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AHSG Tag Single Nucleotide Polymorphisms Associate With Type 2 Diabetes and Dyslipidemia

Studies of Metabolic Traits in 7,683 White Danish Subjects

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

Corresponding author: Gitte Andersen, MSc, PhD, Steno Diabetes Center, Niels Steensens Vej 1, NLC2.12, DK-2820 Gentofte, Denmark. E-mail: gtta{at}steno.dk

Abbreviations: ADRB2, β-2-adrenergic receptor; AHSG, ₂ Heremans-Schmid glycoprotein; IRS1, insulin receptor substrate-1; LD, linkage disequilibrium; MAF, minor allele frequency; SNP, single nucleotide polymorphism

OBJECTIVE—The gene encoding the 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 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 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 · l^–1 · pmol^–1 · 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.

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