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Public Library of Science, PLoS ONE, 3(10), p. e0119752

DOI: 10.1371/journal.pone.0119752

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Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans

Journal article published in 2015 by Jennifer E. Huffman, Eva Albrecht, Alexander Teumer, Kao Wh, Massimo Mangino, Henry Voelzke, Karen Kapur, Toby Johnson ORCID, Huffman Je, Nicola Pirastu, Giorgio Pistis, Lorna M. Lopez, Toomas Haller, Zoltn Kutalik, Perttu Salo and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.