivity haplotype is determined by SNP rs6269 (located in the 5′ regulatory region of COMT), suggesting that inherited variation in gene expression may underlie individual differences in pain modulation. Analysis of 13 global populations revealed that the COMT low pain sensitivity haplotype varies in frequency from 13% to 44% and showed that two SNPs are sufficient to distinguish all COMT haplotypes in most populations.

Concussion-Associated Gene Variant COMT rs4680 Is Associated With Elite Rugby Athlete Status

“…60 In addition, the Met allele has been associated with experiencing anxiety and pain sensitivity characteristics unfavorable for elite rugby competition in some studies 61,62 but not all. [63][64][65] For APOE e2/e3/e4, there were no differences in e4/e4 genotype or e4 allele frequency between elite rugby athletes and nonathletes (Table 1). Previous findings indicate that e4 allele carriers experience more severe cognitive and physical symptoms after TBI, [18][19][20] so we hypothesized that the e4 allele would be underrepresented in elite rugby athletes compared with nonathletes.…”

“…Optimal cognitive function is affected by the prefrontal cortex's (PFC) sensitivity to dopamine [54] This greater executive function and working memory of Met allele carriers is attributed to the effects of higher levels of extracellular dopamine in the PFC [41,42], although some differences between sexes might also exist [60]. In addition, the Met allele has been associated with experiencing anxiety and pain sensitivity characteristics unfavorable for elite rugby competition in some studies [61,62] but not all [63][64][65].…”

“…60 In addition, the Met allele has been associated with experiencing anxiety and pain sensitivity characteristics unfavorable for elite rugby competition in some studies 61,62 but not all. 63–65…”

Pharmacogenetic Approaches in Personalized Medicine for Postoperative Pain Management

“…This involves a guanosine (G) to adenosine (A) transition, resulting in a valine (Val) to methionine (Met) amino acid substitution. This substitution may lead to three possible SNP genotypes: GG (Val/Val) genotype, characterized by high enzymatic activity; AA (Met/Met) genotype, associated with defective enzymes; and GA (Val/Met) genotype, demonstrating moderate enzymatic activity [67,68]. In the existing literature, three primary haplotypes have shown a strong correlation with sensitivity to experimental pain [69].…”