Original Clinical Science
Variants in mycophenolate and CMV antiviral drug pharmacokinetic and pharmacodynamic genes and leukopenia in heart transplant recipients

https://doi.org/10.1016/j.healun.2021.05.020Get rights and content

Background

The objective was to assess the relationship between single nucleotide polymorphisms in mycophenolate and cytomegalovirus antiviral drug pharmacokinetic and pharmacodynamic genes and drug-induced leukopenia in adult heart transplant recipients.

Methods

This retrospective analysis included n = 148 patients receiving mycophenolate and a cytomegalovirus antiviral drug. In total, 81 single nucleotide polymorphisms in 21 pharmacokinetic and 23 pharmacodynamic genes were selected for investigation. The primary and secondary outcomes were mycophenolate and/or cytomegalovirus antiviral drug-induced leukopenia, defined as a white blood cell count <3.0 × 109/L, in the first six and 12 months post-heart transplant, respectively.

Results

Mycophenolate and/or cytomegalovirus antiviral drug-induced leukopenia occurred in 20.3% of patients. HNF1A rs1169288 A>C (p.I27L) was associated with drug-induced leukopenia (unadjusted p = 0.002; false discovery rate <20%) in the first six months post-transplant. After adjusting for covariates, HNF1A rs1169288 variant C allele carriers had significantly higher odds of leukopenia compared to A/A homozygotes (odds ratio 6.19; 95% CI 1.97-19.43; p = 0.002). Single nucleotide polymorphisms in HNF1A, SLC13A1, and MBOAT1 were suggestively associated (p < 0.05) with the secondary outcome but were not significant after adjusting for multiple comparisons.

Conclusion

Our data suggest genetic variation may play a role in the development of leukopenia in patients receiving mycophenolate and cytomegalovirus antiviral drugs after heart transplantation. Following replication, pharmacogenetic markers, such as HNF1A rs1169288, could help identify patients at higher risk of drug-induced leukopenia, allowing for more personalized immunosuppressant therapy and cytomegalovirus prophylaxis following heart transplantation.

Section snippets

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Leukopenia is a major cause of morbidity following heart transplantation, occurring in approximately 30% of patients.1,2 In the heart transplant setting, leukopenia is often caused by administration of mycophenolate and cytomegalovirus (CMV) antiviral drugs (i.e., ganciclovir and valganciclovir). The occurrence of leukopenia often results in a dose reduction or temporary discontinuation of one or both of these medications.3 When the mycophenolate dose is reduced or held, it places patients at

Study population

Patients recruited from a previous pharmacogenetic study (ClinicalTrials.gov, NCT01686191), hereafter referred to as the parent study, were considered for inclusion in this retrospective analysis. The parent study enrolled 253 adult heart transplant recipients followed at the University of Colorado Advanced Heart Failure and Transplant Program who were transplanted between March 1985 and August 2016. Participants were included in the parent study if they received a heart-only transplant, were

Patient characteristics

Demographic and clinical characteristics of the 148 participants that met the inclusion criteria for this analysis are listed in Table 1. The cohort consisted primarily of men (76.4%) and individuals of European ancestry (77.7%), with the mean ± SD age at transplant of 49 ± 13 years. Patients were transplanted between October 1996 and August 2016. All patients received mycophenolate mofetil, although four patients (2.7%) were transitioned to mycophenolate sodium due to gastrointestinal adverse

Discussion

This is the first pharmacogenetic study to comprehensively assess the relationship between SNPs in a broad range of mycophenolate and CMV antiviral drug pharmacokinetic and pharmacodynamic genes and drug-induced leukopenia in adult heart transplant recipients. In addition to lower pre-transplant weight and reason for transplant other than ischemic cardiomyopathy, the HNF1A rs1169288 variant C allele was associated with a higher odds of mycophenolate and/or CMV antiviral drug-induced leukopenia

Disclosure statement

J.L. reports consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards Lifesciences, Impulse Dynamics, and VWave and grants from AstraZeneca, Volumetrix, and Sensible Medical. All other authors have no conflicts of interest to report.

Acknowledgments

The parent study was funded by a grant from the American Heart Association (12GRNT12040211). This project/publication is supported by the National Institutes of Health/ National Center for Advancing Translational Sciences (NIH/NCATS) Colorado Clinical and Translational Science Award (CTSA) Grant Number UL1 TR002535 and by NIH/NCATS Colorado CTSA Grant Number TL1 TR002533. Contents are the authors’ sole responsibility and do not necessarily represent official NIH views. The authors are thankful

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