Extreme phenotype sampling and next generation sequencing to identify genetic variants associated with tacrolimus in African American kidney transplant recipients

Moataz E Mohamed; Bin Guo; Baolin Wu; David P Schladt; Amutha Muthusamy; Weihua Guan; Juan E Abrahante; Guillaume Onyeaghala; Abdelrahman Saqr; Nathan Pankratz; Gaurav Agarwal; Roslyn B Mannon; Arthur J Matas; William S Oetting; Rory P Remmel; Ajay K Israni; Pamala A Jacobson; DeKAF Genomics and GEN03 Investigators; Casey R Dorr

doi:10.1038/s41397-024-00349-8

Extreme phenotype sampling and next generation sequencing to identify genetic variants associated with tacrolimus in African American kidney transplant recipients

Pharmacogenomics J. 2024 Aug 23;24(5):29. doi: 10.1038/s41397-024-00349-8.

Authors

Moataz E Mohamed¹, Bin Guo², Baolin Wu³, David P Schladt⁴, Amutha Muthusamy⁴, Weihua Guan², Juan E Abrahante⁵, Guillaume Onyeaghala^{4

6}, Abdelrahman Saqr¹, Nathan Pankratz⁷, Gaurav Agarwal⁸, Roslyn B Mannon⁹, Arthur J Matas¹⁰, William S Oetting¹, Rory P Remmel¹¹, Ajay K Israni^{4

6

12}, Pamala A Jacobson¹; DeKAF Genomics and GEN03 Investigators; Casey R Dorr^{13

14

15

16}

Collaborators

DeKAF Genomics and GEN03 Investigators:
Michael Cecka, John E Connett, Fernando G Cosio, Robert S Gaston, Sita Gourishankar, Joseph P Grande, Lawrence G Hunsicker, David N Rush, Bertram L Kasiske

Affiliations

¹ Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
² Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
³ Department of Epidemiology and Biostatistics, University of California Irvine, Irvine, CA, USA.
⁴ Hennepin Healthcare Research Institute, Minneapolis, MN, USA.
⁵ Research Informatics, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA.
⁶ Nephrology Division, Hennepin Healthcare, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
⁷ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁸ Division of Nephrology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
⁹ Division of Nephrology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁰ Division of Transplantation, Department of Surgery, Medical School, University of Minnesota, Minneapolis, MN, USA.
¹¹ Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
¹² Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
¹³ Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA. [email protected].
¹⁴ Hennepin Healthcare Research Institute, Minneapolis, MN, USA. [email protected].
¹⁵ Nephrology Division, Hennepin Healthcare, Department of Medicine, University of Minnesota, Minneapolis, MN, USA. [email protected].
¹⁶ Clinical and Translational Sciences Institute, University of Minnesota, Minneapolis, MN, USA. [email protected].

PMID: 39179559
DOI: 10.1038/s41397-024-00349-8

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.

MeSH terms

Adult
Black or African American* / genetics
Cytochrome P-450 CYP3A / genetics
Female
Genetic Variation
High-Throughput Nucleotide Sequencing
Humans
Immunosuppressive Agents* / pharmacokinetics
Kidney Transplantation*
Male
Middle Aged
Pharmacogenomic Variants
Phenotype
Tacrolimus* / pharmacokinetics
Tacrolimus* / therapeutic use
Transplant Recipients

Substances

CYP3A5 protein, human
Cytochrome P-450 CYP3A
Immunosuppressive Agents
Tacrolimus

Abstract

MeSH terms

Substances

Grants and funding