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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。

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

机构信息

Hennepin Healthcare Research Institute, Minneapolis, MN, USA.

Department of Medicine, Hennepin Healthcare, University of Minnesota, Minneapolis, MN, USA.

出版信息

Pharmacogenomics J. 2019 Aug;19(4):375-389. doi: 10.1038/s41397-018-0063-z. Epub 2018 Nov 16.

DOI:10.1038/s41397-018-0063-z
PMID:30442921
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6522337/
Abstract

An extreme phenotype sampling (EPS) model with targeted next-generation sequencing (NGS) identified genetic variants associated with tacrolimus (Tac) metabolism in subjects from the Deterioration of Kidney Allograft Function (DeKAF) Genomics cohort which included 1,442 European Americans (EA) and 345 African Americans (AA). This study included 48 subjects separated into 4 groups of 12 (AA high, AA low, EA high, EA low). Groups were selected by the extreme phenotype of dose-normalized Tac trough concentrations after adjusting for common genetic variants and clinical factors. NGS spanned > 3 Mb of 28 genes and identified 18,661 genetic variants (3961 previously unknown). A group of 125 deleterious variants, by SIFT analysis, were associated with Tac troughs in EAs (burden test, p = 0.008), CYB5R2 was associated with Tac troughs in AAs (SKAT, p = 0.00079). In CYB5R2, rs61733057 (increased allele frequency in AAs) was predicted to disrupt protein function by SIFT and PolyPhen2 analysis. The variants merit further validation.

摘要

采用靶向下一代测序（NGS）的极端表型抽样（EPS）模型，鉴定了与来自肾功能恶化的肾移植功能丧失（DeKAF）基因组学队列中他克莫司（Tac）代谢相关的遗传变异，该队列包括 1442 名欧洲裔美国人（EA）和 345 名非裔美国人（AA）。这项研究包括 48 名受试者，分为 4 组，每组 12 名（AA 高、AA 低、EA 高、EA 低）。根据调整常见遗传变异和临床因素后的剂量标准化 Tac 谷浓度的极端表型选择组。NGS 跨越了 28 个基因的 3Mb 以上区域，鉴定出 18661 个遗传变异（3961 个以前未知）。通过 SIFT 分析，一组 125 个有害变异与 EA 的 Tac 谷浓度相关（负担测试，p=0.008），CYB5R2 与 AA 的 Tac 谷浓度相关（SKAT，p=0.00079）。在 CYB5R2 中，rs61733057（AA 中增加的等位基因频率）通过 SIFT 和 PolyPhen2 分析预测会破坏蛋白功能。这些变异值得进一步验证。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f97/6522337/542efeee4559/nihms-1508276-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f97/6522337/b1ce73c4656f/nihms-1508276-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f97/6522337/d0f00bf0f18e/nihms-1508276-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f97/6522337/947daa6a80ec/nihms-1508276-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f97/6522337/542efeee4559/nihms-1508276-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f97/6522337/b1ce73c4656f/nihms-1508276-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f97/6522337/d0f00bf0f18e/nihms-1508276-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f97/6522337/947daa6a80ec/nihms-1508276-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f97/6522337/542efeee4559/nihms-1508276-f0004.jpg

相似文献

[1]
Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing.

Pharmacogenomics J. 2018-11-16

[2]
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Am J Transplant. 2016-2

[3]
Tacrolimus trough and dose intra-patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European American and African American kidney transplant recipients.

Clin Transplant. 2018-10-31

[4]
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[5]
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[6]
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[7]
Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients.

Am J Kidney Dis. 2017-11-20

[8]
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[9]
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Am J Transplant. 2019-5-13

[10]
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引用本文的文献

[1]
Pharmacogenomics education, research and clinical implementation in the state of Minnesota.

Pharmacogenomics. 2021-7

[2]
Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients.

Clin Transl Sci. 2021-5

[3]
A Machine Learning-Based Identification of Genes Affecting the Pharmacokinetics of Tacrolimus Using the DMET Plus Platform.

Int J Mol Sci. 2020-4-4

[4]
Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Int J Mol Sci. 2020-1-29

[5]
Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups.

Am J Transplant. 2019-5-13

本文引用的文献

[1]
Genome-wide association study identifies the common variants in CYP3A4 and CYP3A5 responsible for variation in tacrolimus trough concentration in Caucasian kidney transplant recipients.

Pharmacogenomics J. 2018-5-22

[2]
CRISPR/Cas9 Genetic Modification of in HuH-7 Human Hepatocyte Cell Line Leads to Cell Lines with Increased Midazolam and Tacrolimus Metabolism.

Drug Metab Dispos. 2017-8

[3]
High Tacrolimus Clearance Is a Risk Factor for Acute Rejection in the Early Phase After Renal Transplantation.

Transplantation. 2017-8

[4]
Optimized pipeline of MuTect and GATK tools to improve the detection of somatic single nucleotide polymorphisms in whole-exome sequencing data.

BMC Bioinformatics. 2016-11-8

[5]
A New CYP3A5*3 and CYP3A4*22 Cluster Influencing Tacrolimus Target Concentrations: A Population Approach.

Clin Pharmacokinet. 2017-8

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Impact of FOXP3 Polymorphisms on the Blood Level of Tacrolimus in Renal Transplant Recipients.

Transplant Proc. 2016

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Genome Biol. 2016-6-6

[8]
Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer.

J Thorac Oncol. 2016-1

[9]
Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility.

Hum Genomics. 2016-1-7

[10]
Exome-based case-control association study using extreme phenotype design reveals novel candidates with protective effect in diabetic retinopathy.

Hum Genet. 2015-12-22

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