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.

葡萄糖葡萄糖共转运蛋白-2抑制剂是最近批准的抗糖尿病药物类。这些药物具有吸引人的效率 - 包括降低重大不良心血管事件的风险除了降低葡萄糖，减肥和降压降压。但是，SGLT2抑制剂也具有明显的不希望的副作用 - 包括骨质流失以及骨折的风险增加，尿刺，和酮症酸中毒。就效率和安全性而言，对这些药物的响应存在明显的可变性，目前，没有一个很好的方法来识别可能反应或经历副作用的个人。这应用建议在旧秩序阿米什人种群中进行全基因组的关联研究，以识别遗传预测个体对Canagliflozin（使用最广泛使用的SGLT2抑制剂）的反应的变体 300毫克/天5天。基于主要研究者研究的初步数据来自文献的信息，拟议的项目将衡量与两者相关的药效终点 SGLT2抑制剂的有益和不利影响。该提案包含两个具体目标：目标1。确定与临床效率生物标志物相关的变体（24小时尿葡萄糖排泄）目标2。确定与预测性生物标志物相关的安全终点的变体，包括等离子体胰高血糖素，酮体，心血管生物标志物（尿酸和血压）以及骨骼的生物标志物健康（血清磷，血浆FGF23，等离子体1,25-二羟基乙他素D和血浆PTH）。基因分型将使用具有全面覆盖DNA序列的高密度阵列进行变体。该项目将利用由整个基因组序列产生的特定于Amish特定的插补面板关于通过NHLBI赞助的跨词的〜1100个Amish个体的数据（顶）程序。根据先前研究的历史，以旧顺序Amish获得的遗传数据人口已经高度预测了普通人群和相关患者人群的观察结果。基于这些先例，我们预计本研究中的遗传变异很可能可以预测 SGLT2抑制剂治疗的2型糖尿病患者的临床反应。拟议的研究是朝着鉴定遗传生物标志物预测遗传生物标志物的长期目标的一步个体患者对SGLT2抑制剂的反应。预测生物标志物的可用性将使医生根据有益反应的预测指标和对不利影响的敏感性。基于预测性的这种精确医学方法药物基因组生物标志物将是糖尿病药物处方的方式的转变。

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。