Richards, JB;
Waterworth, D;
O'Rahilly, S;
Hivert, MF;
Loos, RJF;
Perry, JRB;
Tanaka, T;
... GIANT Consortium; + view all
(2009)
A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels.
PLOS GENET
, 5
(12)
, Article e1000768. 10.1371/journal.pgen.1000768.
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Abstract
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 <= 5x10(-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 = 9.2x10(-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 = 8.5610 26, 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.
| Type: | Article |
|---|---|
| Title: | A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pgen.1000768 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pgen.1000768 |
| Language: | English |
| Additional information: | © 2009 Richards et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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 Bristol provide core support for ALSPAC; and this ALSPAC study was specifically funded by the British Heart Foundation # MRC PG/07/002. The gene expression work was supported by Genome Quebec, Genome Canada, and the CIHR. TP holds a Canada Research Chair, and Drs. O. Nilsson, Ljunggren, and H. Mallmin (Uppsala University, Sweden) are acknowledged for collection of the osteoblasts. The Framingham Heart Study component of this work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), its contract with Affymetrix for genotyping services (Contract No.N02-HL-6-4278), and the resources of the Framingham Heart Study SNP Health Association Resource (SHARe) project, the National Institutes of Health, National Center for Research Resources, General Clinical Research Centers Program (Grant Number M01-RR-01066), an American Diabetes Association Career Development Award (JBM), a research grant from sanofi-aventis (JBM), the Boston University Linux Cluster for Genetic Analysis (LinGA) funded by the NIH NCRR Shared Instrumentation grant (1S10RR163736-01A1), and the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center, by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616 to JBM, JD, and JCF, NIDDK K24 DK080140 to JBM, NIDDK Research Career Award K23 DK65978, a Massachusetts General Hospital Physician Scientist Development Award and a Doris Duke Charitable Foundation Clinical Scientist Development Award to JCF, and the Boston University Linux Cluster for Genetic Analysis (LinGA) funded by the NIH NCRR Shared Instrumentation grant (1S10RR163736-01A1). MFH was supported by the Centre de Recherche Medicale de l'Universite de Sherbrooke (CRMUS) and the CIHR. TwinsUK: The study was funded by the Wellcome Trust, European Community’s Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F2-2008-201865-GEFOS and (FP7/2007-2013), ENGAGE project grant agreement HEALTH-F4-2007-201413, and the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. TDS is an NIHR senior Investigator. The project also received support from a Biotechnology and Biological Sciences Research Council (BBSRC) project grant (G20234). The authors acknowledge the funding and support of the National Eye Institute via an NIH/CIDR genotyping project (PI: Terri Young). We thank the staff from the Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, quality control, and genotyping led by Leena Peltonen and Panos Deloukas; Le Centre National de Genotypage, France, led by Mark Lathrop, for genotyping; Duke University, North Carolina, USA, led by David Goldstein, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by Aarno Palotie. Genotyping was also performed by CIDR as part of an NEI/NIH project grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | MOLECULAR-WEIGHT ADIPONECTIN, BONE-MINERAL DENSITY, SMALL G-PROTEINS, INSULIN-RESISTANCE, PLASMA ADIPONECTIN, METABOLIC SYNDROME, CIRCULATING ADIPONECTIN, MYOCARDIAL-INFARCTION, SERUM CONCENTRATION, APM1 GENE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Clinical Science |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1318655 |
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