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Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups
Author(s) -
Mohamed Moataz E.,
Schladt David P.,
Guan Weihua,
Wu Baolin,
Setten Jessica,
Keating Brendan J.,
Iklé David,
Remmel Rory P.,
Dorr Casey R.,
Man Roslyn B.,
Matas Arthur J.,
Israni Ajay K.,
Oetting William S.,
Jacobson Pamala A.
Publication year - 2019
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15385
Subject(s) - cyp3a5 , tacrolimus , medicine , kidney transplant , genetic genealogy , cyp3a4 , allele , kidney transplantation , trough level , transplantation , demography , biology , genetics , genotype , population , gene , metabolism , environmental health , sociology , cytochrome p450
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 CYP 3A4 /5 gene‐wide analysis to identify new variants. Daily doses, and dose‐normalized troughs were significantly different between the four groups ( P < .001). CYP 3A5 *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 CYP 3A5*6 (rs10264272) and *7 (rs413003343) variants were only present in African Americans. CYP 3A4*22 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP 3A4 /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.