Extended report 1Arc Epidemiology Unit, University of Manchester, Manchester, UK 2Aberdeen Pain Research Collaboration (Epidemiology Group), School of Medicine and Dentistry, University of Aberdeen, UK Correspondence to Dr Kate L Holliday, arc Epidemiology Unit, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK; kate.holliday@ manchester.ac.uk KLH and BIN contributed equally to this work. Accepted 17 August 2009 556 Genetic variation in the hypothalamic–pituitary–adrenal stress axis inﬂuences susceptibility to musculoskeletal pain: results from the EPIFUND study Kate L Holliday,1 Barbara I Nicholl,1 Gary J Macfarlane,2 Wendy Thomson,1 Kelly A Davies,1 John McBeth1 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 comorbidity data was collected at three time points in a prospective population-based cohort study. Pairwise tagging single nucleotide polymorphisms (SNPs) were selected and genotyped for seven 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 three time points in participants reporting pain, reported as proportional changes with 95% CIs. SNPs were also tested for association with chronic widespread pain (CWP) using logistic regression reporting odds ratios and 95% CI. Results A total of 75 SNPs were successfully genotyped in 994 participants including 164 cases with persistent CWP and 172 pain-free controls. Multiple SNPs in SERPINA6 were associated with the maximum number of pain sites; for example, each copy of the T allele of rs941601 was associated with having 16% (proportional change=1.16, 95% CI 1.04 to 1.28, p=0.006) more pain sites compared to participants with the CC genotype. SERPINA6 gene SNPs were also associated with CWP. Signiﬁcant associations between the maximum number of pain sites and SNPs in the CRHBP and POMC genes were also observed and a SNP in MC2R was also associated with CWP. Associations between SNPs and comorbidity 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 comorbidities. Replication of these ﬁndings is required in independent cohorts. INTRODUCTION Musculoskeletal pain is common in the general population with up to 33% of people reporting low back pain (LBP) and approximately 11% reporting chronic widespread pain (CWP).1 Stress has been associated with musculoskeletal pain syndromes2 3 and psychological distress has been shown to be a strong predictor for the onset of CWP.4 The body’s primary stress response system, the hypothalamic–pituitary–adrenal (HPA) axis, has been shown to be hyporesponsive in patients with ﬁbromyalgia and patients with LBP.5 6 In a cohort of participants free of CWP those who went onto develop it showed reduced morning and increased evening levels of cortisol and higher levels of cortisol following a dexamethasone test (HPA axis suppression test). This suggests that individuals developing CWP show a blunting of the cortisol diurnal rhythm and a failure to suppress the HPA axis indicating a hypoactive HPA axis. It has been hypothesised that the abnormal functioning of the HPA axis in musculoskeletal pain could be due stressors such as severe adverse events in early life, which have been shown to result in dysfunction of the HPA axis7 8 or altered levels of neurotransmitters such as reduced seroto- nin levels, as observed in ﬁbromyalgia,9 10 which stimulates adrenocorticotrophin (ACTH) and corti- cotrophin releasing hormone (CRH) in response to stress. Genetic variation in genes key to HPA axis function could also play a role in musculoskeletal pain susceptibility. Individuals may respond inef- ﬁciently to stressors due to their genetic makeup, which may in turn render them more susceptible to developing musculoskeletal pain. Twin studies have estimated that genetics explains 50% of the variance in pain syndromes.11 12 Pain thresholds, which are reduced in patients with CWP,13 have also been shown to have a genetic component,14, 15 however, one study did not ﬁnd evidence of this.16 Attempts to identify the genes involved in CWP susceptibility and experimen- tal pain sensitivity have been limited to date and problematic in their study design. The most prev- alent problem is a lack of sufﬁcient sample size to detect the likely modest effects of individual genes. Insufﬁcient representation of the genetic variation within candidate genes and not considering the role of comorbidities are also common problems.17 In this study we aimed to determine if genetic variation within the HPA axis pathway genes CRH, CRH receptor 1 (CRHR1), CRH binding protein (CRHBP), the ACTH precursor pro-opiomelanocortin (POMC) and its receptor (MC2R), the glucocorti- coid receptor (NR3C1) and corticosteroid binding glob- ulin (SERPINA6), is associated with susceptibility to musculoskeletal pain while accounting for the effects of comorbidities. METHODS Participants Pain and psychological data was collected at three time points over a 4-year period via a postal survey as part of a prospective population-based cohort study, EPIFUND (for ‘Epidemiology of Functional Disorders’). Participants aged 25–65 years were recruited from three primary care registers in the northwest of England. Ann Rheum Dis 2010;69:556–560. doi:10.1136/ard.2009.116137