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 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.


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.
Andersen
Gitte
G
Steno Diabetes Center, Niels Steensens Vej 1, NLC2.12, DK-2820 Gentofte, Denmark. gtta@steno.dk
Burgdorf
Kristoffer Sølvsten
KS
Sparsø
Thomas
T
Borch-Johnsen
Knut
K
Jørgensen
Torben
T
Hansen
Torben
T
Pedersen
Oluf
O
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001798:Blood Proteins / Q000235:genetics*; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D050171:Dyslipidemias / Q000150:complications / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics*; D060749:alpha-2-HS-Glycoprotein
D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; D006442:Glycated Hemoglobin; D055504:Insulin Receptor Substrate Proteins; D060749:alpha-2-HS-Glycoprotein; C556354:AHSG protein, human; C526292:IRS1 protein, human