Background/Purpose: Gout is caused by an interplay of genetic and environmental factors. Epidemiological and prospective studies suggest that current-smoking may be protective for developing gout and that smoking cessation may increase risk, although there are conflicting data. The aim of this study was to identify interactions between smoking, genes and the risk of gout.

Methods: New Zealand (NZ) East and West Polynesian and European people with (n=582) or without gout (n=645) genotyped at 10 loci, were compared with 349,748 Europeans from the UK Biobank. The 10 loci were urate-transporter genes (SLC2A9, ABCG2, SLC22A11, SLC22A12, SLC17A1), gout-associated genes encoding apolipoproteins (APOA1 and APOC3), and loci previously shown to interact with smoking and serum urate (GCKR, TRIM46 and HNF4G). Gout was defined by ACR criteria or by self-report and urate-lowering therapy use. Current- and ex-smokers were each compared to never-smokers. The interaction effect on gout between risk allele count and smoking was modelled at each loci and for each population, adjusted for age, gender, alcohol and BMI. Odds ratios (OR) and 95% confidence intervals were calculated. NZ populations were analyzed separately, and combined by meta-analysis, adjusting for genetic admixture using the first 10 principal components generated from genome-wide genotype data. A Bonferroni corrected p <0.005 was used.

Results: An association between ex-smoker status and increased prevalence of gout was observed in NZ [OR_meta=1.61 (1.21-2.15), p=0.001] and UK Biobank [OR=1.22 (1.16-1.29), p=2.2×10^-14] datasets. No association was observed in current-smokers. The only statistically significant interaction between genotype and smoking on gout risk was between ex-smoker status and rs11264341–TRIM46 C allele in NZ East and West Polynesians [Interaction OR_meta=0.38 (0.19-0.75), p=0.0049], but not in NZ Europeans (p=0.63) or the UK Biobank (p=0.21). Meta-analysis of rs11264341-TRIM46 genotype-stratified East and West Polynesian datasets suggests that the risk of gout is higher in ex-smokers without the C allele [OR_meta=4.20 (1.72-10.26), p=0.002] relative to never-smokers without the C allele, but not significantly different in never- or ex-smokers with the C allele [OR=1.20 (0.66-2.21), p=0.55; and 1.89 [0.92-3.88], p=0.08, respectively]. No gout-associated loci interactions were observed for pooled current- and ex-smokers compared to never smokers in the NZ dataset. Interactions influencing gout observed in the UK Biobank dataset were for current smoking with rs2231142-ABCG2 and rs670-APOA1 [Interaction OR=1.17 (1.00-1.36), p=0.04 and 0.79 (0.66-0.95), p=0.01, respectively], however these were not significant following Bonferroni correction.

Conclusion: We demonstrate that ex-smokers have higher prevalence of gout than people who have never smoked, and an ancestry-specific interaction between ex-smoker status and TRIM46 in New Zealanders of Polynesian ancestry. It is unclear how TRIM46, a regulator of axonal microtubule organization and neuron polarity, influences risk of gout. There was little evidence of genetic interaction of the loci assessed with smoking and gout.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/an-ancestral-specific-interaction-of-trim46-with-a-past-history-of-smoking-may-influence-gout-risk/