Polymorphisms in Mycophenolate Mofetil Glucuronidation Gene Are Associated with Leukopenia and Decreased CLAD-Free Survival

A. Barnes, D. R. Calabrese, E. Henricksen, R. Florez, K. Dewey, P. Wang, J. Teraoka, K. Lien, S. Hays, J. P. Singer, J. Golden, J. Kukreja, J. R. Greenland

UCSF Medical Center, San Francisco, CA

Meeting: 2019 American Transplant Congress

Abstract number: 397

Keywords: Gene polymorphism, Immunosuppression, Lung transplantation, Mycophenolate mofetil

Session Information

Session Name: Concurrent Session: Non-Organ Specific: Pharmacogenomics / Pharmacokinetics

Session Type: Concurrent Session

Date: Monday, June 3, 2019

Session Time: 4:30pm-6:00pm

Presentation Time: 5:18pm-5:30pm

Location: Room 210

*Purpose: Lung transplant recipients vary in their tolerance of the immunosuppressant mycophenolate mofetil (MMF). Single nucleotide polymorphisms (SNPs) in UDP-glucuronosyltransferase 2B7 (UGT2B7) increase conversion of MMF into the active and potentially toxic metabolite MPA-acyl-glucuronide (AcMPAG). We hypothesized that these UGT2B7 polymorphisms would result in worse chronic lung allograft dysfunction (CLAD)-free survival due to effects of toxic metabolites.

*Methods: We performed a single-center retrospective cohort study of 322 lung transplant recipients from 3/2000 to 12/2016. Patients were excluded if they were not taking MMF immediately post-transplant. Two SNPs, rs7438135 and rs28365063, in the UGT2B7 gene were measured with the iGeneTRAiN consortium SNP chip. Clinical data including medication dosing, baseline characteristics, spirometry, and mortality were collected via chart review. Outcomes of interest were time to leukopenia, time to MMF dose reduction, and CLAD-free survival. Cox proportional hazards models were used to assess hazard ratios between SNPs and outcomes of interest.

*Results: There were no significant differences in subject characteristics for carriers of SNPs of interest. Subjects homozygous for rs7438135 (AA) conferring increased glucuronidation had decreased time to leukopenia (n = 88, 81 IQR 54-521 days, p = 0.004) compared to wild-type (GG) and heterozygous (GA) carriers (n = 234, 162 IQR 54-521 days). Similarly, subjects with GG genotypes of the rs28365063 SNP (n = 7) demonstrated decreased time to leukopenia (42 IQR 24-63 days) compared to wild-type (AA) and heterozygous (AG) carriers (n = 315, 131.5 days IQR 51-540 days, p = 0.003). Decreased CLAD-free survival was observed in subjects homozygous for rs7438135 (HR 1.5, p = 0.01) and rs28365063 (HR 3.2, p = 0.02) compared to wild-type and heterozygous subjects. There were no differences observed in time to MMF dose reduction between genotypes of these two SNPs.

*Conclusions: SNPs in genes involved in MMF glucuronidation are associated with clinically significant lung transplant outcomes. This association may be attributable to leukopenia from accumulation of toxic metabolites.

To cite this abstract in AMA style:

Barnes A, Calabrese DR, Henricksen E, Florez R, Dewey K, Wang P, Teraoka J, Lien K, Hays S, Singer JP, Golden J, Kukreja J, Greenland JR. Polymorphisms in Mycophenolate Mofetil Glucuronidation Gene Are Associated with Leukopenia and Decreased CLAD-Free Survival [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/polymorphisms-in-mycophenolate-mofetil-glucuronidation-gene-are-associated-with-leukopenia-and-decreased-clad-free-survival/. Accessed November 22, 2024.

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