Higher tacrolimus (TAC) dose requirements and lower TAC troughs (TT) in African Americans (AA) relative to Caucasians (CA) have been presumed to be due to a higher frequency of the CYP3A5*1 allele in AAs which results in expression of CYP3A enzyme (and more rapid TAC metabolism). We hypothesized that the CYP3A5*1 allele is not the only reason for enhanced TAC clearance observed in AA. To determine if additional genes may be associated with variation in TT, we compared CA to AA kidney transplant recipients, where all recipients of both populations carried two CYP3A5 loss-of-function alleles (*3, rs776746; *6, rs10264272; or *7, rs41303343) resulting in an absence of CYP3A5 expression. The cohort consisted of 1,430 individuals (100 AA and 1,330 CA) from five study sites. TT were clinically measured at each site. A total of 14,427 TT were analyzed (950 from AA and 13,477 from CA). We found that TT early post-transplant were approximately 1 ng/ml lower in the AA compared to CA recipients, but after day 35 post-tx TT were similar and in a multivariable model including transplant center, time from transplant and simultaneous pancreas-kidney transplant race was not significant variable (p=0.32). Total daily TAC doses were approximately 0.9 mg/day higher in AA than in CA after day 24 post-tx (p=6.6E-4). Even after normalizing for dose and weight, TT remained lower in AA (p=0.02). These data suggest that there may be additional variants in genes that result in higher tacrolimus dose requirements in AA. Potential genes that result in greater AA TAC clearance may be CYP3A4 (which is also involved in tacrolimus metabolism), genes known to influence CYP3A expression or genes which affect enzyme activity. A complete understanding of the impact of population specific genomic variants in genes responsible for TAC metabolism is important to a precision medicine approach to transplant immunosuppression. (Funded by NIAID).

CITATION INFORMATION: Oetting W, Schladt D, Guan W, Remmel R, Dorr C, Sanghavi K, Matas A, Mannon R, Israni A, Jacobson P, For DeKAF Genomics, GEN-03 Investigators Differences in Tacrolimus Troughs and Doses Between Caucasians and African Americans with Two CYP3A5 Loss-of-Function Alleles: Looking Beyond CYP3A5 Expression. Am J Transplant. 2016;16 (suppl 3).

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