Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles

William S. Oetting, D. P. Schladt, W. Guan, M. B. Miller, R. P. Remmel, C. Dorr, K. Sanghavi, R. B. Mannon, B. Herrera, A. J. Matas, D. R. Salomon, P. Y. Kwok, B. J. Keating, A. K. Israni, P. A. Jacobson

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5∗3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5∗6 (rs10264272) and CYP3A5∗7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.

Original languageEnglish (US)
Pages (from-to)574-582
Number of pages9
JournalAmerican Journal of Transplantation
Volume16
Issue number2
DOIs
StatePublished - Feb 1 2016

Bibliographical note

Funding Information:
The authors wish to thank the research participants 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 and Danielle Berglund; Hennepin County Medical Center, Lisa Berndt; Mayo Clinic, Tom DeLeeuw; University of Iowa, Wendy Wallace and Tammy Lowe; University of Alabama, Jacquelin Vaughn and Tena Hilario. We also acknowledge the dedicated work of our research scientists Marcia Brott and Amutha Muthusamy. This study was supported in part by NIH/NIAID grants 5U19-AI070119 and 5U01-AI058013.

Publisher Copyright:
Copyright © 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Keywords

  • basic (laboratory) research/science
  • genetics
  • genomics
  • immunosuppressant; calcineurin inhibitor: tacrolimus
  • immunosuppression/immune modulation
  • microarray/gene array
  • molecular biology: DNA
  • molecular biology: single polynucleotide polymorphism

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