posted on 2012-10-24, 09:02authored byJ. B. Richards, D. Waterworth, S. O'Rahilly, M. F. Hivert, R. J. Loos, J. R. Perry, T. Tanaka, N. J. Timpson, R. K. Semple, N. Soranzo, K. Song, N. Rocha, E. Grundberg, J. Dupuis, J. C. Florez, C. Langenberg, I. Prokopenko, R. Saxena, R. Sladek, Y. Aulchenko, D. Evans, G. Waeber, J. Erdmann, M. S. Burnett, N. Sattar, J. Devaney, C. Willenborg, A. Hingorani, J. C. Witteman, P. Vollenweider, B. Glaser, C. Hengstenberg, L. Ferrucci, D. Melzer, K. Stark, J. Deanfield, J. Winogradow, M. Grassl, A. S. Hall, J. M. Egan, John R. Thompson, S. L. Ricketts, I. R. König, W. Reinhard, S. Grundy, H. E. Wichmann, P. Barter, R. Mahley, Y. A. Kesaniemi, D. J. Rader, M. P. Reilly, S. E. Epstein, A. F. Stewart, Van Duijn C. M., H. Schunkert, K. Burling, P. Deloukas, T. Pastinen, Nilesh J. Samani, R. McPherson, Davey Smith G., T. M. Frayling, N. J. Wareham, J. B. Meigs, V. Mooser, T. D. Spector, Consortium GIANT
The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P< or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P< or =0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.
The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10−8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10−19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10−8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10−6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10−3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.
Funding
This work was supported, in part, by grants from the Wellcome Trust (to RKS: Intermediate Clinical Fellowship 080952/Z/06/Z; to SOR: Programme Grant 078986/Z/06/Z), the United Kingdom Medical Research Council Centre for Obesity and Related Metabolic Diseases. The Canadian Institutes of Health Research (CIHR) provided support to this project to JBR, MFH, and TP). DELFIA Adiponectin Assays were performed by the NIHR Cambridge Biomedical Research Centre, Core Biochemical Assay Laboratory. Recruitment of the PennCATH cohort was supported by the Cardiovascular Institute of the University of Pennsylvania. Recruitment of the MedStar cohort was supported by a research grant from GlaxoSmithKline. Genotyping was performed at the Center for Applied Genomics at the Children's Hospital of Philadelphia and supported by GlaxoSmithKline through an Alternate Drug Discovery Initiative research alliance award (to MPR and DJR) with the University of Pennsylvania School of Medicine. The German Study was supported by the Deutsche Forschungsgemeinschaft and the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus) and the EU-funded integrated project Cardiogenics (LSHM-CT-2006-037593). The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the GSF National Research Centre for Environment and Health, which is funded by the German Federal Ministry of Education and Research and the State of Bavaria. The EPIC Norfolk Study is funded by Cancer Research United Kingdom and the Medical Research Council. The WTCCC Study was funded by the Wellcome Trust. Recruitment of cases for the WTCCC Study was carried out by the British Heart Foundation (BHF) Family Heart Study Research Group and supported by the BHF and the UK Medical Research Council. NJS holds a Chair funded by the BHF. The UK Medical Research Council, the Wellcome Trust, and the University of Bris
History
Citation
PLoS Genetics, 2009, 5 (12), pp. e1000768-e1000768