Common variation in the NOS1AP gene is associated with reduced glucose-lowering effect and with increased mortality in users of sulfonylurea
Common variation in the NOS1AP gene is associated with reduced glucose-lowering effect and with increased mortality in users of sulfonylurea
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DOI：
10.1097/fpc.0b013e328300e8c5
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发表时间：
2008-07-01
影响因子：
2.6
通讯作者：
Stricker, Bruno H. Ch.
中科院分区：
文献类型：
--
作者：
Becker, Matthijs L.;Aarnoudse, Albert-Jan L. H. J.;Stricker, Bruno H. Ch.
目的 一氧化氮合酶 1 连接蛋白 (NOS1AP) 基因中的单核苷酸多态性 rs10494366 通过影响细胞内 Ca2+ 水平与 QTc 延长相关。由于磺酰脲类通过增加 21 Ca2+ 流入来刺激胰岛素分泌，我们假设这种多态性与磺酰脲类使用者的降血糖作用和死亡风险相关。方法 在鹿特丹研究（一项针对 7983 名老年人的基于人群的队列研究）中评估了磺酰脲类、二甲双胍和胰岛素使用者的 NOS1AP 多态性、处方剂量和死亡率之间的关联。 619 名参与者在随访期间服用了口服抗糖尿病药物。携带 TG 基因型的格列本脲使用者的处方剂量高于携带 TT 基因型的格列本脲使用者[0.38 规定每日剂量单位，95% 置信区间 (Cl) 0.14-0.63]。与具有TT基因型的格列本脲使用者相比，具有TG或GG基因型的格列本脲使用者的死亡风险增加[风险比(HR) 2.80，95% Cl：1.09-722]。与 TT 基因型的甲苯磺丁脲和格列美脲使用者相比，TG 或 GG 基因型的甲苯磺丁脲使用者（HR：0.30，95% Cl：0.14-0.63）和 TG 或 GG 基因型的格列美脲使用者（HR：0.18，95% Cl：0.04-0.74）的死亡风险降低。 NOS1AP 基因 rs10494366 处的 GG 基因型，与 TT 基因型的格列本脲使用者相比，格列本脲降低血糖水平的效果较差，死亡率较高。在甲苯磺丁脲和格列美脲使用者中，TG 和 GG 基因型与死亡率降低相关。药物遗传学和基因组学 18:591-597 (c) 2008 Wolters Kluwer Health 垂直条 Lippincott Williams & Wilkins。
Objective The single nucleotide polymorphism rs10494366 in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene is associated with QTc prolongation, through an effect on the intracellular Ca2+ levels. As sulfonylurea stimulate insulin secretion by an increased 21 influx of Ca2+ we hypothesized that this polymorphism is associated with the glucose-lowering effect and mortality risk in sulfonylurea users.Methods Associations between the NOS1AP polymorphism, prescribed doses, and mortality rates in sulfonylurea, metformin, and insulin users were assessed in the Rotterdam Study, a population-based cohort study of 7983 elderly people.Results We identified 619 participants who were prescribed oral antidiabetic drugs during follow-up. In glibenclamide users carrying the TG genotype, the prescribed doses were higher compared with the glibenclamide users carrying the TT genotype [0.38 defined daily dose units, 95% confidence interval (Cl) 0.14-0.63]. Glibenclamide users with the TG or GG genotype had an increased mortality risk compared with glibenclamide users with the TT genotype [hazard ratio (H R) 2.80, 95% Cl: 1.09-722]. Tolbutamide users with the TG or GG genotype HR: 0.30, 95% Cl: 0.14-0.63) and glimepiride users with the TG or GG genotype (H R: 0.18, 95% Cl: 0.04-0.74) had a decreased mortality risk compared with tolbutamide and glimepiride users with the TT genotype.Conclusion In participants with the TG or GG genotype at rs10494366 in the NOS1AP gene, glibenclamide is less effective in reducing glucose levels and mortality rates were higher compared with glibenclamide users with the TT genotype. In tolbutamide and glimepiride users, the TG and GG genotype were associated with a reduced mortality rate. Pharmacogenetics and Genomics 18:591-597 (c) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.