Pharmacogenomics of risk factors and therapies outcomes for kidney disease

 描述（由申请人提供）： 肾脏疾病的风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20万名患者，并且与心血管发病率和死亡率增加相关。主要风险因素的药物治疗，包括2型糖尿病（T2 D）、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）、进展为终末期肾脏病（ESRD）和过早死亡的主要手段。然而，对治疗的药理学反应和风险因素的广泛异质性限制了治疗的全部潜在益处。本提案的总体目标是通过增加我们对以下三个领域的理解，使用全基因组关联研究（GWAS）来促进有发生和进行性CKD风险的患者的个性化用药：1）二甲双胍治疗T2 D的药物基因组学：二甲双胍是治疗糖尿病的推荐一线疗法，在降低CV死亡和CKD发生率方面上级其他替代品.然而，二甲双胍的血糖反应存在显著的个体间差异5，6。有几个基因组广泛的关联研究，这些都受到样本量的限制。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理解，这将允许二甲双胍的个性化处方，并可能预防糖尿病并发症，如CKD。2)HT和耐药HT（RHT）的遗传决定因素：高血压（HT）是肾功能丧失的主要因素，特别是在RHT患者中（定义为使用三种或更多种药物未能达到BP目标或使用四种或更多种药物成功）。在VA人群中，高血压患病率接近70%。据估计，RHT的患病率为9-17%，非洲裔美国人（AA）的患病率差异很大。GWAS在非洲祖先中发现了一些与BP性状有关的新位点。然而，尽管不受控制的HT和RHT对健康有严重的长期影响，但尚未发表关于RHT风险的GWAS研究。3)KTx后免疫抑制治疗（IT）的药物基因组学：钙调磷酸酶抑制剂（CNI），如他克莫司，是IT方案的支柱，通过预防排斥反应对长期肾移植存活至关重要。IT的获益因剂量不足导致的肾功能丧失或剂量过量导致的肾毒性而减轻。我们已经证明，他克莫司的血药浓度受细胞色素P450 3A 5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给药和预防排斥反应或CNI肾毒性至关重要。在这项提案中，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，这些数据提供了前所未有的大型队列，以进行一系列GWAS，以发现和验证对这些关键疗法和风险因素的药理学反应的遗传决定因素。我们会在范德比尔特的DNA库中复制我们的结果。我们将通过以下具体目标实现我们的目标：目标1：使用二甲双胍处方后18个月内的最低HbA 1c评价二甲双胍治疗对降糖反应的遗传决定因素。目标二：评价HT和RHT的遗传决定因素目的3：通过使用常规测量的血药浓度进行治疗药物监测和剂量滴定，评价KTx接受者中与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CKD患者或有CKD风险的患者提供护理。我们已经组建了一个多学科小组，我们已做好充分准备开展拟议的工作。

 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.