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

for DeKAF Genomics

doi:10.1038/s41397-018-0063-z

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

for DeKAF Genomics

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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 language	English (US)
Pages (from-to)	375-389
Number of pages	15
Journal	Pharmacogenomics Journal
Volume	19
Issue number	4
DOIs	https://doi.org/10.1038/s41397-018-0063-z
State	Published - Aug 1 2019

Bibliographical note

Funding Information:
Acknowledgements The authors wish to thank the research subjects for their participation in this study. We acknowledge the dedication and hard work of our coordinators at each of the DeKAF Genomics clinical sites: University of Alberta, Nicoleta Bobocea, Tina Wong, Adrian Geambasu and Alyssa Sader; University of Manitoba, Myrna Ross and Kathy Peters; University of Minnesota, Mandi DeGrote, Monica Meyers, Danielle Berglund and Ashley Roman; Hennepin County Medical Center, Lisa Berndt; Mayo Clinic, Tom DeLeeuw; University of Iowa, Wendy Wallace and Tammy Lowe; University of Alabama, Jacquelin Vaughn, Valencia Stephens and Tena Hilario. We also acknowledge the dedicated work of our research scientist Marcia Brott. This study was supported in part by NIH/NIAID grants 5U19-AI070119 and 5U01-AI058013 and by NIH/NIAID grant K01AI130409 to Casey Dorr.

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© 2018, Springer Nature Limited.

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10.1038/s41397-018-0063-z

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522337

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@article{78b45c185bfe47918e72d2b74eb77883,

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 P.} and Hunsicker, {Lawrence G.} and Kasiske, {Bertram L.} and Rush, {David N.}",

note = "Funding Information: Acknowledgements The authors wish to thank the research subjects for their participation in this study. We acknowledge the dedication and hard work of our coordinators at each of the DeKAF Genomics clinical sites: University of Alberta, Nicoleta Bobocea, Tina Wong, Adrian Geambasu and Alyssa Sader; University of Manitoba, Myrna Ross and Kathy Peters; University of Minnesota, Mandi DeGrote, Monica Meyers, Danielle Berglund and Ashley Roman; Hennepin County Medical Center, Lisa Berndt; Mayo Clinic, Tom DeLeeuw; University of Iowa, Wendy Wallace and Tammy Lowe; University of Alabama, Jacquelin Vaughn, Valencia Stephens and Tena Hilario. We also acknowledge the dedicated work of our research scientist Marcia Brott. This study was supported in part by NIH/NIAID grants 5U19-AI070119 and 5U01-AI058013 and by NIH/NIAID grant K01AI130409 to Casey Dorr. Publisher Copyright: {\textcopyright} 2018, Springer Nature Limited.",

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doi = "10.1038/s41397-018-0063-z",

language = "English (US)",

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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 P.

AU - Hunsicker, Lawrence G.

AU - Kasiske, Bertram L.

AU - Rush, David N.

N1 - Funding Information: Acknowledgements The authors wish to thank the research subjects for their participation in this study. We acknowledge the dedication and hard work of our coordinators at each of the DeKAF Genomics clinical sites: University of Alberta, Nicoleta Bobocea, Tina Wong, Adrian Geambasu and Alyssa Sader; University of Manitoba, Myrna Ross and Kathy Peters; University of Minnesota, Mandi DeGrote, Monica Meyers, Danielle Berglund and Ashley Roman; Hennepin County Medical Center, Lisa Berndt; Mayo Clinic, Tom DeLeeuw; University of Iowa, Wendy Wallace and Tammy Lowe; University of Alabama, Jacquelin Vaughn, Valencia Stephens and Tena Hilario. We also acknowledge the dedicated work of our research scientist Marcia Brott. This study was supported in part by NIH/NIAID grants 5U19-AI070119 and 5U01-AI058013 and by NIH/NIAID grant K01AI130409 to Casey Dorr. Publisher Copyright: © 2018, Springer Nature Limited.

PY - 2019/8/1

Y1 - 2019/8/1

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

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