Genetics of Response to Canagliflozin

钠-葡萄糖共转运体-2抑制剂是最近批准的一类抗糖尿病药物。这些 药物具有诱人的疗效-包括降低发生重大心血管不良事件的风险 除了降血糖、减肥和降血压外。然而，SGLT2抑制剂也有 严重的不良副作用--包括骨质流失、骨折风险增加、尿毒症、 以及酮症酸中毒。在有效性和安全性方面对这些药物的响应存在显著的变异性， 而且目前还没有好的方法来识别可能产生反应或副作用的个人。这 应用全基因组关联研究在旧秩序阿米什人群体中识别基因 预测个体对Canagliflzin(最广泛使用的SGLT2抑制剂)在以下剂量下的反应的变体 300毫克/天，连服5天。基于首席调查人员研究的初步数据以及 来自文献的信息，拟议的项目将测量与两者相关的药效学终点 SGLT2抑制剂的有益和不良反应。该提案包含两个具体目标： ·目的1.确定与临床疗效生物标记物(24小时尿糖排泄)相关的变异 ·目标2.确定与安全终点预测生物标记物相关的变种--包括血浆 胰高血糖素、酮体、心血管生物标志物(尿酸和血压)和骨生物标志物 健康(血清磷、血浆FGF23、血浆1，25-二羟基维生素D和血浆甲状旁腺素)。 基因分型将使用全面覆盖DNA序列的高密度阵列进行 变种。该项目将利用从全基因组序列产生的阿米什人特有的归属小组 通过NHLBI赞助的精密医学转基因技术获得的约1100名阿米什人的数据 (TOPMed)计划。根据先前研究的历史，在旧亚米希人秩序中获得的基因数据 人群对普通人群和相关患者群体的观察结果具有很高的预测性。 基于这些先例，我们预计这项研究中的基因变异很可能是 SGLT2抑制剂治疗2型糖尿病患者的临床疗效。 这项拟议的研究是朝着识别遗传生物标志物以预测高血压的长期目标迈出的一步 单个患者对SGLT2抑制剂的反应。预测性生物标记物的可用性将使医生能够 根据有益反应的预测因素，为每个患者开出最佳的治疗方案 对不良反应的敏感性。这种类型的精确医学方法，基于预测 药物基因组生物标记物，将是糖尿病药物处方方式的变革性进步。

Sodium-glucose cotransporter-2 inhibitors are the most recently approved class of antidiabetic drugs. These drugs have an attractive efficacy profile – including a decreased risk of major adverse cardiovascular events in addition to glucose-lowering, weight loss, and blood pressure-lowering. However, SGLT2 inhibitors also have significant undesired side effects – including bone loss as well as increased risk of bone fractures, urosepsis, and ketoacidosis. Significant variability exists in response to these drugs in terms of both efficacy and safety, and there are not currently good ways to identify individuals likely to respond or experience side effects. This application proposes a genome-wide association study in the Old Order Amish population to identify genetic variants that predict individuals' responses to canagliflozin (the most widely used SGLT2 inhibitor) at a dose of 300 mg/day for 5 days. Based on preliminary data from the Principal Investigators' research as well as information from the literature, the proposed project will measure pharmacodynamic end-points related to both the beneficial and adverse effects of SGLT2 inhibitors. The proposal contains two specific aims: · Aim 1. To identify variants associated with a clinical efficacy biomarker (24 hr urinary glucose excretion) · Aim 2. To identify variants associated with predictive biomarkers for safety end-points – including, plasma glucagon, ketone bodies, cardiovascular biomarkers (uric acid and blood pressure) and biomarkers of bone health (serum phosphorus, plasma FGF23, plasma 1,25-dihydroxyvitamin D, and plasma PTH). Genotyping will be conducted using a high-density array with comprehensive coverage of DNA sequence variants. The project will leverage an Amish-specific imputation panel generated from whole genome sequence data on ~1100 Amish individuals obtained through the NHLBI-sponsored Trans-Omics for Precision Medicine (TOPMed) program. Based on the history of previous studies, genetic data obtained in the Old Order Amish population have been highly predictive of observations in the general population and relevant patient populations. Based on these precedents, we anticipate that genetic variants in this study are very likely to be predictive of clinical responses of SGLT2 inhibitor-treated type 2 diabetic patients. The proposed study is a step toward the long-term objective of identifying genetic biomarkers to predict an individual patient's response to SGLT2 inhibitors. Availability of predictive biomarkers would enable physicians to prescribe optimal therapies for each individual patient based on predictors of beneficial response and susceptibility to adverse effects. This type of Precision Medicine approach, based on predictive pharmacogenomic biomarkers, would be a transformational advance in the way diabetes drugs are prescribed.