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

Jennifer Huffman;Eva Albrecht;Alexander Teumer;Massimo Mangino;Karen Kapur;Toby Johnson;Zoltan Kutalik;Nicola Pirastu;Giorgio Pistis;Lorna Lopez;Toomas Haller;Perttu Salo;Anuj Goel;Man Li;Toshiko Tanaka;Abbas Dehghan;Daniella Ruggiero;Giovanni Malerba;Albert Smith;Ilja Nolte;Laura Portas;Amanda Phipps Green;Lora Boteva;Pau Navarro;Asa Johansson;Andrew Hicks;Ozren Polasek;Tonu Esko;John Peden;Sarah Harris;Federico Murgia;Sarah Wild;Albert Tenesa;Adrienne Tin;Evelin Mihailov;Anne Grotevendt;Gauti Gislason;Josef Coresh;Pio D'Adamo;Sheila Ulivi;Peter Vollenweider;Gerard Waeber;Susan Campbell;Ivana Kolcic;Krista Fisher;Margus Viigimaa;Jeffrey Metter;Corrado Masciullo;Elisabetta Trabetti;Cristina Bombieri;Rossella Sorice;Angela Doring;Eva Reischl;Konstantin Strauch;Albert Hofman;Andre Uitterlinden;Melanie Waldenberger;H. Erich Wichmann;Gail Davies;Alan Gow;Nicola Dalbeth;Lisa Stamp;Johannes Smit;Mirna Kirin;Ramaiah Nagaraja;Matthias Nauck;Claudia Schurmann;Kathrin Bude;Susan Farrington;Evropi Theodoratou;Antti Jula;Veikko Salomaa;Cinzia Sala;Christian Hengstenberg;Michel Burnier;Reedik Magi;Norman Klopp;Stefan Kloiber;Sabine Schipf;Samuli Ripatti;CABRAS, STEFANO;Nicole Soranzo;Georg Homuth;Teresa Nutile;Patricia Munroe;Nicholas Hastie;Harry Campbell;Igor Rudan;Claudia Cabrera;Chris Haley;Oscar Franco;Tony Merriman;Vilmundur Gudnason;Mario Pirastu;Brenda Penninx;Harold Snieder;Andres Metspalu;Marina Ciullo;Peter Pramstaller;Cornelia van Duijn;Luigi Ferrucci;Giovanni Gambaro;Ian Deary;Malcolm Dunlop;James Wilson;Paolo Gasparini;Ulf Gyllensten;Tim Spector;Alan Wright;Caroline Hayward;Hugh Watkins;Markus Perola;Murielle Bochud;WH~Linda Kao;Mark Caulfield;Daniela Toniolo;Henry Volzke;Christian Gieger;Anna Kottgen;Veronique Vitart

2015-01-01

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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, Pinter= 2.6 × 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 × 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight = 9.1 × 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 (P difflean-obese= 2 × 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 obsogenic environment.