Functional prostaglandin-endoperoxide synthase 2 polymorphism predicts poor outcome in sarcoidosis.
BACKGROUND
The majority of patients with sarcoidosis resolve their condition; however 5-10% of patients with sarcoidosis develop pulmonary fibrosis with poor prognosis. Prostaglandin-endoperoxide synthase 2 (PTGS2) is a key regulatory enzyme in the synthesis of the antifibrotic agent prostaglandin E(2) and is reduced in sarcoidosis lung. A promoter polymorphism in PTGS2, -765G>C, is reported to reduce its expression.


OBJECTIVE
To investigate if -765G>C is associated with susceptibility to, and poorer outcome within, sarcoidosis and to examine a possible mechanism by which -765G>C reduces PTGS2 expression.


METHODS
We used a case-control design study and genotyped -765G>C in a white British population of 198 patients with sarcoidosis and 166 control subjects. Patients with sarcoidosis were classified before genotyping as having persistent or nonpersistent disease using clinical criteria that included chest radiography staging, need for treatment, lung function, and longitudinal follow-up. Electrophoretic mobility shift assays were used to identify changes in transcription factor binding caused by the -765G>C polymorphism.


RESULTS
Carriage of the -765C allele was strongly associated with susceptibility to sarcoidosis (odds ratio, 2.50; 95% confidence interval, 1.51-4.13; p=0.006) and, within this disease, with poorer outcome (odds ratio, 3.11; 95% confidence interval, 1.35-7.13; p=0.008). The association with sarcoidosis was replicated in a second Austrian population. Electrophoretic mobility shift assays revealed that the -765C allele causes a loss of Sp1/Sp3 transcription factor binding and an increase in Egr-1 binding to the region.


CONCLUSIONS
Our data suggest that the -765G>C polymorphism identifies individuals who are susceptible to sarcoidosis and, more importantly, at risk of pulmonary fibrotic disease. An altered Sp1/Sp3 binding to the -765 region may contribute to the mechanism by which -765G>C reduces PTGS2 expression.
Hill
Michael R
MR
Centre for Respiratory Research, Department of Medicine, Royal Free and University College Medical School, The Rayne Institute, and Department of Rheumatology, Royal Free Hospital, London WC1E 6JJ, UK. michael.hill@ucl.ac.uk
Papafili
Anastasia
A
Booth
Helen
H
Lawson
Phillippa
P
Hubner
Marianne
M
Beynon
Huw
H
Read
Catherine
C
Lindahl
Gisela
G
Marshall
Richard P
RP
McAnulty
Robin J
RJ
Laurent
Geoffrey J
GJ
D000328:Adult; D000483:Alleles; D051546:Cyclooxygenase 2 / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011379:Prognosis; D011658:Pulmonary Fibrosis / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D012189:Retrospective Studies; D017565:Sarcoidosis, Pulmonary / Q000150:complications / Q000201:enzymology* / Q000235:genetics
D008565:Membrane Proteins; D004247:DNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human