# 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.

## Key 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.