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 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 vs. 8.6 mmol/l·pmol/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.