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


OBJECTIVE
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.


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.
1 Pulmonary, Allergy, and Critical Care Division.
Joshua M
JM
Diamond
Tatiana
T
Akimova
Altaf
A
Kazi
Rupal J
RJ
Shah
Edward
E
Cantu
Rui
R
Feng
Matthew H
MH
Levine
Steven M
SM
Kawut
Nuala J
NJ
Meyer
James C
JC
Lee
Wayne W
WW
Hancock
Richard
R
Aplenc
Lorraine B
LB
Ware
Scott M
SM
Palmer
Sangeeta
S
Bhorade
Vibha N
VN
Lama
Ann
A
Weinacker
Jonathan
J
Orens
Keith
K
Wille
Maria
M
Crespo
David J
DJ
Lederer
Selim
S
Arcasoy
Ejigayehu
E
Demissie
Jason D
JD
Christie
D015415:Biomarkers / Q000097:blood; D019295:Computational Biology; D015232:Dinoprostone / Q000097:blood; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055031:Primary Graft Dysfunction / Q000097:blood / Q000235:genetics* / Q000276:immunology; D011446:Prospective Studies; D000071876:Prostaglandin-E Synthases; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
D015415:Biomarkers; D005819:Genetic Markers; C545650:PTGER4 protein, human; D058309:Receptors, Prostaglandin E, EP4 Subtype; D019746:Intramolecular Oxidoreductases; C000605863:PTGES2 protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone