TY - JOUR
T1 - Extreme Phenotype Sampling and Next Generation Sequencing to Identify Genetic Variants Associated with Tacrolimus in African American Kidney Transplant Recipients
AU - Mohamed, Moataz
AU - Guo, Bin
AU - Wu, Baolin
AU - Schladt, David
AU - Muthusamy, Amutha
AU - Guan, Weihua
AU - Abrahante, Juan
AU - Onyeaghala, Guillaume
AU - Saqr, Abdelrahman
AU - Pankratz, Nathan
AU - Agarwal, Gaurav
AU - Mannon, Roslyn
AU - Matas, Arthur
AU - Oetting, William
AU - Remmel, Rory
AU - Israni, Ajay
AU - Jacobson, Pamala
AU - Dorr, Casey
PY - 2024/3/14
Y1 - 2024/3/14
N2 - 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.
AB - 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.
U2 - 10.21203/rs.3.rs-4050136/v1
DO - 10.21203/rs.3.rs-4050136/v1
M3 - Article
C2 - 38558983
JO - Research square
JF - Research square
ER -