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: 10054651
• 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/10054651
• 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.



项目成果

Racial Differences and Contributory Cardiovascular and Non-Cardiovascular Risk Factors Towards Chronic Kidney Disease Progression.

• DOI: 10.2147/vhrm.s416395
• 发表时间: 2023
• 期刊: Vascular health and risk management
• 影响因子: 2.9

Publisher Correction: Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

出版商更正：通过对 130 万人的荟萃分析发现了与血压调节相关的罕见变异。

• DOI: 10.1038/s41588-021-00832-z
• 发表时间: 2021
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Surendran,Praveen;Feofanova,ElenaV;Lahrouchi,Najim;Ntalla,Ioanna;Karthikeyan,Savita;Cook,James;Chen,Lingyan;Mifsud,Borbala;Yao,Chen;Kraja,AldiT;Cartwright,JamesH;Hellwege,JacklynN;Giri,Ayush;Tragante,Vinicius;Thorleifsson,
• 通讯作者: Thorleifsson,