TY - JOUR

T1 - AHSG tag single nucleotide polymorphisms associate with type 2 diabetes and dyslipidemia: studies of metabolic traits in 7,683 white Danish subjects

AU - Andersen, Gitte

AU - Burgdorf, Kristoffer Sølvsten

AU - Sparsø, Thomas

AU - Borch-Johnsen, Knut

AU - Jørgensen, Torben

AU - Hansen, Torben

AU - Pedersen, Oluf

N1 - Keywords: Adaptor Proteins, Signal Transducing; Blood Proteins; Denmark; Diabetes Mellitus, Type 2; Dyslipidemias; European Continental Ancestry Group; Female; Genetic Variation; Hemoglobin A, Glycosylated; Humans; Insulin Receptor Substrate Proteins; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide

PY - 2008

Y1 - 2008

N2 - OBJECTIVE: The gene encoding the alpha2 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 x l(-1) x pmol(-1) x 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.

AB - OBJECTIVE: The gene encoding the alpha2 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 x l(-1) x pmol(-1) x 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.

U2 - 10.2337/db07-0558

DO - 10.2337/db07-0558

M3 - Journal article

C2 - 18316360

VL - 57

SP - 1427

EP - 1432

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 5

ER -