Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema

Cigarette smoke, containing reactive oxygen species, is the most important risk factor for chronic pulmonary emphysema (CPE). Heme oxygenase-1 (HO-1) plays a protective role as an antioxidant in the lung. A (GT)(n) dinucleotide repeat in the 5'-flanking region of human HO-1 gene shows length polymorphism and could modulate the level of gene transcription. To investigate the correlation between the length of the (GT)(n) repeat and susceptibility to the development of CPE, we screened the frequencies of alleles with varying numbers of (GT)(n) repeats in the HO-1 gene in 101 smokers with CPE and in 100 smokers without CPE. Polymorphisms of the (GT)(n) repeat were grouped into three classes: class S alleles (<25 repeats), class M alleles (25-29 repeats), and class L alleles (≥30 repeats). The proportion of allele frequencies in class L, as well as the proportion of genotypic frequencies in the group with class L alleles (L/L, L/M, and L/S), was significantly higher in the smokers with CPE than in smokers without CPE. Moreover, we analyzed the promoter activities of the HO-1 gene carrying different (GT)(n) repeats (n = 16, 20, 29, and 38), by transient-transfection assay in cultured cell lines. H₂O₂ exposure up-regulated the transcriptional activity of the HO-1 promoter/luciferase fusion genes with (GT)₁₆ or (GT)₂₀ but did not do so with (GT)₂₉ or (GT)₃₈. These findings suggest that the large size of a (GT)(n) repeat in the HO-1 gene promoter may reduce HO-1 inducibility by reactive oxygen species in cigarette smoke, thereby resulting in the development of CPE.