Andersen Gitte, Burgdorf Kristoffer Sølvsten, Sparsø Thomas, Borch-Johnsen Knut, Jørgensen Torben, Hansen Torben, Pedersen Oluf
Steno Diabetes Center, Niels Steensens Vej 1, NLC2.12, DK-2820 Gentofte, Denmark.
Diabetes. 2008 May;57(5):1427-32. doi: 10.2337/db07-0558. Epub 2008 Mar 3.
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.
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.
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.
Based on present and previous findings, common variation in AHSG may contribute to the interindividual variation in metabolic traits.
编码α2赫里曼斯-施密德糖蛋白（AHSG）的基因是2型糖尿病和代谢综合征可靠的生物学及定位候选基因，此前在瑞典和法国白种人中尝试将AHSG变异与2型糖尿病和肥胖关联起来的研究大多取得了成功。我们将7个常见的AHSG标签单核苷酸多态性与一系列代谢性状相关联，包括2型糖尿病、肥胖和血脂异常。
采用Taqman等位基因鉴别法或基于芯片的基质辅助激光解吸/电离飞行时间质谱法，对7683名丹麦白人受试者的多态性进行基因分型，为重复先前的研究结果提供了>99%的统计学效能。在病例对照和单倍型分析中对数据进行分析，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）及β-2-肾上腺素能受体多态性之间的上位效应。
-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，或经多重假设检验校正后分别为P(corr) = 0.04和P(corr) = 0.03），在本研究与先前一项研究的联合分析中，-469T>G仍然具有显著性（优势比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）倾向于与较低的空腹及口服葡萄糖耐量试验后血清胰岛素释放相关（空腹时P = 0.02，P(corr) = 0.1；胰岛素曲线下面积P = 0.04，P(corr) = 0.2），并且通过胰岛素抵抗稳态模型评估估计的胰岛素敏感性有所改善（9.0对8.6 mmol·L⁻¹·pmol⁻¹·L⁻¹；P = 0.01，P(corr) = 0.06）。观察到AHSG变异与IRS1 Gly971Arg多态性对空腹血清甘油三酯浓度存在上位效应的迹象。
基于目前及先前的研究结果，AHSG的常见变异可能导致个体间代谢性状的差异。
