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 journalArticle

35 Citations (Scopus)

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

Fingerprint

Cytochrome P-450 CYP3A
Tacrolimus
African Americans
Alleles
Kidney
Allografts
Glomerular Filtration Rate
Cytochrome P-450 Enzyme System
Transplant Recipients
Pancreas
Demography
Transplants
Antibodies
Enzymes
Pharmaceutical Preparations
Genes

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

Cite this

Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles. / Oetting, William S.; Schladt, D. P.; Guan, W.; Miller, M. B.; Remmel, R. P.; Dorr, C.; Sanghavi, K.; Mannon, R. B.; Herrera, B.; Matas, A. J.; Salomon, D. R.; Kwok, P. Y.; Keating, B. J.; Israni, A. K.; Jacobson, P. A.

In: American Journal of Transplantation, Vol. 16, No. 2, 01.02.2016, p. 574-582.

Research output: Contribution to journalArticle

Oetting, William S. ; Schladt, D. P. ; Guan, W. ; Miller, M. B. ; Remmel, R. P. ; Dorr, C. ; Sanghavi, K. ; Mannon, R. B. ; Herrera, B. ; Matas, A. J. ; Salomon, D. R. ; Kwok, P. Y. ; Keating, B. J. ; Israni, A. K. ; Jacobson, P. A. / Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles. In: American Journal of Transplantation. 2016 ; Vol. 16, No. 2. pp. 574-582.
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AU - Guan, W.

AU - Miller, M. B.

AU - Remmel, R. P.

AU - Dorr, C.

AU - Sanghavi, K.

AU - Mannon, R. B.

AU - Herrera, B.

AU - Matas, A. J.

AU - Salomon, D. R.

AU - Kwok, P. Y.

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