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

Jennifer E. Huffman(Institute of Genetics and Cancer), Eva Albrecht(Helmholtz Zentrum München), Alexander Teumer(Universität Greifswald), Massimo Mangino(St Thomas' Hospital), Karen Kapur(SIB Swiss Institute of Bioinformatics), Toby Johnson(Queen Mary University of London), Zoltán Kutalik(SIB Swiss Institute of Bioinformatics), Nicola Pirastu(University of Trieste), Giorgio Pistis, Lorna M. Lopez(University of Edinburgh), Toomas Haller(University of Tartu), Perttu Salo(Finnish Institute for Health and Welfare), Anuj Goel(Centre for Human Genetics), Man Li(Johns Hopkins University), Toshiko Tanaka(National Institute on Aging), Abbas Dehghan(Erasmus MC), Daniela Ruggiero(Institute of Genetics and Biophysics), Giovanni Malerba(University of Verona), Albert V. Smith(University of Iceland), Ilja M. Nolte(University Medical Center Groningen), Laura Portas(National Research Council), Amanda Phipps‐Green(University of Otago), Lora Boteva(Institute of Genetics and Cancer), Pau Navarro(Institute of Genetics and Cancer), Åsa Johansson(Uppsala University), Andrew A. Hicks(Eurac Research), Ozren Polašek(University of Split), Tõnu Esko(Broad Institute), John F. Peden(Centre for Human Genetics), Sarah E. Harris(Institute of Genetics and Cancer), Federico Murgia(National Research Council), Sarah H. Wild(University of Edinburgh), Albert Tenesa(Roslin Institute), Adrienne Tin(Johns Hopkins University), Evelin Mihailov(University of Tartu), Anne Grotevendt(Universitätsmedizin Greifswald), Gauti Kjartan Gíslason(Icelandic Heart Association), Josef Coresh(Johns Hopkins University), Pio D’Adamo(University of Trieste), Sheila Ulivi(IRCCS Materno Infantile Burlo Garofolo), Péter Vollenweider(University of Lausanne), Gérard Waeber(University of Lausanne), Susan Campbell(Institute of Genetics and Cancer), Ivana Kolčić(University of Split), Krista Fisher(University of Tartu), Margus Viigimaa(Tallinn University of Technology), Jeffrey Metter(National Institute on Aging), Corrado Masciullo, Elisabetta Trabetti(University of Verona), Cristina Bombieri(University of Verona), Rossella Sorice(Institute of Genetics and Biophysics), Angela Döring(Helmholtz Zentrum München), Eva Reischl(Helmholtz Zentrum München), Konstantin Strauch(Helmholtz Zentrum München), Albert Hofman(Erasmus MC), André G. Uitterlinden(Erasmus MC), Mélanie Waldenberger(Helmholtz Zentrum München), H‐Erich Wichmann(Helmholtz Zentrum München), Gail Davies(University of Edinburgh), Alan J. Gow(University of Edinburgh), Nicola Dalbeth(University of Auckland), Lisa K. Stamp(University of Otago), Johannes H. Smit(Amsterdam Public Health), Mirna Kirin(University of Edinburgh), Ramaiah Nagaraja(National Institute on Aging), Matthias Nauck(Universitätsmedizin Greifswald), Claudia Schurmann(Universität Greifswald), Kathrin Budde(Universitätsmedizin Greifswald), Susan M. Farrington(Institute of Genetics and Cancer), Evropi Τheodoratou(University of Edinburgh), Antti Jula(Finnish Institute for Health and Welfare), Veikko Salomaa(Finnish Institute for Health and Welfare), Cinzia Sala, Christian Hengstenberg(University Hospital Regensburg), Michel Burnier(University of Lausanne), Reedik Mägi(University of Tartu), Norman Klopp(Ludwig-Maximilians-Universität München), Stefan Kloiber(Max Planck Institute of Psychiatry), Sabine Schipf(Universitätsmedizin Greifswald), Samuli Ripatti(University of Helsinki), Stefano Cabras(University of Cagliari), Nicole Soranzo(Wellcome Sanger Institute), Georg Homuth(Universität Greifswald), Teresa Nutile(Institute of Genetics and Biophysics), Patricia B. Munroe(Queen Mary University of London), Nicholas D. Hastie(Institute of Genetics and Cancer), Harry Campbell(University of Edinburgh), Igor Rudan(University of Split), Claudia Cabrera(Queen Mary University of London), Chris Haley(Roslin Institute), Oscar H. Franco(Erasmus MC), Tony R. Merriman(University of Otago), Vilmundur Guðnason(University of Iceland), Mario Pirastu(National Research Council), Brenda W.J.H. Penninx(Leiden University Medical Center), Harold Snieder(University Medical Center Groningen), Andres Metspalu(University of Tartu), Marina Ciullo(Institute of Genetics and Biophysics), Peter P. Pramstaller(Eurac Research), Cornelia M. van Duijn(Erasmus MC), Luigi Ferrucci(National Institute on Aging), Giovanni Gambaro(Agostino Gemelli University Polyclinic), Ian J. Deary(University of Edinburgh), Malcolm G. Dunlop(Institute of Genetics and Cancer), James F. Wilson(University of Edinburgh), Paolo Gasparini(University of Trieste), Ulf Gyllensten(Uppsala University), Tim D. Spector(St Thomas' Hospital), Alan F. Wright(Institute of Genetics and Cancer), Caroline Hayward(Institute of Genetics and Cancer), Hugh Watkins(Centre for Human Genetics), Markus Perola(University of Helsinki), Murielle Bochud(Institute of Social and Preventive Medicine), W.H. Linda Kao(Johns Hopkins University), Mark J. Caulfield(Queen Mary University of London), Daniela Toniolo, Henry Völzke(Universitätsmedizin Greifswald), Christian Gieger(Helmholtz Zentrum München), Anna Köttgen(Johns Hopkins University), Véronique Vitart(Institute of Genetics and Cancer)
PLoS ONE
March 26, 2015
10.1371/journal.pone.0119752
Cited by 1,234Open Access
Full Text

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.

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