期刊
PLOS GENETICS
卷 5, 期 12, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1000768
关键词
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资金
- Wellcome Trust [080952/Z/06/Z, 078986/Z/06/Z]
- United Kingdom Medical Research Council Centre for Obesity and Related Metabolic Diseases
- Canadian Institutes of Health Research (CIHR)
- the Cardiovascular Institute of the University of Pennsylvania
- GlaxoSmithKline
- Deutsche Forschungsgemeinschaft
- German Federal Ministry of Education and Research ( BMBF) in the context of the German National Genome Research Network [NGFN-2, NGFN-plus]
- EU [LSHM-CT-2006-037593]
- German Federal Ministry of Education and Research
- State of Bavaria
- Cancer Research United Kingdom
- Medical Research Council
- BHF
- UK Medical Research Council
- University of Bristol
- British Heart Foundation [MRC PG/07/002]
- National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, N02-HL-6-4278]
- Framingham Heart Study SNP Health Association Resource (SHARe) project
- National Institutes of Health
- National Center for Research Resources, General Clinical Research Centers Program [M01-RR-01066]
- American Diabetes Association Career Development Award
- sanofi-aventis
- NIH NCRR Shared Instrumentation [1S10RR163736-01A1]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center
- National Institute for Diabetes and Digestive and Kidney Diseases ( NIDDK) [R01 DK078616, K24 DK080140, K23 DK65978]
- Massachusetts General Hospital Physician Scientist Development Award
- Doris Duke Charitable Foundation Clinical Scientist Development Award
- Centre de Recherche Medicale de l'Universite de Sherbrooke (CRMUS)
- CIHR
- European Community [FP7/2007-2013, HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413]
- FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]
- Department of Health via the National Institute for Health Research ( NIHR)
- St Thomas' NHS Foundation Trust in partnership with King's College London
- Biotechnology and Biological Sciences Research Council (BBSRC) [Biotechnology and Biological Sciences Research Council ( BBSRC) project grant (G20234]
- National Eye Institute via an NIH/CIDR genotyping project
- MRC [MC_U106188470, G0800582, G0600705, G0701863] Funding Source: UKRI
- Medical Research Council [G0701863, G0800582, G0600705, G0600717B, MC_U106188470, G9815508, MC_U106179471] Funding Source: researchfish
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.
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