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

for DeKAF Genomics

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2 Citations (Scopus)

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.

Original languageEnglish (US)
JournalPharmacogenomics Journal
DOIs
StateAccepted/In press - Jan 1 2018

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Tacrolimus
African Americans
Phenotype
Kidney
Genomics
Gene Frequency
Allografts
Transplant Recipients
Genes
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

@article{5b6bcb7555964d19a4d53047912267dc,
title = "Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing",
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.",
author = "{for DeKAF Genomics} and Dorr, {Casey R.} and Baolin Wu and Remmel, {Rory P.} and Amutha Muthusamy and Schladt, {David P.} and Abrahante, {Juan E.} and Weihua Guan and Mannon, {Roslyn B.} and Matas, {Arthur J.} and Oetting, {William S.} and Jacobson, {Pamala A.} and Israni, {Ajay K.} and Matas, {Arthur J.} and Cecka, {J. Michael} and Connett, {John E.} and Cosio, {Fernando G} and Gaston, {Robert S.} and Mannon, {Rosalyn B.} and Sita Gourishankar and Grande, {Joseph Peter} and Hunsicker, {Lawrence G.} and Kasiske, {Bertram L.} and Rush, {David N.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1038/s41397-018-0063-z",
language = "English (US)",
journal = "Pharmacogenomics Journal",
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T1 - Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing

AU - for DeKAF Genomics

AU - Dorr, Casey R.

AU - Wu, Baolin

AU - Remmel, Rory P.

AU - Muthusamy, Amutha

AU - Schladt, David P.

AU - Abrahante, Juan E.

AU - Guan, Weihua

AU - Mannon, Roslyn B.

AU - Matas, Arthur J.

AU - Oetting, William S.

AU - Jacobson, Pamala A.

AU - Israni, Ajay K.

AU - Matas, Arthur J.

AU - Cecka, J. Michael

AU - Connett, John E.

AU - Cosio, Fernando G

AU - Gaston, Robert S.

AU - Mannon, Rosalyn B.

AU - Gourishankar, Sita

AU - Grande, Joseph Peter

AU - Hunsicker, Lawrence G.

AU - Kasiske, Bertram L.

AU - Rush, David N.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

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