Positive association between two polymorphic sites (+134 insA/delA and G198T) of the endothelin-1 gene and chronic obstructive pulmonary disease. A case-control study

Endothelin-1 (ET-1) has been implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) for establishing an inflammatory loop in the respiratory mucosa that could become independent from the initial irritant factor. Common causes of COPD exacerbations are associated with elevated ET-1 sputum concentrations. Genetic variants of the ET-1 gene, that lead to elevated ET-1 peptide levels, have not been investigated in COPD. We performed a case control, genetic study to assess possible associations of two polymorphisms of the ET-1 gene, an adenine insertion (+134 insA/delA) and a guanine to thymine transversion (G198T) with the COPD phenotype and disease severity. The genotypes of 209 subjects, 107 COPD smokers (patients) and 102 non-COPD smokers (controls) were examined. Statistical analysis revealed that the 3A/4A and 4A/4A genotypes were more common (P<0.01) in patients. Moreover, a protective effect against COPD of the TT genotype (G198T) was exhibited. COPD smokers were carrying more frequently the GG genotype and less frequently the TT genotype (P=0.047). Diplotypic analysis revealed that subjects carrying the 3A3A;TT genotype had a lower risk of COPD development (P=0.027). Within the COPD patient group carriers of the GT genotype had more often mild or moderate COPD compared to patients carrying the GG genotype (P=0.004). Haplotypic distribution revealed that carriers of the 4A:T and 4A:G haplotypes were in increased risk of COPD development. Additionally, patients with the 3A:G haplotype were in increased risk of developing severe COPD, whereas patients with the 3A:T and 4A:T had most probably mild-moderate COPD.