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.

抽象的 这个K01旨在实现Casey Dorr博士成为一名独立科学家的目标，同时提高 通过遗传流行病学得出临床结果。Dorr 博士将： A) 培养遗传流行病学技能： 药物基因组学研究 B) 通过形式化培养生物信息学和统计建模技能 教育和 C) 验证流行病学鉴定的遗传变异 将来，这些技能将用于 分析大型遗传流行病学数据集，将其转化为其他药物和细胞的剂量模型 培养验证研究。Dorr 博士的咨询委员会由他的初级、流行病学和肾脏病学领导， 导师 Ajay Israni 博士，移植受者科学登记处 (SRTR) 副主任。 导师帕玛拉·雅各布森博士将就剂量模型、药物基因组学和精准医学提供建议。 委员会成员包括：亨内平县医疗中心肾脏病科主任 Bertram Kasiske 博士、 具有临床试验和结果研究专业知识的 SRTR 主任，以及 Claudia Neuhauser 和 Baolin 博士。 吴拥有统计模型和生物信息学专业知识，非裔美国人 (AA) 的同种异体移植物较差。 对于治疗指数较窄的药物，如他克莫司 (Tac)，主要免疫药物的生存率高于白种人。 实体器官移植中使用的抑制剂，剂量不足会导致同种异体移植排斥和用药过量 此外，Tac 血液浓度的患者体内变异性 (IPV) 也会导致不良结果。 通过识别和验证改变药物代谢的遗传变异，饲养者可以选择最佳剂量 降低药物不良反应和 IPV 的风险。三种常见的 CYP3A（药物代谢酶家族）。 最近，我们在 AA 肾的大型全基因组关联研究中发现了改变功能的变异 移植患者，但即使在移植后也只能解释大约 50% 的 Tac 代谢总变化 该项目旨在了解 Tac 代谢模型的变化。 CYP3A 底物，在 AA 肾移植群体中，我追踪了低频变异。 CYP3A 基因（目标 1）或与 Tac 相关的非 CYP3A 基因（目标 2）对于确定 适当的 Tac 剂量 Tac 是一种模型 CYP3A 药物，用于开发精确的个性化剂量。 常规监测肾移植受者的血液浓度。 具有最高和最低 Tac 血液浓度的 AA 肾受者的表型采样模型 （考虑到常见的遗传变异和临床因素）我们将识别低频变异 CYP3A 基因位点，以及影响 Tac 转运、CYP3A 表达或活性的基因 将通过计算机分析确定的变体以鉴定功能变体， 与 Tac 代谢相关的，将通过 CRISPR 技术工程化到培养细胞中进行验证。 我们将使用细胞培养测定来功能验证变异体的识别和验证。 与 Tac 代谢相关的研究将导致更好的 Tac 剂量模型，旨在改善移植结果。

项目成果

Genetic Variants Associated With Immunosuppressant Pharmacokinetics and Adverse Effects in the DeKAF Genomics Genome-wide Association Studies.

DeKAF 基因组全基因组关联研究中与免疫抑制剂药代动力学和不良反应相关的遗传变异。

• 发表时间: 2019-06
• 影响因子: 6.2
• 作者: Oetting, William S;Wu, Baolin;Schladt, David P;Guan, Weihua;van Setten, Jessica;Keating, Brendan J;Iklé, David;Remmel, Rory P;Dorr, Casey R;Mannon, Roslyn B;Matas, Arthur J;Israni, Ajay K;Jacobson, Pamala A;DeKAF Genomics and GEN
• 通讯作者: DeKAF Genomics and GEN

Tacrolimus Elimination in Four Patients With a CYP3A5*3/*3 CYP3A4*22/*22 Genotype Combination.

四名具有 CYP3A5*3/*3 CYP3A4*22/*22 基因型组合的患者中的他克莫司消除。

• 发表时间: 2018-07
• 影响因子: 4.1
• 作者: Scheibner, Aileen;Remmel, Rory;Schladt, David;Oetting, William S;Guan, Weihua;Wu, Baolin;Dorr, Casey;Israni, Ajay;Jacobson, Pamala A
• 通讯作者: Jacobson, Pamala A

Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing.

通过极端表型采样和下一代测序鉴定与肾移植受者他克莫司代谢相关的遗传变异。

• 发表时间: 2019-08
• 作者: Dorr, Casey R;Wu, Baolin;Remmel, Rory P;Muthusamy, Amutha;Schladt, David P;Abrahante, Juan E;Guan, Weihua;Mannon, Roslyn B;Matas, Arthur J;Oetting, William S;Jacobson, Pamala A;Israni, Ajay K;for DeKAF Genomics
• 通讯作者: for DeKAF Genomics

Analysis of 75 Candidate SNPs Associated With Acute Rejection in Kidney Transplant Recipients: Validation of rs2910164 in MicroRNA MIR146A.

与肾移植受者急性排斥相关的 75 个候选 SNP 分析：MicroRNA MIR146A 中 rs2910164 的验证。

• 发表时间: 2019-08
• 影响因子: 6.2
• 作者: Oetting, William S;Schladt, David P;Dorr, Casey R;Wu, Baolin;Guan, Weihua;Remmel, Rory P;Iklé, David;Mannon, Roslyn B;Matas, Arthur J;Israni, Ajay K;Jacobson, Pamala A;DeKAF Genomics and GEN03 Investigators
• 通讯作者: DeKAF Genomics and GEN03 Investigators

Implementing community-engaged pharmacogenomics in Indigenous communities.

在土著社区实施社区参与的药物基因组学。

• 发表时间: 2024-01-31
• 影响因子: 16.6
• 作者: Claw, Katrina G;Dorr, Casey R;Woodahl, Erica L
• 通讯作者: Woodahl, Erica L