AHSG Tag Single Nucleotide Polymorphisms Associate With Type 2 Diabetes and Dyslipidemia
Author:
Andersen Gitte1, Burgdorf Kristoffer Sølvsten1, Sparsø Thomas1, Borch-Johnsen Knut123, Jørgensen Torben2, Hansen Torben1, Pedersen Oluf13
Affiliation:
1. Steno Diabetes Center, Gentofte, Denmark 2. Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark 3. Faculty of Health Science, University of Aarhus, Aarhus, Denmark
Abstract
OBJECTIVE—The gene encoding the α2 Heremans-Schmid glycoprotein (AHSG) is a credible biological and positional candidate gene for type 2 diabetes and the metabolic syndrome, and previous attempts to relate AHSG variation with type 2 diabetes and obesity in Swedish and French Caucasians have been largely successful. We related seven frequent AHSG tag single nucleotide polymorphisms to a range of metabolic traits, including type 2 diabetes, obesity, and dyslipidemia.
RESEARCH DESIGN AND METHODS—The polymorphisms were genotyped in 7,683 white Danish subjects using Taqman allelic discrimination or chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, providing a statistical power of >99% to replicate previous findings. Data were analyzed in case-control and haplotype settings, and quantitative metabolic traits were examined for association. Moreover, epistatic effects between AHSG variants and insulin receptor substrate-1 (IRS1) and β-2-adrenergic receptor polymorphisms were investigated.
RESULTS—The −469T>G (rs2077119) and IVS6+98C>T (rs2518136) polymorphisms were associated with type 2 diabetes (P = 0.007 and P = 0.006, respectively, or Pcorr = 0.04 and Pcorr = 0.03, respectively, following correction for multiple hypothesis testing), and in a combined analysis of the present and a previous study −469T>G remained significant (odds ratio 0.90 [95% CI 0.84–0.97]; P = 0.007). Furthermore, two AHSG haplotypes were associated with dyslipidemia (P = 0.003 and Pcorr = 0.009). Thr248Met (rs4917) tended to associate with lower fasting and post–oral glucose tolerance test serum insulin release (P = 0.02, Pcorr = 0.1 for fasting and P = 0.04, Pcorr = 0.2 for area under the insulin curve) and improved insulin sensitivity estimated by the homeostasis model assessment of insulin resistance (9.0 vs. 8.6 mmol · l−1 · pmol−1 · l−1; P = 0.01, Pcorr = 0.06). Indications of epistatic effects of AHSG variants with the IRS1 Gly971Arg polymorphism were observed for fasting serum triglyceride concentrations.
CONCLUSIONS—Based on present and previous findings, common variation in AHSG may contribute to the interindividual variation in metabolic traits.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
Reference26 articles.
1. Auberger P, Falquerho L, Contreres JO, Pages G, Le Cam G, Rossi B, Le Cam A: Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity. Cell 58:631–640,1989 2. Srinivas PR, Wagner AS, Reddy LV, Deutsch DD, Leon MA, Goustin AS, Grunberger G: Serum α2-HS-glycoprotein is an inhibitor of the human insulin receptor at the tyrosine kinase level. Mol Endocrinol 7:1445–1455,1993 3. Mathews ST, Chellam N, Srinivas PR, Cintron VJ, Leon MA, Goustin AS, Grunberger G: α2-HSG, a specific inhibitor of insulin receptor autophosphorylation, interacts with the insulin receptor. Mol Cell Endocrinol 164:87–98,2000 4. Mori K, Emoto M, Yokoyama H, Araki T, Teramura M, Koyama H, Shoji T, Inaba M, Nishizawa Y: Association of serum fetuin-A with insulin resistance in type 2 diabetic and nondiabetic subjects. Diabetes Care 29:468,2006 5. Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Kröber SM, Machicao F, Fritsche A, Häring HU: α2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care 29:853–857,2006
Cited by
48 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|