Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disorder of unknown etiology and unclear pathogenesis. Matrix metalloproteinase-1 (MMP-1) is strongly upregulated and may contribute to the abnormal remodeling that characterizes the disease. We conducted a case–control study of 130 IPF patients and 305 healthy controls to investigate associations between two polymorphisms of the MMP-1 gene promoter and IPF risk. First, using PCR-restriction fragment length polymorphism (PCR-RFLP) analysis we studied the 2G polymorphism at −1,607, shown previously to generate the core of an AP-1 binding site and correlate with high transcriptional activity and risk for IPF. The frequency of the 2G/2G genotype was higher in IPF than in controls (63 vs. 49%; P < 0.008; OR = 1.7; CI 1.15–2.79). Next, we studied a T/G SNP at position −755, which we identified by sequencing the MMP-1 promoter. Chromatin immunoprecipitation (ChIP) assay performed on IPF fibroblasts with either −755 genotype revealed an AP-1 binding site for TT−755 and GT−755 genotypes. The frequency of this SNP revealed no significant differences between IPF and healthy controls. However, when the study individuals were stratified by their smoking status, a significant increase in the T/T genotype frequency was observed in smoking cases compared with smoking controls (45 vs. 26%; P = 0.03; OR = 2.3; CI 1.15–4.97). These findings indicate that polymorphisms of the MMP-1 promoter may confer increased risk for IPF and reveal a putative gene–environment interaction between the −755 MMP-1 polymorphism and smoking in this disease.
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Acknowledgments
This work was supported by Grants: Universidad Nacional Autonoma de. Mexico: PAPIIT IN200106, and SDI.PTID.05.6. MC was funded by CONACYT.
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This work was submitted in partial fulfillment of the requirements to obtain the Ph.D. degree for M. Checa at Universidad Nacional Autonoma de Mexico.
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Checa, M., Ruiz, V., Montaño, M. et al. MMP-1 polymorphisms and the risk of idiopathic pulmonary fibrosis. Hum Genet 124, 465–472 (2008). https://doi.org/10.1007/s00439-008-0571-z
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DOI: https://doi.org/10.1007/s00439-008-0571-z