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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. Tacrolimus doses and troughs vary between kidney transplant recipients of different ancestries, which is possibly related to new variants identified in recipients of Native American and Asian ancestry.

Genetic variation across the human leukocyte antigen loci is known to influence renal‐transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFRat different time‐points, out to 5 years posttransplantation. We conducted GWASmeta‐analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRScalculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFRat 1‐year posttransplant. Thirty‐two percent of the variability in eGFRat 1‐year posttransplant was explained by our model containing clinical covariates (including weights for death/graft‐failure), principal components and combined donor‐recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFRposttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRSbeing a significant predictor of eGFRposttransplant, the effect size of common genetic factors is limited compared to clinical variables. Polygenic risk score of nontransplant eGFR is a significant predictor of eGFR at 1 year posttransplant, but the effect size contributed by these common genetic variants is limited compared to that of clinical variables.