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.

Public Health Relevance

More than 200,000 veterans have moderate to severe CKD. People with chronic kidney disease (CKD) will die prematurely from cardiovascular disease (CVD) or progress to end stage renal disease (ESRD) and require dialysis. The two main causes of CKD are diabetes and hypertension. Metformin is the first therapy for patients with diabetes, and reduces CVD and progression of CKD. The response to metformin is highly variable and heritable. Additionally there are racial disparities in hypertension and in the way it affects the kidney. Kidney transplan is the only treatment improving survival when ESRD ensues. In this proposal we study the genetic determinants of the response to treatments for diabetes ((pharmacogenomics metformin) and kidney transplant (tacrolimus) and the genetic determinants of hypertension. This will help to personalized treatment choices in the care provided to people with or at risk of kidney disease, in the discovery of new targets for treatment and improve outcomes in the Veteran population afflicted with these conditions.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Initiatives - MVP Projects (SPLM)
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Veterans Health Administration
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Evangelou, Evangelos (see original citation for additional authors) (2018) Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat Genet 50:1412-1425