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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, P-inter= 2.6 x
10(-8)). Two top loci in interaction term analyses, RBFOX3 and
ERO1LB-EDAR-ADD, 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.
