AHSG tag single nucleotide Polymorphisms associate with type 2 diabetes and dyslipidemia:: Studies of metabolic traits in 7,683 white danish subjects
AHSG tag single nucleotide Polymorphisms associate with type 2 diabetes and dyslipidemia:: Studies of metabolic traits in 7,683 white danish subjects
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DOI：
10.2337/db07-0558
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发表时间：
2008-05-01
期刊：
影响因子：
7.7
通讯作者：
Pedersen, Oluf
中科院分区：
文献类型：
--
作者：
Andersen, Gitte;Burgdorf, Kristoffer Solvsten;Pedersen, Oluf
目的——编码α2贺尔曼-施密德糖蛋白（AHSG）的基因是2型糖尿病和代谢综合征的可靠的生物学和位置候选基因，之前在瑞典和法国白种人中将AHSG变异与2型糖尿病和肥胖联系起来的尝试已经取得了很大成功。我们将七个常见的 AHSG 标签单核苷酸多态性与一系列代谢特征相关联，包括 2 型糖尿病、肥胖和血脂异常。 研究设计和方法 - 使用 Taqman 等位基因辨别或基于芯片的基质辅助激光解吸/电离飞行时间质谱法对 7,683 名丹麦白人受试者进行多态性基因分型，提供了 > 99% 的统计功效来重复以前的研究结果。在病例对照和单倍型设置中分析数据，并检查定量代谢性状的关联性。此外，还研究了 AHSG 变异与胰岛素受体底物 1 (IRS1) 和 β2-肾上腺素能受体多态性之间的上位效应。 结果 --469T > G (rs2077119) 和 IVS6+98C > T (rs2518136) 多态性与 2 型糖尿病相关（分别为 P = 0.007 和 P = 0.006，或经过多重假设检验校正后，P-corr = 0.04 和 P-corr = 0.03），并且在本研究和之前研究的综合分析中，-469T > G 仍然显着（比值比 0.90 [95% CI 0.84-0.97]；P = 0.007）。此外，两种 AHSG 单倍型与血脂异常相关（P = 0.003 和 P-corr = 0.009）。 Thr248Met (rs4917) 往往与较低的空腹和口服葡萄糖耐量试验后血清胰岛素释放相关（空腹 P = 0.02，P-corr = 0. 1，胰岛素曲线下面积 P = 0.04，P-corr = 0.2），并通过胰岛素抵抗的稳态模型评估估计胰岛素敏感性改善（9.0 与 8.6 mmol 中心点 l(-1) 中心点） pmol(-1) 中心点 l(-1)) P = 0.01，P-corr = 0.06)。观察到具有 IRS1 Gly971Arg 多态性的 AHSG 变异对空腹血清甘油三酯浓度的上位效应的迹象。结论-基于当前和以前的发现，AHSG 的常见变异可能导致代谢性状的个体间变异。
OBJECTIVE-The gene encoding the alpha 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 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 center dot l(-1)center dot pmol(-1) center dot 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.