Abstract

Objectives: To determine if genetic variation in genes in the Hypothalamic-Pituitary-Adrenal (HPA) axis, the primary stress-response system, influences susceptibility to developing musculoskeletal pain.

Methods: Pain and co-morbidity data was collected at 3 time-points in a prospective population-based cohort study. Pair-wise tagging SNPs were selected and genotyped for 7 genes. Genetic association analysis was carried out using zero-inflated negative binomial regression to test for association between SNPs and the maximum number of pain sites across the 3 time-points in subjects reporting pain, reported as proportional change with 95% confidence intervals (95%CI). SNPs were also tested for association with chronic widespread pain (CWP) using logistic regression reporting Odds Ratios and 95%CI.

Results: Seventy-five SNPs were successfully genotyped in 994 subjects including 164 cases with persistent CWP and 172 pain-free controls. Multiple SNPs in SERPINA6 were associated with the maximum number of pain sites e.g. each copy of the T allele of rs941601 was associated with having 16% (proportional change=1.16 (1.04, 1.28) p=0.006) more pain sites compared to subjects with the CC genotype. SERPINA6 SNPs were also associated with CWP. Significant associations between the maximum number of pain sites and SNPs in CRHBP and POMC were also observed and a SNP in MC2R was also associated with CWP. Associations between SNPs and co-morbidity of poor sleep quality and depression explained some of the associations observed.

Conclusions: Genetic variation in HPA axis genes was associated with musculoskeletal pain; however, some of the associations were explained by co-morbidities. Replication of these findings is required in independent cohorts.