Background/Purpose: Genome-wide association studies (GWAS) have identified loci associated with serum urate levels and the risk of gout. Some of these loci interact in a non-additive fashion with dietary exposures to influence the risk of gout. This study aimed to systematically investigate non-additive interaction between alcohol exposure and urate-associated loci for the risk of gout.

Methods: A total of 3,312 New Zealand European and Polynesian (Maori/Pacific) people with and without gout were genotyped for 28 urate-associated genetic variants and tested for non-additive interaction with alcohol exposure (none versus any intake) influencing the risk of gout. Publicly-available genotype and serum urate data from the Atherosclerosis Risk in Communities (ARIC) study and the Framingham Heart Study (FHS) (n=7,110 European subjects) were used to test for non-additive interaction between specific genetic variants and alcohol exposure for the risk of hyperuricaemia (HU). Multivariate-adjusted logistic regression was done including an interaction term. P<8.6×10^-4 was the significance level after application of a correction factor of 58.

Results: Non-additive interaction of alcohol exposure with GCKR (rs780094) and A1CF (rs10821905) was observed in Europeans to influence the risk of gout (OR_Interaction=0.28, P=1.5×10^-4 and OR_Interaction=0.29, P=1.4×10^-4, respectively). There was evidence for interaction of A1CF with alcohol exposure in determining HU in the ARIC/FHS sample set (OR_Interaction=0.60, P=0.018), but not for GCKR (OR_Interaction=0.82, P=0.18). Analysis of genotype groups stratified by alcohol exposure revealed that at A1CF alcohol exposure suppressed the gout risk conferred by the A-positive genotype (OR_{No Alcohol}=2.21; OR_Alcohol=0.93) (Table). At GCKR alcohol exposure eliminated the genetic effect on gout – the ORs for each genotype group were equivalent (OR_T-=2.07; OR_T+=2.39) (Table). In Polynesians there was no experiment-wide evidence for non-additive interaction with alcohol in the risk of gout for any locus (P>8.6×10^-4). However at GCKR there was nominal evidence for interaction in a direction consistent with that observed in Europeans (OR_Interaction=0.62, P=0.05). At the five urate transporter loci (SLC2A9, ABCG2, SLC17A1, SLC22A11, SLC22A12) there was little or no evidence of interaction with alcohol in determining the risk of gout, with nominal evidence only in Europeans at SLC17A1 (OR_Interaction=0.46, P_Uncorrected=0.027).

Conclusion: We describe a novel non-additive interaction of alcohol exposure with GCKR (glycolytic gene) and A1CF (apolipoprotein B mRNA editing gene) to influence the risk of gout in Europeans. These data support the hypothesis that alcohol influences the risk of gout via glucose and apolipoprotein metabolism. Table. Alcohol intake and gout association in genotype-stratified groups in Europeans for A1CF and GCKR.

Adjusted for age, sex and BMI.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/non-additive-interaction-of-the-glucokinase-regulatory-protein-and-apobec1-complementation-factor-loci-with-alcohol-consumption-to-influence-the-risk-of-gout/