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

Publication ,  Journal Article
Diamond, JM; Akimova, T; Kazi, A; Shah, RJ; Cantu, E; Feng, R; Levine, MH; Kawut, SM; Meyer, NJ; Lee, JC; Hancock, WW; Aplenc, R; Ware, LB ...
Published in: Am J Respir Crit Care Med
March 1, 2014

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: We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase 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 × 10(-5)) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5' promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 × 10(-5)). 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.

Duke Scholars

Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

March 1, 2014

Volume

189

Issue

5

Start / End Page

567 / 575

Location

United States

Related Subject Headings

  • T-Lymphocytes, Regulatory
  • Respiratory System
  • Receptors, Prostaglandin E, EP4 Subtype
  • Prostaglandin-E Synthases
  • Prospective Studies
  • Primary Graft Dysfunction
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Male
  • Lung Transplantation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Diamond, J. M., Akimova, T., Kazi, A., Shah, R. J., Cantu, E., Feng, R., … Lung Transplant Outcomes Group, . (2014). Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction. Am J Respir Crit Care Med, 189(5), 567–575. https://doi.org/10.1164/rccm.201307-1283OC
Diamond, Joshua M., Tatiana Akimova, Altaf Kazi, Rupal J. Shah, Edward Cantu, Rui Feng, Matthew H. Levine, et al. “Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction.Am J Respir Crit Care Med 189, no. 5 (March 1, 2014): 567–75. https://doi.org/10.1164/rccm.201307-1283OC.
Diamond JM, Akimova T, Kazi A, Shah RJ, Cantu E, Feng R, et al. Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction. Am J Respir Crit Care Med. 2014 Mar 1;189(5):567–75.
Diamond, Joshua M., et al. “Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction.Am J Respir Crit Care Med, vol. 189, no. 5, Mar. 2014, pp. 567–75. Pubmed, doi:10.1164/rccm.201307-1283OC.
Diamond JM, Akimova T, Kazi A, Shah RJ, Cantu E, Feng R, Levine MH, Kawut SM, Meyer NJ, Lee JC, Hancock WW, Aplenc R, Ware LB, Palmer SM, Bhorade S, Lama VN, Weinacker A, Orens J, Wille K, Crespo M, Lederer DJ, Arcasoy S, Demissie E, Christie JD, Lung Transplant Outcomes Group. Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction. Am J Respir Crit Care Med. 2014 Mar 1;189(5):567–575.

Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

March 1, 2014

Volume

189

Issue

5

Start / End Page

567 / 575

Location

United States

Related Subject Headings

  • T-Lymphocytes, Regulatory
  • Respiratory System
  • Receptors, Prostaglandin E, EP4 Subtype
  • Prostaglandin-E Synthases
  • Prospective Studies
  • Primary Graft Dysfunction
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Male
  • Lung Transplantation