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: 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.
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Authors | 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 Crespo, David J Lederer, Selim Arcasoy, Ejigayehu Demissie, Jason D Christie, Lung Transplant Outcomes Group |
Journal | American journal of respiratory and critical care medicine
(Am J Respir Crit Care Med)
Vol. 189
Issue 5
Pg. 567-75
(Mar 01 2014)
ISSN: 1535-4970 [Electronic] United States |
PMID | 24467603
(Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural)
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Chemical References |
- Biomarkers
- Genetic Markers
- PTGER4 protein, human
- Receptors, Prostaglandin E, EP4 Subtype
- Intramolecular Oxidoreductases
- PTGES2 protein, human
- Prostaglandin-E Synthases
- Dinoprostone
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Topics |
- Biomarkers
(blood)
- Computational Biology
- Dinoprostone
(blood)
- Female
- Genetic Association Studies
- Genetic Markers
- Genotype
- Genotyping Techniques
- Humans
- Intramolecular Oxidoreductases
(genetics)
- Lung Transplantation
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Primary Graft Dysfunction
(blood, genetics, immunology)
- Prospective Studies
- Prostaglandin-E Synthases
- Receptors, Prostaglandin E, EP4 Subtype
(genetics)
- T-Lymphocytes, Regulatory
(metabolism)
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