Pharmacogenomics of risk factors and therapies outcomes for kidney disease

肾脏疾病危险因素和治疗结果的药物基因组学

• 批准号: 9794745
• 负责人: Adriana Hung
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9794745
• 关键词: Affect; African; African American; Benefits and Risks; Blood; Calcineurin inhibitor; Cardiovascular Diseases; Cardiovascular system; Caring; Cessation of life; Chronic Kidney Failure; Complications of Diabetes Mellitus; Computerized Medical Record; Cytochrome P450; DNA Repository; Data; Data Set; Diabetes Mellitus; Diabetes prevention; Dialysis procedure; Disease Progression; Dose; Drug Kinetics; Drug Monitoring; End stage renal failure; Failure; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic study; Glomerular Filtration Rate; Glycosylated hemoglobin A; Goals; Graft Survival; Health; Healthcare; Heritability; Heterogeneity; High Prevalence; Hypertension; Immunosuppression; Incidence; Individual; Intervention; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Link; Long-Term Effects; Measures; Metformin; Methodology; Mission; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Patients; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacogenomics; Pharmacological Treatment; Pharmacology; Population; Population Programs; Positioning Attribute; Prevalence; Prevention; Publishing; Recurrence; Regimen; Renal function; Resistance; Resistant Hypertension; Resources; Risk; Risk Factors; Sample Size; Series; Severity of illness; Single Nucleotide Polymorphism; Tacrolimus; Therapeutic; Therapeutic Index; Therapeutic immunosuppression; Titrations; Translating; Transplant Recipients; Treatment outcome; United States Department of Veterans Affairs; United States National Institutes of Health; Variant; Vertebral column; Veterans; Work; care systems; cohort; diabetes mellitus genetics; genetic variant; genome wide association study; improved; improved outcome; inter-individual variation; mortality; multidisciplinary; nephrotoxicity; novel; personalized approach; personalized care; personalized medicine; premature; prevent; programs; public health relevance; racial disparity; response; success; therapy outcome; trait; treatment choice; treatment response

 DESCRIPTION (provided by applicant): Pharmacogenomics of risk factors and therapies outcomes for kidney disease Kidney disease is highly prevalent among US Veterans, affecting more than 200,000 patients and it is associated with increased cardiovascular morbidity and mortality. Pharmacologic treatment of major risk factors, including type 2 diabetes mellitus (T2D), hypertension (HT), and immunosuppression after kidney transplantation (KTx), remain the mainstays of preventing chronic kidney disease (CKD), progression to end stage renal disease (ESRD) and premature death. However, wide heterogeneity in both the pharmacologic response to therapies and risk factors limits the full potential benefit of therapy. The overall aim of this proposal is to use genome wide association studies (GWAS) to promote personalized medicine for patients at risk of incident and progressive CKD by increasing our understanding in the following three domains: 1) The pharmacogenomics of metformin for the treatment of T2D: Metformin is the recommended first line therapy for the treatment of diabetes and is superior for reducing CV death and CKD incidence compared to other alternatives. However, marked inter individual variability in the glycemic response to metformin exists5,6. There have been few genome wide association studies and these are limited by the sample size. The NIH recently highlighted the need to improve our understanding of the genetic determinants of the glycemic response to metformin, which will allow personalized prescription of metformin and potentially prevention of diabetes complications like CKD. 2) The Genetic determinants of HT and Resistant HT (RHT): Hypertension (HT) is a major contributor to loss of kidney function, especially among patients with RHT (defined as failure to achieve BP targets with three or more drugs or success with four or more drugs). In the VA population, hypertension prevalence approaches 70%. The prevalence of RHT has been estimated at 9-17% with strong disparities for African Americans (AA). GWAS have identified in African ancestry few novel loci involved in BP traits. However, despite the severe long-term effects of uncontrolled HT and RHT on health, no GWAS studies of RHT risk have been published. 3) The pharmacogenomics of immunosuppressive therapy (IT) after KTx: Calcineurin inhibitors (CNI), such as tacrolimus, are the backbone of IT regimens, and are essential for long-term kidney graft survival by preventing rejection. The benefits of IT are mitigated by loss of kidney function due to under dosing or nephrotoxicity due to over dosing. We have shown that blood concentrations of tacrolimus are influenced by cytochrome P450 3A5 single nucleotide polymorphism (SNP) rs776746. This study will further expand our knowledge in genetic determinants of tacrolimus levels, which are essential for personalized dosing of tacrolimus in KTx and prevention of rejection or CNI nephrotoxicity. In this proposal, we will leverage the resources from the Million Veterans Program (MVP) genetic data linked to the Veterans Administration national electronic medical record, which provide an unprecedented large cohort, to perform a series of GWAS to discover and validate the genetic determinants of the pharmacologic response to these key therapies and risk factors. We will replicate our results in the Vanderbilt DNA Repository. We will accomplish our goals with the following specific aims: Aim 1: To evaluate the genetic determinants of the response to metformin therapy on glycemic lowering response using the lowest HbA1c in the 18 months following an incident metformin prescription. Aim 2: To evaluate the genetic determinants of HT and RHT Aim 3: To evaluate the genetic variants associated with the pharmacokinetic response to tacrolimus in KTx recipients by using routinely measured blood concentrations for therapeutic drug monitoring and dose titration. The current proposal will promote personalized medicine in the VA system for the care provided to patients with or at risk of CKD. We have assembled a multidisciplinary team and we are well poised to conduct the work proposed.

