Effects of Minor SNPs on Enzymatic Activity Regulated By Common Human Haplotypes Of The COMT Gene (2008)

Undergraduates: Matthew Conrad, Jason Lambert

Faculty Advisor: Andrea Neely
Department: Biology

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Catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, plays a key role the modulation of persistent pain. Our group demonstrated that three common haplotypes of the human catechol-O-methyltransferase (COMT) gene are associated with experimental pain sensitivity and the risk of developing temporomandibular disorder (TMD), a chronic musculoskeletal pain condition (Diatchenko et al., HMG 2005). Based on subjects’ pain responsiveness, haplotypes were designated as low (LPS), average (APS), or high (HPS) pain sensitive. The APS and HPS haplotypes associated with heightened pain sensitivity were found to produce 3- to 15-fold reductions in COMT enzymatic activity (Nackley et al., Science 2006). Several minor frequency SNPs naturally occur within the APS and HPS haplotypes, but their functional impact is unknown. We hypothesized that these minor SNPs, one occurring in the APS construct and three in the HPS construct, may compensate for the observed reductions in enzymatic activity. Thus, the purpose of the present study was to assess the compensatory potential of minor SNPs situated in the APS and HPS haplotypes on COMT enzymatic activity. Consistent with previous results, the APS and HPS haplotypes exhibited reduced enzymatic activity. However, no differences between the minor SNP mutants and their respective parent haplotypes were observed for RNA abundance, protein expression, or enzymatic activity.