Modulation of genetic associations with serum urate levels by body-mass-index in humans

Abstract

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

Fig 1. Mean effect across BMI strata of allelic substitutions at representative variants displaying genome-wide significant association with SU in at least one BMI stratum and displaying nominally significant difference in effect size across BMI strata.

Effect size is on standardised age-adjusted SU levels. Error bars indicate the standard errors of the mean effect estimates within a BMI category. Horizontal lines indicate nominally significant (p < 0.05) differences in mean effect sizes between BMI categories, ** indicates significance at the 1% level taking into account the multiple comparisons performed. Differences in mean effect sizes between BMI strata were tested pairwise using the classical z-test, and P_diff denotes the 2-sided test corresponding P-value. Lean: BMI < 25 kg/m², overweight: 25 ≤ BMI ≤ 30 kg/m², obese: BMI > 30 kg/m².

Fig 2. Forest plots of effect sizes within BMI stratum for variants with the two most significant mean effect size differences between BMI stratum.

A. RBMS1-TANK locus and B. TSPYL5 locus. The overall inverse—variance-weighted mean effect per BMI stratum is calculated assuming fixed effect across studies and represented by a lozenge, associated P-value displayed as P. Measure of heterogeneity between studies is reported (I-squared) with associated P-value for significance (p). P_diff is the test of difference in mean-effect size P-value. For study abbreviations and references, see S1 Table.