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A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.

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< 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.

SUBMITTER: Richards JB

PROVIDER: S-EPMC2781107 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.

Richards J Brent JB Waterworth Dawn D O'Rahilly Stephen S Hivert Marie-France MF Loos Ruth J F RJ Perry John R B JR Tanaka Toshiko T Timpson Nicholas John NJ Semple Robert K RK Soranzo Nicole N Song Kijoung K Rocha Nuno N Grundberg Elin E Dupuis Josée J Florez Jose C JC Langenberg Claudia C Prokopenko Inga I Saxena Richa R Sladek Robert R Aulchenko Yurii Y Evans David D Waeber Gerard G Erdmann Jeanette J Burnett Mary-Susan MS Sattar Naveed N Devaney Joseph J Willenborg Christina C Hingorani Aroon A Witteman Jaquelin C M JC Vollenweider Peter P Glaser Beate B Hengstenberg Christian C Ferrucci Luigi L Melzer David D Stark Klaus K Deanfield John J Winogradow Janina J Grassl Martina M Hall Alistair S AS Egan Josephine M JM Thompson John R JR Ricketts Sally L SL König Inke R IR Reinhard Wibke W Grundy Scott S Wichmann H-Erich HE Barter Phil P Mahley Robert R Kesaniemi Y Antero YA Rader Daniel J DJ Reilly Muredach P MP Epstein Stephen E SE Stewart Alexandre F R AF Van Duijn Cornelia M CM Schunkert Heribert H Burling Keith K Deloukas Panos P Pastinen Tomi T Samani Nilesh J NJ McPherson Ruth R Davey Smith George G Frayling Timothy M TM Wareham Nicholas J NJ Meigs James B JB Mooser Vincent V Spector Tim D TD

PLoS genetics 20091211 12

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 ...[more]

PMID: 20011104

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Project description:OBJECTIVE: The plasma adiponectin level, a potential upstream and internal facet of metabolic and cardiovascular diseases, has a reasonably high heritability. Whether other novel genes influence the variation in adiponectin level and the roles of these genetic variants on subsequent clinical outcomes has not been thoroughly investigated. Therefore, we aimed not only to identify genetic variants modulating plasma adiponectin levels but also to investigate whether these variants are associated with adiponectin-related metabolic traits and cardiovascular diseases. RESEARCH DESIGN AND METHODS: We conducted a genome-wide association study (GWAS) to identify quantitative trait loci (QTL) associated with high molecular weight forms of adiponectin levels by genotyping 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 SNP chips. The culpable single nucleotide polymorphism (SNP) variants responsible for lowered adiponectin were then confirmed in another 559 YOH subjects, and the association of these SNP variants with the risk of metabolic syndrome (MS), type 2 diabetes mellitus (T2DM), and ischemic stroke was examined in an independent community-based prospective cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS, n = 3,350). RESULTS: The SNP (rs4783244) most significantly associated with adiponectin levels was located in intron 1 of the T-cadherin (CDH13) gene in the first stage (P = 7.57 × 10(-9)). We replicated and confirmed the association between rs4783244 and plasma adiponectin levels in an additional 559 YOH subjects (P = 5.70 × 10(-17)). This SNP was further associated with the risk of MS (odds ratio [OR] = 1.42, P = 0.027), T2DM in men (OR = 3.25, P = 0.026), and ischemic stroke (OR = 2.13, P = 0.002) in the CVDFACTS. CONCLUSIONS: These findings indicated the role of T-cadherin in modulating adiponectin levels and the involvement of CDH13 or adiponectin in the development of cardiometabolic diseases.

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A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.

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A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.

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