1 A FUNCTIONAL POLYMORPHISM IN THE CATECHOL-O METHYLTRANSFERASE (COMT) GENE IS ASSOCIATED WITH OA-RELATED PAIN

Abstract

Purpose: Joint complaints are very common in the elderly and a major reason for disability and reduced quality of life. It is clear that radiographic evidence of joint damage predisposes to joint pain, but the severity of the joint damage is only weakly related to the severity of the pain experienced. Whether a person develops chronic pain or not in a (radiographically) damaged joint is partly determined by genetic variations and heritability estimates for joint pain range between 35-65%. Thus, persons that develop chronic pain might possess a combination of genetic variations that increase their sensitivity to pain. The COMT-gene (catechol-O-methyltransferase) is involved in pain perception; inhibition of COMT was shown to increase pain sensitivity. The aim of our study was to examine whether a well-known functional polymorphism in the COMT-gene (Val158Met) influences OArelated pain. Methods: We studied 3033 individuals aged 55 years and over from a large population-based study (Rotterdam study). All subjects were scored for radiographic hip OA (defined as Kellgren& Lawrence ≥2) as well as hip pain (assessed by interview). Genotypes of the Val158Met polymorphism of the COMT-gene were assessed by Taqman. Results: Allele frequency of the low activity allele of the COMT gene (158Met) was 55%. In the total population, the COMT variant was not associated with hip pain. However, when we selected individuals who had radiographically defined hip-OA (n =288), we observed that carriers of the 158-Met variant had 2.7 times higher risk (95% CI: 1.2-6.1; p=0.02) for hip pain as compared to the ValVal-genotype. This effect was fully driven by the women (n =171). Female carriers of the 158-Val allele were 4.9 times more likely to have pain (95% CI: 1.6-14.8; p=0.005) while radiographical damage to the hip was present in both genotype groups. These results were not affected by adjustments for age and BMI, two well known risk factors for OA. Conclusions: The low activity allele of the COMT-gene (158Met) is associated with increased hip pain in individuals with radiological damage of the hip. This finding is in line with previous studies in mice which showed that inhibition of COMT increases pain sensitivity, presumably via the β2/3 adrenergic pathways. Our findings need to be replicated in other large study populations, but might have important clinical implications, since the prevalence of the COMT low activity allele is very high. Our results also highlight the importance of studying joint related pain as a separate trait in genetic epidemiological studies. 2