Abstract
Background: Epidemiological and prospective studies suggest that current-smoking may be protective against developing gout and that smoking cessation may increase risk. The aim of this study was to identify interactions between smoking, genetic risk variants and the risk of gout. Methods: A cohort of 520 New Zealand (NZ) East and West Polynesian participants with and 629 without gout were included in our discovery analysis. A cohort of European participants (7576 with and 364,445 without) and South Asian participants (156 with and 7504 without gout) of the UK Biobank were used for replication. Five loci with previous evidence of smoking-influenced associations with serum urate levels were tested for their interaction with smoking status (current-smoker or ex-smoker vs. never-smoker as the reference group) in determining gout risk. The 5 loci were in genes, SLC2A9, ABCG2, GCKR, TRIM46, and HNF4G.Results: A non-additive interaction between genotype and smoking on gout risk was observed between ex-smoker status and TRIM46 (rs11264341) in NZ East and West Polynesian people [interaction ORmeta = 0.58 (0.37-0.92), p = 0.021], but not in European (OR = 0.94 (0.88-1.01), p = 0.10) or South Asian (0.96 (0.55-1.66), p = 0.88) participants of the UK Biobank. TRIM46 (rs11264341) interacted with current-smoker status in the Asian UK Biobank cohort [interaction OR = 2.68 (1.26-5.68), p = 0.010]. In smoking status subgroups the C-allele of rs11264341 increased risk of gout specifically in never-smokers (OR= 1.41 (1.04-1.92), p = 0.029) of the NZ Polynesian sample set and in current-smokers (2.39 (1.13-5.05), p=0.022) of the South Asian sample set. There was no evidence of interaction between smoking-status and the 4 remaining loci in 2 or more of the ancestral populations analysed in this study.Conclusion: We provide evidence for a non-additive interaction between TRIM46 (rs11264341) and smoking behaviour associated with gout risk in a NZ Polynesian sample set and a South Asian sample set, but not in a European sample set. MUC1, that encodes a transmembrane mucin in the lungs whose expression and function is affected by cigarette smoke, is a possible candidate gene at the TRIM46 locus.