 描述（由申请人提供）： 肾脏疾病危险因素和治疗结果的药物基因组学 肾脏疾病在美国退伍军人中非常普遍，影响超过 200,000 名患者，并且与心血管发病率和死亡率增加相关。主要危险因素的药物治疗，包括 2 型糖尿病 (T2D)、高血压 (HT) 和肾移植后免疫抑制 (KTx)，仍然是预防慢性肾脏病 (CKD)、进展为终末期肾病 (ESRD) 和过早死亡的主要手段。然而，对治疗的药理反应和危险因素的广泛异质性限制了治疗的全部潜在益处。该提案的总体目标是利用全基因组关联研究（GWAS），通过增加我们对以下三个领域的理解，促进对有发生和进行性 CKD 风险的患者进行个性化医疗：1）二甲双胍治疗 T2D 的药物基因组学：二甲双胍是治疗糖尿病的推荐一线疗法，与其他替代药物相比，二甲双胍在减少 CV 死亡和 CKD 发病率方面具有优越性。然而，二甲双胍的血糖反应存在明显的个体差异5,6。几乎没有全基因组关联研究，并且这些研究受到样本量的限制。美国国立卫生研究院 (NIH) 最近强调，需要提高我们对二甲双胍血糖反应的遗传决定因素的了解，这将允许个性化二甲双胍处方，并有可能预防 CKD 等糖尿病并发症。 2) HT 和耐药性 HT (RHT) 的遗传决定因素：高血压 (HT) 是肾功能丧失的主要原因，特别是在 RHT 患者中（定义为使用三种或更多药物未能达到血压目标，或使用四种或更多药物成功）。在 VA 人群中，高血压患病率接近 70%。 RHT 的患病率估计为 9-17%，非洲裔美国人 (AA) 的患病率差异很大。 GWAS 在非洲血统中发现了一些涉及 BP 特征的新位点。然而，尽管不受控制的 HT 和 RHT 对健康产生严重的长期影响，但尚未发表有关 RHT 风险的 GWAS 研究。 3) KTx 后免疫抑制治疗 (IT) 的药物基因组学：钙调神经磷酸酶抑制剂 (CNI)，如他克莫司，是 IT 方案的支柱，通过防止排斥反应对于肾移植物的长期存活至关重要。由于剂量不足导致肾功能丧失或剂量过多导致肾毒性，从而削弱了 IT 的益处。我们已经证明他克莫司的血液浓度受细胞色素 P450 3A5 单核苷酸多态性 (SNP) rs776746 的影响。这项研究将进一步扩大我们对他克莫司水平遗传决定因素的了解，这对于 KTx 中他克莫司的个性化剂量以及预防排斥或 CNI 肾毒性至关重要。在本提案中，我们将利用与退伍军人管理局国家电子病历相关的百万退伍军人计划 (MVP) 遗传数据的资源，该数据提供了前所未有的大型队列，进行一系列 GWAS，以发现和验证对这些关键疗法和风险因素的药理反应的遗传决定因素。我们将在范德比尔特 DNA 存储库中复制我们的结果。我们将通过以下具体目标来实现我们的目标： 目标 1：使用二甲双胍处方后 18 个月内的最低 HbA1c 来评估二甲双胍治疗对血糖降低反应的遗传决定因素。目标 2：评估 HT 和 RHT 的遗传决定因素 目标 3：通过使用常规测量的血液浓度进行治疗药物监测和剂量滴定，评估与 KTx 接受者对他克莫司药代动力学反应相关的遗传变异。目前的提案将促进 VA 系统中的个性化医疗，为患有 CKD 或有 CKD 风险的患者提供护理。我们已经组建了一支多学科团队，并做好了开展拟议工作的准备。