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

The Pharmacogenomics Journal volume 24, Article number: 29 (2024) Cite this article

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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.

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Fig. 1: The distribution of the Extreme Phenotype Sampling (EPS) tacrolimus trough residuals from 128 African American (AA) kidney transplant recipients.
Fig. 2: Tacrolimus troughs and doses in high and low groups.

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Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to patient consent agreements but may be available from the corresponding author on reasonable request if the data use is within patient consent.

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Acknowledgements

The authors would like to thank the research participants for their participation in this study. We thank people at the University of Minnesota Genomic Center for doing the sequencing. We acknowledge the dedication and hard work of our coordinators at each of the DeKAF and GEN03 Genomics clinical sites. This study was supported in part by NIH/NIAID grants 5U19-AI070119, 5U01-AI058013 and K01AI130409 and R21AI171826.

Author information

Authors and Affiliations

  1. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

    Moataz E. Mohamed, Abdelrahman Saqr, William S. Oetting, Pamala A. Jacobson & Casey R. Dorr

  2. Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, MN, USA

    Bin Guo, Weihua Guan & John E. Connett

  3. Department of Epidemiology and Biostatistics, University of California Irvine, Irvine, CA, USA

    Baolin Wu

  4. Hennepin Healthcare Research Institute, Minneapolis, MN, USA

    David P. Schladt, Amutha Muthusamy, Guillaume Onyeaghala, Ajay K. Israni & Casey R. Dorr

  5. Research Informatics, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA

    Juan E. Abrahante

  6. Nephrology Division, Hennepin Healthcare, Department of Medicine, University of Minnesota, Minneapolis, MN, USA

    Guillaume Onyeaghala, Ajay K. Israni, Bertram L. Kasiske & Casey R. Dorr

  7. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA

    Nathan Pankratz

  8. Division of Nephrology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Gaurav Agarwal & Robert S. Gaston

  9. Division of Nephrology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    Roslyn B. Mannon

  10. Division of Transplantation, Department of Surgery, Medical School, University of Minnesota, Minneapolis, MN, USA

    Arthur J. Matas

  11. Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

    Rory P. Remmel

  12. Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA

    Ajay K. Israni

  13. Clinical and Translational Sciences Institute, University of Minnesota, Minneapolis, MN, USA

    Casey R. Dorr

  14. UCLA Immunogenetics Center, Los Angeles, CA, USA

    Michael Cecka

  15. Division of Nephrology, Mayo Clinic, Rochester, MN, USA

    Fernando G. Cosio

  16. Division of Nephrology and Immunology, University of Alberta, Edmonton, AB, Canada

    Sita Gourishankar

  17. Mayo Clinic College of Medicine, Rochester, MN, USA

    Joseph P. Grande

  18. Division of Nephrology, Department of Medicine, University of Iowa, Iowa City, IA, USA

    Lawrence G. Hunsicker

  19. Health Sciences Center, Winnipeg, MB, Canada

    David N. Rush

Authors
  1. Moataz E. Mohamed
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  2. Bin Guo
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  3. Baolin Wu
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  4. David P. Schladt
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  5. Amutha Muthusamy
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  6. Weihua Guan
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  7. Juan E. Abrahante
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  8. Guillaume Onyeaghala
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  9. Abdelrahman Saqr
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  11. Gaurav Agarwal
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Consortia

DeKAF Genomics and GEN03 Investigators

  • Arthur J. Matas
  • , Michael Cecka
  • , John E. Connett
  • , Fernando G. Cosio
  • , Robert S. Gaston
  • , Roslyn B. Mannon
  • , Sita Gourishankar
  • , Joseph P. Grande
  • , Lawrence G. Hunsicker
  • , David N. Rush
  •  & Bertram L. Kasiske

Contributions

Research Design: 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, Casey R. Dorr. Data Analysis: Moataz E. Mohamed, Bin Guo, Baolin Wu, David P. Schladt, Amutha Muthusamy, Weihua Guan, Juan E. Abrahante, William S. Oetting, Rory P. Remmel, Ajay K. Israni, Pamala A. Jacobson, Casey R. Dorr. Lab Experiments: Amutha Muthusamy, Casey R. Dorr. Manuscript Preparation: 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, Casey R. Dorr

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Correspondence to Casey R. Dorr.

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Mohamed, M.E., Guo, B., Wu, B. et al. Extreme phenotype sampling and next generation sequencing to identify genetic variants associated with tacrolimus in African American kidney transplant recipients. Pharmacogenomics J 24, 29 (2024). https://doi.org/10.1038/s41397-024-00349-8

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