AHSG tag single nucleotide Polymorphisms associate with type 2 diabetes and dyslipidemia:: Studies of metabolic traits in 7,683 white danish subjects

OBJECTIVE-The gene encoding the alpha 2 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 beta-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 P-corr = 0.04 and P-corr = 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 P-corr = 0.009). Thr248Met (rs4917) tended to associate with lower fasting and post-oral glucose tolerance test serum insulin release (P = 0.02, P-corr = 0. 1 for fasting and P = 0.04, P-corr = 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 center dot l(-1)center dot pmol(-1) center dot l(-1)) P = 0.01, P-corr = 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.