The presence of two reduced function variants in CYP2C9 influences the acute response to glipizide
The presence of two reduced function variants in CYP2C9 influences the acute response to glipizide
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DOI：
10.1111/dme.14176
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发表时间：
2019-11-25
影响因子：
3.5
通讯作者：
Florez, J. C.
中科院分区：
文献类型：
--
作者：
Chen, L.;Li, J. H.;Florez, J. C.
目的研究CYP 2C 9基因中两种常见错义变体（rs 1799853，编码Arg 144 Cys，表示为 *2，rs 1057910，编码Ile 359 Leu，表示为 *3）的存在是否影响糖尿病药物初治个体对单次格列吡嗪剂量的急性生理反应。方法在了解人类对二甲双胍和格列吡嗪急性反应的遗传学研究（SUGAR-MGH）中，786名基因分型为rs 1799853/rs 41291560（*2）和rs 1057910/rs 9332214（*3）的个体在空腹状态下接受5 mg格列吡嗪治疗。在基线、30、60、90、120、180和240 min测量葡萄糖和胰岛素水平，以计算格列吡嗪反应的表型终点。由于低血糖而中止激发，低血糖定义为具有两个功能降低等位基因的葡萄糖携带者的胰岛素曲线下面积比具有零或一个拷贝的携带者大50%（P=0.037），尽管该结果主要由具有稳健胰岛素应答的个体驱动。在校正分析中，双拷贝携带者放弃格列吡嗪挑战的风险加倍（P=0.034）。在基于葡萄糖的终点中未观察到显著结果。结论：CYP 2C 9中两个功能降低等位基因的携带者可能会经历对格列吡嗪的胰岛素反应增加，并倾向于更高的低血糖风险，尽管在基于葡萄糖的测量中没有观察到基因型的影响。需要进一步的研究来阐明CYP 2C 9基因分型指导磺脲类药物治疗的效用。
Aims To examine whether the presence of two common missense variants in the CYP2C9 gene (rs1799853, encoding Arg144Cys and denoted as *2, and rs1057910, encoding Ile359Leu and denoted as *3) influences the acute physiological response to a single glipizide dose in individuals naive to diabetes medications. Methods In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), 786 individuals genotyped for rs1799853/rs41291560 (*2) and rs1057910/rs9332214 (*3) were treated with 5 mg glipizide in the fasting state. Glucose and insulin levels were measured at baseline, 30, 60, 90, 120, 180 and 240 min for calculation of phenotypic endpoints of glipizide response. The challenge was aborted as a result of hypoglycaemia, defined as glucose Carriers with two reduced function alleles had a 50% larger insulin area under the curve than carriers with zero or one copy (P=0.037), although this finding was primarily driven by an individual with a robust insulin response. In adjusted analyses, the risk of aborting the glipizide challenge was doubled in two-copy carriers (P=0.034). No significant findings were observed in glucose-based endpoints. Conclusions Carriers of two reduced function alleles in CYP2C9 may experience an increased insulin response to glipizide and be predisposed to a higher risk of hypoglycaemia, although no effect of genotype was seen in glucose-based measurements. Further studies are needed to clarify the utility of CYP2C9 genotyping to guide sulfonylurea treatment.