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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere0119752
JournalPLoS One
Volume10
Issue number3
DOIs
Publication statusPublished - Mar 26 2015

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Huffman, J. E., Albrecht, E., Teumer, A., Mangino, M., Kapur, K., Johnson, T., Kutalik, Z., Pirastu, N., Pistis, G., Lopez, L. M., Haller, T., Salo, P., Goel, A., Li, M., Tanaka, T., Dehghan, A., Ruggiero, D., Malerba, G., Smith, A. V., ... Vitart, V. (2015). Modulation of genetic associations with serum urate levels by body-mass-index in humans. PLoS One, 10(3), [e0119752]. https://doi.org/10.1371/journal.pone.0119752