Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction

Joshua M. Diamond, Tatiana Akimova, Altaf Kazi, Rupal J. Shah, Edward Cantu, Rui Feng, Matthew H. Levine, Steven M. Kawut, Nuala J. Meyer, James C. Lee, Wayne W. Hancock, Richard Aplenc, Lorraine B. Ware, Scott M. Palmer, Sangeeta Bhorade, Vibha N. Lama, Ann Weinacker, Jonathan Orens, Keith Wille, Maria CrespoDavid J. Lederer, Selim Arcasoy, Ejigayehu Demissie, Jason D. Christie

Research output: Contribution to journalArticle

Abstract

Rationale: Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses. Objectives:Wesought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a twophase large-scale genotyping approach. Methods: Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1. Measurements and Main Results: After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 3 1025) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 59 promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P , 5 3 1025). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells. Conclusions: Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted.

Original languageEnglish (US)
Pages (from-to)567-575
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume189
Issue number5
DOIs
StatePublished - Mar 1 2014

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Keywords

  • Lung tra

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Diamond, J. M., Akimova, T., Kazi, A., Shah, R. J., Cantu, E., Feng, R., Levine, M. H., Kawut, S. M., Meyer, N. J., Lee, J. C., Hancock, W. W., Aplenc, R., Ware, L. B., Palmer, S. M., Bhorade, S., Lama, V. N., Weinacker, A., Orens, J., Wille, K., ... Christie, J. D. (2014). Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction. American journal of respiratory and critical care medicine, 189(5), 567-575. https://doi.org/10.1164/rccm.201307-1283OC