Causal Relationship between Adiponectin and Metabolic Traits: A Mendelian Randomization Study in a Multiethnic Population

et al. (2013) Causal Relationship between Adiponectin and Metabolic Traits: A Mendelian Randomization Study in a Multiethnic Population. PLoS ONE 8(6): e66808. doi:10.1371/journal.pone.0066808 Causal Relationship between Adiponectin and Metabolic Traits: A Mendelian Randomization Study in a Multiethnic Population Andrew Mente 0 1 2 David Meyre 0 1 2 Matthew B. Lanktree 0 1 2 Mahyar Heydarpour 0 1 2 A. Darlene Davis 0 1 2 Ruby Miller 0 1 2 Hertzel Gerstein 0 1 2 Robert A. Hegele 0 1 2 Salim Yusuf 0 1 2 Sonia S. Anand 0 1 2 for the 0 1 2 Rocio I. Pereira, University of Colorado Denver, United States of America 0 Canada, 5 Six Nations Health Services , Ohsweken , Canada , 6 Department of Medicine, McMaster University , Hamilton , Canada 1 Cardiovascular Genetics Laboratory, Robarts Research Institute , London, Ontario , Canada , 4 Department of Medicine, University of Western Ontario , London, Ontario 2 1 Population Health Research Institute , Hamilton , Canada , 2 Department of Clinical Epidemiology and Biostatistics, McMaster University , Hamilton , Canada , 3 Blackburn Background: Adiponectin, a secretagogue exclusively produced by adipocytes, has been associated with metabolic features, but its role in the development of the metabolic syndrome remains unclear. Objectives: We investigated the association between serum adiponectin level and metabolic traits, using both observational and genetic epidemiologic approaches in a multiethnic population assembled in Canada. Methods: Clinical data and serum adiponectin level were collected in 1,157 participants of the SHARE/SHARE-AP studies. Participants were genotyped for the functional rs266729 and rs1260326 SNPs in ADIPOQ and GCKR genes. Results: Adiponectin level was positively associated with HDL cholesterol and negatively associated with body mass index, waist-to-hip ratio, triglycerides, fasting glucose, fasting insulin, systolic and diastolic pressure (all P,0.002). The rs266729 minor G allele was associated with lower adiponectin and higher HOMA-IR (P = 0.004 and 0.003, respectively). The association between rs266729 SNP and HOMA-IR was no longer significant after adjustment for adiponectin concentration (P = 0.10). The rs266729 SNP was associated with HOMA-IR to an extent that exceeded its effect on adiponectin level (0.15 SD 95% C.I. [0.06, 0.24], P,0.001). There was no significant interaction between rs266729 SNP and ethnicity on adiponectin or HOMA-IR. In contrast, the SNP rs1260326 in GCKR was associated with HOMA-IR (P,0.001), but not with adiponectin level Conclusion: The association of the functional promoter polymorphism rs266729 with lower serum adiponectin and increased insulin resistance in diverse ethnic groups may suggest a causal relationship between adiponectin level and PLOS ONE | www.plosone.org - Funding: A. Mente is supported by an Early Career Award from Hamilton Health Sciences Foundation. D. Meyre is supported by a Canada Research Chair in Genetics of Obesity and Diabetes. M.B. Lanktree was supported by the Canadian Institutes of Health Research (CIHR) MD/PhD Studentship Award and the University of Western Ontario MD/PhD Program and is a CIHR Fellow in Vascular Research. R.A. Hegele is a Career Investigator of the Heart and Stroke Foundation of Ontario and holds the Edith Schulich Vinet Canada Research Chair (Tier I) in Human Genetics, the Martha G. Blackburn Chair in Cardiovascular Research, and the Jacob J. Wolfe Distinguished Medical Research Chair at the University of Western Ontario. H. Gerstein holds a Aventis Population Health Institute Chair in Diabetes Research, McMaster University. S. Yusuf holds an endowed chair in Cardiovascular Research from the Heart and Stroke Foundation of Ontario. S.S. Anand holds the Michael G. DeGroote/Heart and Stroke Foundation of Ontario endowed Chair in Population Health Research, Canada Research Chair in Ethnicity and Cardiovascular Disease, and the Eli Lilly-May Cohen Chair in Womens Health Research. This work was supported by CIHR (MOP-13430, MOP-79523, CTP-79853), the Heart and Stroke Foundation of Ontario (NA-6059, T-6018, PRG-4854, NA-03785), Genome Canada through the Ontario Genomics Institute, and the Pfizer Jean Davignon Distinguished Cardiovascular and Metabolic Research Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors received funding from a commercial source (Jean Davignon Distinguished Cardiovascular and Metabolic Research Award, sponsored by Pfizer). This does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. Adiponectin is a secretagogue exclusively produced by adipocytes and abundantly secreted into the bloodstream where it accounts for 0.01% of total plasma protein [1]. Extensive study of adiponectin function in animal models led to the conclusion that adiponectin promotes insulin sensitivity in the muscle and liver [2,3]. Cross-sectional epidemiological studies in humans have shown that low serum adiponectin is associated with insulin resistance, obesity, dyslipidemia, coronary artery disease, hypertension or type 2 diabetes (T2D) [48]. In longitudinal studies, hypoadiponectionemia was shown to predict the development of insulin resistance [9], dyslipidemia [10], T2D [11], hypertension [12], coronary artery disease [13] but was not a predictor of subsequent weight gain [14]. Heritability studies provided strong evidence that plasma adiponectin level is genetically determined and that an overlap exists between the genetic architecture of adiponectin and features of the metabolic syndrome such as fasting insulin or HDL-cholesterol [15,16]. The gene encoding adiponectin (ADIPOQ) is located on chromosome 3q27 and comprises three exons [17]. Candidate gene studies [18], and more recently genome-wide association (GWA) studies [19], fine-mapping [20] or large-scale deep resequencing experiments [21] have identified numerous common and rare variants at the ADIPOQ locus associated with serum adiponectin level. Even though ADIPOQ is the major genetic determinant of serum adiponectin level, 12 additional contributing loci have been identified through largescale GWA meta-analyses [2225]. Datsani and colleagues recently showed convincing evidence of association between a multiple SNP adiponectin-decreasing gene score and decreased body mass index (BMI), increased waist to hip ratio (WHR), higher triglyceride (TG) levels, lower HDL-C concentrations, higher post oral glucose tolerance test (OGTT) 2-hr glucose level, higher homeostatic model assessment-insulin resistance (HOMA-IR) and increased T2D risk using large datasets from international consortia [25]. Overall, these data suggest that adiponectin may be a key hormone in the development of metabolic syndrome. The common SNP -11377 C.G (rs266729) is located in the promoter region of the gene ADIPOQ and has functional consequences on ADI (...truncated)