Extreme Phenotype Sampling and Next Generation Sequencing to Identify Genetic Variants Associated with Tacrolimus in African American Kidney Transplant Recipients

TL;DR

This study explores genetic factors affecting tacrolimus levels in African American kidney transplant recipients to improve treatment outcomes.

Contribution

The study uses extreme phenotype sampling and sequencing to identify low-frequency genetic variants influencing tacrolimus pharmacokinetics.

Findings

1,406 variants were suggestively associated with tacrolimus trough levels, but none were significant after correction.

High and low tacrolimus trough groups showed significant differences in dose and concentration despite similar genetic backgrounds.

The study highlights the need to explore additional factors like drug-drug-gene interactions and the pharmacomicrobiome.

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 12mg, respectively. Of 34,542 identified variants across 99 genes, 1,406 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.

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