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

the DeKAF Genomics and GEN03 Investigators

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Tacrolimus trough and dose requirements vary dramatically between individuals of European and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism. We studied the well-known variants and conducted a CYP3A4/5 gene-wide analysis to identify new variants. Daily doses, and dose-normalized troughs were significantly different between the four groups (P <.001). CYP3A5*3 (rs776746) was associated with higher dose-normalized tacrolimus troughs in all groups but occurred at different allele frequencies and had differing effect sizes. The CYP3A5*6 (rs10264272) and *7 (rs413003343) variants were only present in African Americans. CYP3A4*22 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP3A4/5 genes associated with dose-normalized troughs in Native Americans (P = 1.1 × 10−5-8.8 × 10−6) and one suggestive variant in Asian Americans (P = 5.6 × 10−6). Tacrolimus daily doses and dose-normalized troughs vary significantly among different ancestry groups. We identified potential new variants important in Asians and Native Americans. Studies with larger populations should be conducted to assess the importance of the identified suggestive variants.

Original languageEnglish (US)
Pages (from-to)2795-2804
Number of pages10
JournalAmerican Journal of Transplantation
Volume19
Issue number10
DOIs
StatePublished - Oct 1 2019

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Cytochrome P-450 CYP3A
Tacrolimus
North American Indians
Kidney
African Americans
Asian Americans
Gene Frequency
Population
Genes
Multicenter Studies
Transplant Recipients
Prospective Studies

Keywords

  • clinical research/practice
  • genetics
  • immunosuppressant - calcineurin inhibitor: tacrolimus
  • pharmacokinetics/pharmacodynamics
  • pharmacology
  • translational research/science

PubMed: MeSH publication types

  • Journal Article

Cite this

Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients : A comparison of four ancestry groups. / the DeKAF Genomics and GEN03 Investigators.

In: American Journal of Transplantation, Vol. 19, No. 10, 01.10.2019, p. 2795-2804.

Research output: Contribution to journalArticle

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abstract = "Tacrolimus trough and dose requirements vary dramatically between individuals of European and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism. We studied the well-known variants and conducted a CYP3A4/5 gene-wide analysis to identify new variants. Daily doses, and dose-normalized troughs were significantly different between the four groups (P <.001). CYP3A5*3 (rs776746) was associated with higher dose-normalized tacrolimus troughs in all groups but occurred at different allele frequencies and had differing effect sizes. The CYP3A5*6 (rs10264272) and *7 (rs413003343) variants were only present in African Americans. CYP3A4*22 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP3A4/5 genes associated with dose-normalized troughs in Native Americans (P = 1.1 × 10−5-8.8 × 10−6) and one suggestive variant in Asian Americans (P = 5.6 × 10−6). Tacrolimus daily doses and dose-normalized troughs vary significantly among different ancestry groups. We identified potential new variants important in Asians and Native Americans. Studies with larger populations should be conducted to assess the importance of the identified suggestive variants.",
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AU - Schladt, David P.

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AU - Wu, Baolin

AU - van Setten, Jessica

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AU - Gaston, Robert

AU - Gourishankar, Sita

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AU - Kasiske, Bertram

AU - Rush, David

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