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.
Bibliographical noteFunding Information:
The authors wish to thank the research subjects for their participation in this study. We acknowledge the dedication and hard work of our coordinators at each of the DeKAF Genomics and GEN03 clinical sites: University of Alberta, Nicoleta Bobocea, Tina Wong, Adrian Geambasu and Alyssa Sader; University of Manitoba, Myrna Ross and Kathy Peters; University of Minnesota, Mandi DeGrote, Monica Myers, and Danielle Berglund; Hennepin County Medical Center, Lisa Berndt; Mayo Clinic, Tom DeLeeuw; University of Iowa, Wendy Wallace and Tammy Lowe; University of Alabama, Jacquelin Vaughn, Valencia Stephens, and Tena Hilario. We also acknowledge the dedicated work of our research scientists Marcia Brott and Amutha Muthusamy. This study was supported by NIH/NIAID grants 5U19-AI070119, K01AI130409, and 5U01-AI058013.
© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons
- clinical research/practice
- immunosuppressant - calcineurin inhibitor: tacrolimus
- translational research/science