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Genetics of Response to Canagliflozin

卡格列净反应的遗传学

基本信息

批准号：
10382252
负责人：
AMBER L BEITELSHEES
金额：
$ 63.93万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382252
关键词：
ABCG2 gene Acetoacetates Adverse effects Advocate Agreement American Amish Antidiabetic Drugs Attention Biological Biological Markers Blood Pressure Body Weight Body Weight decreased Candidate Disease Gene Cardiovascular Diseases Cardiovascular system Cessation of life Consensus Cyclophosphamide DNA Sequence Data Diabetes Mellitus Dihydroxycholecalciferols Disease Dose Drug Kinetics Drug Prescriptions Equilibrium European Event Excretory function Fracture GLUT-2 protein General Population Genes Genetic Genetic Markers Genetic Variation Genotype Glucagon Glucose Glycosylated hemoglobin A Hydroxybutyrates Individual Ketone Bodies Literature Measurement Measures Mediating Metabolic Metformin National Heart, Lung, and Blood Institute Outcome Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Pharmacology Phosphorus Physicians Physiological Plasma Population Predisposition Principal Investigator Recording of previous events Reporting Research Research Subjects Risk Safety Serum Sodium Testing Trans-Omics for Precision Medicine Type 2 diabetic Uric Acid Variant base bone health bone loss cardiovascular risk factor clinical efficacy clinical predictors clopidogrel density diabetic patient diet and exercise endophenotype experience genetic variant genome wide association study healthy volunteer individual patient individual response inhibitor inhibitor therapy inorganic phosphate inter-individual variation non-diabetic optimal treatments patient oriented patient population patient response personalized medicine precision medicine predictive marker primary endpoint programs renal tubular reabsorption response secondary endpoint side effect urinary whole genome

项目摘要

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.

钠-葡萄糖协同转运蛋白-2抑制剂是最近批准的一类抗糖尿病药物。这些药物具有吸引人的疗效特征-包括降低主要不良心血管事件的风险，除此之外，还能降糖、减肥和降血压。然而，SGLT 2抑制剂也具有显著的不希望的副作用-包括骨丢失以及骨折，尿脓毒症，和酮症酸中毒在疗效和安全性方面，对这些药物的反应存在显著差异，并且目前没有好的方法来识别可能响应或经历副作用的个体。这申请提出了一个基因组范围内的关联研究，在旧秩序阿米什人口，以确定遗传预测个体对卡格列净（最广泛使用的SGLT 2抑制剂）的反应的变异，剂量为 300 mg/天，持续5天。根据主要研究者的初步研究数据以及根据文献中的信息，拟议项目将测量与以下两项相关的药效学终点： SGLT 2抑制剂的有利和不利影响。该提案包含两个具体目标： ·目标1。确定与临床疗效生物标志物（24小时尿糖排泄）相关的变体 ·目标2。确定与安全性终点的预测性生物标志物相关的变异，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FGF 23、血浆1，25-二羟维生素D和血浆PTH）。将使用高密度阵列进行基因分型，该阵列具有DNA序列的全面覆盖变体。该项目将利用从全基因组序列产生的阿米什特定插补面板通过NHLBI赞助的精准医学Trans-Omics获得的约1100名阿米什人的数据（TOPMed）程序。根据以往的研究历史，在旧秩序阿米什人获得的遗传数据，在一般人群和相关患者人群中的观察结果具有高度预测性。基于这些先例，我们预计这项研究中的遗传变异很可能预测 SGLT 2受体治疗的2型糖尿病患者的临床反应。这项拟议中的研究是朝着确定遗传生物标志物以预测癌症的长期目标迈出的一步。个体患者对SGLT 2抑制剂的反应。预测性生物标志物的可用性将使医生根据有益反应的预测因素为每位患者开出最佳治疗方案，对不良反应的敏感性。这种基于预测的精准医疗方法药物基因组学生物标志物，将是糖尿病药物处方方式的变革性进步。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adverse effects of SGLT2 inhibitors on bone health.

DOI：
10.1038/s41581-018-0028-0
发表时间：
2018-08
期刊：
Nature reviews. Nephrology
影响因子：
0
作者：
Blau JE;Taylor SI
通讯作者：
Taylor SI

YIPF5 mutations cause neonatal diabetes and microcephaly: progress for precision medicine and mechanistic understanding.

YIPF5 突变导致新生儿糖尿病和小头畸形：精准医学和机制理解的进展。

DOI：
10.1172/jci142364
发表时间：
2020
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Pollin,ToniI;Taylor,SimeonI
通讯作者：
Taylor,SimeonI

The High Cost of Diabetes Drugs: Disparate Impact on the Most Vulnerable Patients.

DOI：
10.2337/dci20-0039
发表时间：
2020-10
期刊：
Diabetes care
影响因子：
16.2
作者：
Taylor SI
通讯作者：
Taylor SI

Vitamin D deficiency increases vulnerability to canagliflozin-induced adverse effects on 1,25-dihydroxyvitamin D and PTH.

维生素 D 缺乏会增加卡格列净对 1,25-二羟基维生素 D 和 PTH 产生不利影响的可能性。

DOI：
10.1101/2023.05.11.23289854
发表时间：
2023
期刊：
medRxiv : the preprint server for health sciences
影响因子：
0
作者：
Yazdi,ZhinousShahidzadeh;Streeten,ElizabethA;Whitlatch,HilaryB;Montasser,MayE;Beitelshees,AmberL;Taylor,SimeonI
通讯作者：
Taylor,SimeonI

Individualized Glycemic Goals for Older Adults Are a Moving Target.

老年人的个性化血糖目标是一个不断变化的目标。