1. Extreme phenotype sampling and next generation sequencing to identify genetic variants associated with tacrolimus in African American kidney transplant recipients.
- Author
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Mohamed ME, Guo B, Wu B, Schladt DP, Muthusamy A, Guan W, Abrahante JE, Onyeaghala G, Saqr A, Pankratz N, Agarwal G, Mannon RB, Matas AJ, Oetting WS, Remmel RP, Israni AK, Jacobson PA, and Dorr CR
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Cytochrome P-450 CYP3A genetics, Genetic Variation, High-Throughput Nucleotide Sequencing, Pharmacogenomic Variants, Phenotype, Transplant Recipients, Black or African American genetics, Immunosuppressive Agents pharmacokinetics, Kidney Transplantation, Tacrolimus pharmacokinetics, Tacrolimus therapeutic use
- Abstract
African American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n = 58) and low (n = 60) TAC troughs (N = 515 AA KTRs). Targeted next generation sequencing was conducted in these two groups. Median TAC troughs in the high group were 7.7 ng/ml compared with 6.3 ng/ml in the low group, despite lower daily doses of 5 versus 12 mg, respectively. Of 34,542 identified variants across 99 genes, 1406 variants were suggestively associated with TAC troughs in univariate models (p-value < 0.05), however none were significant after multiple testing correction. We suggest future studies investigate additional sources of TAC pharmacokinetic variability such as drug-drug-gene interactions and pharmacomicrobiome., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
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