Genetic Determinants of Renal Transplant Survival from African American Donors

非洲裔美国捐赠者肾移植存活的遗传决定因素

• 批准号: 9054671
• 负责人: Jasmin Divers
• 金额: $ 39.4万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054671
• 关键词: ABCB1 gene; AIDS-Associated Nephropathy; Affect; African; African American; Alabama; Allografting; American; Apolipoproteins; BK Virus; CAV1 gene; Cellular biology; Chronic Kidney Failure; Clinical; Code; DNA; Data; Databases; Development; Dialysis procedure; Donor person; End stage renal failure; Environmental Risk Factor; Epithelial Cells; Ethnic Origin; European; Exposure to; Failure; Fibrosis; Focal Segmental Glomerulosclerosis; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Risk; Genetic Translation; Genetic screening method; Genotype; Glomerular Filtration Rate; Goals; Graft Survival; Health; Human; Hypertension; Immunosuppression; Infection; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Link; Lipoproteins; Medical; Medicare; Modality; Modeling; Molecular Profiling; Multi-Drug Resistance; Nephrectomy; Nephrons; Nephrotoxic; Organ; Outcome; P-Glycoprotein; Pathogenesis; Patients; Perfusion; Pharmaceutical Preparations; Phase; Population; Predisposition; Public Health; Quality of life; Quantitative Trait Loci; Registries; Renal function; Reporting; Rodent; Sampling; Scheme; Stress; Survival Rate; Susceptibility Gene; Testing; Time; Translating; Transplant Recipients; Transplantation; United Network for Organ Sharing; Universities; Validation; Variant; Virus Diseases; Work; base; caveolin 1; clinical practice; clinically relevant; cost; disorder risk; environmental stressor; follow-up; forest; gene environment interaction; gene interaction; genetic analysis; genetic association; genetic risk factor; genetic variant; genome wide association study; improved; improved outcome; kidney allograft; kidney cell; mRNA Expression; programs; protein expression; repository; risk variant; screening; tool; transplantation medicine

DESCRIPTION (provided by applicant): Kidney transplantation is the preferred treatment modality for patients with end-stage kidney disease. Compared to dialysis, transplantation leads to improved quality of life, longer patient survival, and considerable cost reductions. Progress in medical therapy has dramatically improved short-term survival of deceased donor kidney transplants (DDKT); however, long-term results remain poor with ten year graft survival rates of only 33.8% in African Americans (AAs), significantly shorter than the 45% survival in European Americans (EAs). New tools to improve long-term graft survival are urgently needed. Genetic risk variants in the Apo lipoprotein L1 (APOL1), multi-drug resistance 1 encoding P-glycoprotein (ABCB1), and caveolin-1 (CAV1) genes in kidney donors significantly shorten allograft survival, providing strong evidence that donor kidney gene variants impact transplant outcomes. This proposal would systematically search for genetic and environmental factors that impact graft survival after DDKT from AA donors. We propose to test variants in 58 replicated nephropathy susceptibility loci for association with long-term kidney transplant graft survival from AA donors. Interactive effects of gene variants with each other and with environmental stressors will be assessed. Human primary kidney cells containing the risk variants associated with allograft failure will then be assessed for alterations in gene expression profiles supporting the genetic association results. Analyses will be conducted in two phases: a discovery phase involving genetic data in 600 unrelated AA donor-kidney DNA samples (yielding 800-900 transplants) with validation in gene expression analyses and follow-up gene*gene and gene*environment interaction studies. A replication phase with an additional 200 AA DDKT DNA samples will be performed along with a combined analysis in all 800 AA kidney donors. Top donor gene associations will be assessed in kidney transplant recipient DNA samples to determine whether effects are specific to donor kidneys. These 58 nephropathy risk variants have improved our understanding of the pathogenesis of kidney disease; however, most have relatively weak effects and low predictive ability limiting clinical utility. We propose a systematic approach, analyzing nephropathy genes identified in genome-wide association studies in kidney transplantation where organs are stressed by prolonged lack of perfusion and exposure to nephrotoxic medications. These factors likely provide a suitable contrast to detect genetic contributors to renal graft survival. This work will likely improve outcomes after DDKT from donors of African ancestry and allow translation of genetic results in an important clinical realm.

描述（申请人提供）：肾移植是终末期肾病患者的首选治疗方式。与透析相比，移植可提高生活质量，延长患者生存时间，并显著降低成本。的进展