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Impact of SLCO1B3 polymorphisms on clinical outcomes in lung allograft recipients receiving mycophenolic acid

The Pharmacogenomics Journal volume 20, pages 69–79 (2020)Cite this article

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Abstract

Single-nucleotide polymorphisms (SNPs) in genes involved in mycophenolic acid (MPA) metabolism have been shown to contribute to variable MPA exposure, but their clinical effects are unclear. We aimed to determine if SNPs in key genes in MPA metabolism affect outcomes after lung transplantation. We performed a retrospective cohort study of 275 lung transplant recipients, 228 receiving mycophenolic acid and a control group of 47 receiving azathioprine. Six SNPs known to regulate MPA exposure from the SLCO, UGT and MRP2 families were genotyped. Primary outcome was 1-year survival. Secondary outcomes were 3-year survival, nonminimal (≥A2 or B2) acute rejection, and chronic lung allograft dysfunction (CLAD). Statistical analyses included time-to-event Kaplan–Meier with log-rank test and Cox regression modeling. We found that SLCO1B3 SNPs rs4149117 and rs7311358 were associated with decreased 1-year survival [rs7311358 HR 7.76 (1.37–44.04), p = 0.021; rs4149117 HR 7.28 (1.27–41.78), p = 0.026], increased risk for nonminimal acute rejection [rs4149117 TT334/T334G: OR 2.01 (1.06–3.81), p = 0.031; rs7311358 GG699/G699A: OR 2.18 (1.13–4.21) p = 0.019] and lower survival through 3 years for MPA patients but not for azathioprine patients. MPA carriers of either SLCO1B3 SNP had shorter survival after CLAD diagnosis (rs4149117 p = 0.048, rs7311358 p = 0.023). For the MPA patients, Cox regression modeling demonstrated that both SNPs remained independent risk factors for death. We conclude that hypofunctional SNPs in the SLCO1B3 gene are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with MPA.

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Acknowledgements

LK Tague is supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 and by the Washington University Division of Pulmonary and Critical Care Medicine grant T32HL007317-39 from the National Institutes of Health (NIH). HS Kulkarni is supported by the National Center for Advancing Translational Sciences grant KL2 TR002346 from the NIH. AE Gelman is supported by grants from the Barnes Jewish Foundation, R01HL113436-01A1, 2RHL094601, R01HL121218-01, and P01AI116501-01. The content is solely the responsibility of the authors and does not necessarily represent the official view of Washington University, Barnes Jewish Foundation or the NIH.

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Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University in Saint Louis, Saint Louis, MO, USA

    Laneshia K. Tague, Derek E. Byers, Ramsey Hachem & Hrishikesh S. Kulkarni

  2. Division of Cardiothoracic Surgery, Department of Surgery, Washington University in Saint Louis, Saint Louis, MO, USA

    Daniel Kreisel & Andrew Gelman

  3. Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia, Charlottesville, VA, USA

    Alexander S. Krupnick

  4. Division of Pulmonary and Critical Care Medicine, Department of Medicine, UT Southwestern Medical Center, Dallas, TX, USA

    Catherine Chen

  5. Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, USA

    Howard J. Huang

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Tague, L.K., Byers, D.E., Hachem, R. et al. Impact of SLCO1B3 polymorphisms on clinical outcomes in lung allograft recipients receiving mycophenolic acid. Pharmacogenomics J 20, 69–79 (2020). https://doi.org/10.1038/s41397-019-0086-0

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