Genetic Variants Associated with Tacrolimus Metabolism in Kidney Transplant Recipients

肾移植受者中与他克莫司代谢相关的遗传变异

• 批准号: 10318932
• 负责人: Casey R Dorr
• 金额: $ 12.54万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-03 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318932
• 关键词: ABCB1 gene; Accounting; Acute; Advisory Committees; African American; African American population; Allografting; American; Atrophic; Bioinformatics; Biological Assay; Blood; CRISPR/Cas technology; CYP3A5 gene; Caucasians; Cell Culture Techniques; Cell Line; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Committee Members; Communicable Diseases; County; Cultured Cells; Cytochrome P450; DNA; Data; Data Set; Deterioration; Dose; Education; Engineering; Enrollment; Enzymes; Epidemiology; European; Family; Fibrosis; Frequencies; Future; Gene Activation; Genes; Genetic; Genomic DNA; Genotype; Goals; Grant; Hepatocyte; Human; Immune; Immune System Diseases; Individual; Kidney; Kidney Transplantation; Lesion; Medical center; Mentors; Metabolic; Metabolism; Modeling; Monitor; Nephrology; Organ; Organ Transplantation; Outcome; Outcomes Research; Overdose; Oxidoreductase; Pathway interactions; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Population; Process; Renal function; Research; Research Personnel; Resources; Risk; Role; Sampling; Scientist; Solid; Statistical Models; Tacrolimus; Therapeutic; Therapeutic Index; Time; Toxic effect; Training; Translating; Transplant Recipients; Transplantation; Tubular formation; Update; Validation; Variant; adverse drug reaction; allograft rejection; base; cell bank; clinically relevant; cytochrome P450 3A; dosage; drug metabolism; epidemiology study; genetic epidemiology; genetic variant; genome wide association study; genomic locus; improved; improved outcome; in silico; interpatient variability; kidney allograft; next generation sequencing; precision medicine; prevent; prospective; response; skills; transplant registry; validation studies

ABSTRACT This K01 aims to achieve Dr. Casey Dorr’s objective to become an independent scientist while improving clinical outcomes via genetic epidemiology. Dr. Dorr will: A) Develop genetic epidemiology skills for pharmacogenomics research B) Develop skills in bioinformatics and statistical modeling through formal education and C) Validate epidemiologically identified genetic variants. In the future, these skills will be used to analyze large genetic epidemiology data sets, translate them into dosing models for other drugs, and for cell culture validation studies. Dr. Dorr’s advisory committee is led by his primary, epidemiology and nephrology, mentor, Dr. Ajay Israni, the Deputy Director of the Scientific Registry of Transplant Recipients (SRTR). Co- mentor Dr. Pamala Jacobson will advise on dosing models, pharmacogenomics and precision medicine. Other committee members include: Dr. Bertram Kasiske, Chief of Nephrology at Hennepin County Medical Center, SRTR Director with clinical trials and outcomes research expertise, and Drs. Claudia Neuhauser and Baolin Wu, with statistical modeling and bioinformatics expertise. African Americans (AAs) have worse allograft survival than Caucasians. For narrow therapeutic index drugs, like tacrolimus (Tac), the primary immune suppressant used in solid organ transplantation, inadequate dosing results in allograft rejection and overdosing results in toxicity. Also, intrapatient variability (IPV) of Tac blood concentrations leads to poor outcomes. By identifying and validating the genetic variants that alter drug metabolism, clinicians can select optimal doses to reduce the risk for adverse drug reactions and IPV. Three common CYP3A (drug metabolism enzyme family) variants that alter function were recently identified in our large genome-wide association study of AA kidney transplant patients but only able to explained ~50% of the total variation in Tac metabolism even after accounting for clinical factors. This project aims to understand the variation in Tac metabolism, a model CYP3A substrate, in an AA kidney transplant population. I hypothesize that low-frequency variants in the CYP3A genes (Aim 1), or in non-CYP3A genes associated with Tac (Aim 2), are critical for determining the appropriate Tac dosage. Tac is a model CYP3A drug for developing personalized dosing in precision medicine as blood concentrations are routinely monitored in kidney transplant recipients. Using an extreme phenotype sampling model of AA renal recipients with the highest and lowest Tac blood concentrations (accounting for common genetic variants and clinical factors) we will identify low-frequency variants in the CYP3A gene locus, and genes that influence Tac transport, CYP3A expression or activity using next generation sequencing. Identified variants will be analyzed in silico to identify functional variants. Variants, associated with Tac metabolism, will be validated by engineering into cultured cells via CRISPR technology. We will use cell culture assays to functionally validate variants. Identification and validation of genetic variants associated with Tac metabolism will lead to better Tac dosing models aimed at improving transplant outcomes.

摘要

项目成果

Genetics of acute rejection after kidney transplantation.

• DOI: 10.1111/tri.13084
• 发表时间: 2018-03
• 期刊: Transplant international : official journal of the European Society for Organ Transplantation
• 作者: Dorr CR;Oetting WS;Jacobson PA;Israni AK
• 通讯作者: Israni AK

Implementing community-engaged pharmacogenomics in Indigenous communities.

• DOI: 10.1038/s41467-024-45032-5
• 发表时间: 2024-01-31
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Claw, Katrina G.;Dorr, Casey R.;Woodahl, Erica L.
• 通讯作者: Woodahl, Erica L.

Extreme Phenotype Sampling and Next Generation Sequencing to Identify Genetic Variants Associated with Tacrolimus in African American Kidney Transplant Recipients.

通过极端表型采样和下一代测序来识别非裔美国肾移植受者中与他克莫司相关的遗传变异。

• DOI: 10.21203/rs.3.rs-4050136/v1
• 发表时间: 2024
• 期刊: Research square
• 作者: Mohamed,Moataz;Guo,Bin;Wu,Baolin;Schladt,David;Muthusamy,Amutha;Guan,Weihua;Abrahante,Juan;Onyeaghala,Guillaume;Saqr,Abdelrahman;Pankratz,Nathan;Agarwal,Gaurav;Mannon,Roslyn;Matas,Arthur;Oetting,William;Remmel,Rory;Israni,Aj
• 通讯作者: Israni,Aj