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Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

2012; Public Library of Science; Volume: 8; Issue: 3 Linguagem: Inglês

10.1371/journal.pgen.1002607

1553-7404

Zari Dastani, Marie‐France Hivert, Nicholas J. Timpson, John R. B. Perry, Xin Yuan, Robert A. Scott, Peter Henneman, Iris M. Heid, Jorge R. Kizer, Leo‐Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P. Morris, Kerrin S. Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula Kanoni, James S. Pankow, Hae‐Won Uh, Ying Wu, Aurelian Bidulescu, Laura J. Rasmussen‐Torvik, Celia M.T. Greenwood, Nicholas G. Martin, Jonna Grimsby, Man Li, Yongmei Liu, Jaspal S. Kooner, Vincent Mooser, Péter Vollenweider, Karen Kapur, John C. Chambers, Nicholas J. Wareham, Claudia Langenberg, Rune R. Frants, Ko Willems van Dijk, Ben A. Oostra, Sara M. Willems, Claudia Lamina, Thomas W. Winkler, Bruce M. Psaty, Russell P. Tracy, Jennifer A. Brody, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P. Pramstaller, David M. Evans, Beaté St Pourcain, Naveed Sattar, Andrew R. Wood, Stefania Bandinelli, Olga D. Carlson, Josephine M. Egan, Stefan Böhringer, Diana van Heemst, Lyudmyla Kedenko, Kati Kristiansson, Marja-Liisa Nuotio, Britt-Marie Loo, Tamara Harris, Melissa García, Alka M. Kanaya, Margot Haun, Norman Klopp, H.‐Erich Wichmann, Panos Deloukas, E. A. Katsareli, David Couper, Bruce Bartholow Duncan, M. Kloppenburg, Linda S. Adair, Judith B. Borja, James G. Wilson, Solomon K. Musani, Xiuqing Guo, Toby Johnson, Robert K. Semple, Tanya M. Teslovich, Matthew Allison, Susan Redline, Sarah G. Buxbaum, Karen L. Mohlke, Ingrid Meulenbelt, Christie M. Ballantyne, George Dedoussis, Frank B. Hu, Yongmei Liu, Bernhard Paulweber, Timothy D. Spector, P. Eline Slagboom, Luigi Ferrucci, Antti Jula, Markus Perola, Olli T. Raitakari, Jose C. Florez, Veikko Salomaa, Johan G. Eriksson, Timothy M. Frayling, Andrew A. Hicks, Terho Lehtimäki, George Davey Smith, David S. Siscovick, Florian Kronenberg, Cornelia M. van Duijn, Ruth J. F. Loos, Dawn Waterworth, James B. Meigs, Josée Dupuis, J. Brent Richards,

Adipose Tissue and Metabolism

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.