AHSG tagSNPs associate with type 2 diabetes and dyslipidemia: studies of metabolic traits in 7,683 Danish whites

Objective: The gene encoding the α 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 tagSNPs to a range of metabolic traits including type 2 diabetes, obesity, and dyslipidemia. Research Design And Methods: The polymorphisms were genotyped in 7,683 Danish whites using Taqman allelic discrimination or chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, providing a statistical power of more than 99% to replicate previous findings. Data were analysed in case-control and haplotype settings, and quantitative metabolic traits were examined for association. Moreover, epistatic effects between AHSG variants and IRS1 and ADRB2 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 following correction for multiple hypothesis testing), and in a combined analysis of the present and a previous study -469T>G remained significant (OR 0.90 [0.84-0.97], P =0.007). Furthermore, two AHSG haplotypes were associated with dyslipidemia ( P =0.003, P corr =0.009). Thr248Met (rs4917) tended to associate with lower fasting and post-OGTT 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 mmol/l ⋅ pmol/l mmol/l 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 upon present and previous findings common variation in AHSG may contribute to the inter-individual variation in metabolic traits.