Pharmacogenomics of risk factors and therapies outcomes for kidney disease

 描述(由申请人提供)： 肾脏疾病的危险因素和治疗结果的药物基因组学在美国退伍军人中非常普遍，影响着20多万名患者，并与心血管疾病发病率和死亡率的增加有关。对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疾病(CKD)、进展到终末期肾脏疾病(ESRD)和过早死亡的主要手段。然而，药物对治疗的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。这项建议的总体目标是通过在以下三个领域增加我们的理解，利用全基因组关联研究(GWAS)来促进有发病风险和进展性CKD风险的患者的个性化药物治疗：1)治疗T2D的二甲双胍的药物基因组学：二甲双胍是推荐的治疗糖尿病的一线药物，与其他替代方案相比，在减少心血管死亡和CKD发病率方面更具优势。然而，二甲双胍对血糖的反应存在显著的个体间差异5，6。很少有全基因组相关性研究，而且这些研究受到样本量的限制。美国国立卫生研究院最近强调，有必要提高我们对二甲双胍血糖反应的遗传决定因素的理解，这将使二甲双胍的个性化处方成为可能，并有可能预防像CKD这样的糖尿病并发症。2)高血压和难治性高血压(RHT)的遗传决定因素：高血压(HT)是导致肾功能丧失的主要因素，尤其是在RHT患者(定义为用三种或更多药物未能达到血压目标或使用4种或更多药物成功)。在退伍军人中，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在非洲血统中发现了几个与BP性状有关的新基因座。然而，尽管失控的高血压和高血压对健康有严重的长期影响，但还没有关于高血压风险的研究发表。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，并通过防止排斥反应而对移植肾的长期存活至关重要。IT的好处会因剂量不足造成的肾功能损失或因剂量过大而产生的肾毒性而减轻。我们发现他克莫司的血药浓度受细胞色素P450 3A5单核苷酸多态(SNP)rs776746的影响。这项研究将进一步扩大我们对他克莫司水平的遗传决定因素的了解，这对于在KTX中个性化使用他克莫司和预防排斥反应或CNI肾毒性是必不可少的。在这项提案中，我们将利用百万退伍军人计划(MVP)基因数据与退伍军人管理局国家电子病历相关联的资源，提供前所未有的大规模队列，以执行一系列GWA，以发现和验证对这些关键疗法和风险因素的药物反应的遗传决定因素。我们将在范德比尔特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：评估二甲双胍治疗后18个月内使用最低HbA1c的降糖反应的遗传决定因素。目的2：评价高血压病和高血压病的遗传决定因素。目的3：通过常规监测血药浓度和剂量滴定，评价与他克莫司在KTX受者中的药代动力学反应相关的遗传变异。目前的提案将在退伍军人管理局系统中推广个性化医疗，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，我们已经做好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.