Published ahead of print on July 13, 2006, doi:10.1164/rccm.200512-1839OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200512-1839OC
Functional Prostaglandin-Endoperoxide Synthase 2 Polymorphism Predicts Poor Outcome in SarcoidosisCentre for Respiratory Research, Department of Medicine, Royal Free and University College Medical School, The Rayne Institute; Department of Rheumatology, Royal Free Hospital, London, United Kingdom; and Wilhelminenspital, Vienna, Austria Correspondence and requests for reprints should be addressed to Michael R. Hill, D.Phil., Centre for Respiratory Research, Department of Medicine, Royal Free and University College Medical School, The Rayne Institute, 5 University Street, London WC1E 6JJ, UK. E-mail: michael.hill{at}ucl.ac.uk Rationale: 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 E2 and is reduced in sarcoidosis lung. A promoter polymorphism in PTGS2, –765G>C, is reported to reduce its expression. Objectives: 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. Conclusion: 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.
Key Words: cyclooxygenase-2 • gene regulation • PTGS2 • sarcoidosis This article has been cited by other articles:
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
