TY - JOUR
T1 - Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema
AU - Yamada, Norihiro
AU - Yamaya, Mutsuo
AU - Okinaga, Shoji
AU - Nakayama, Katsutoshi
AU - Sekizawa, Kiyohisa
AU - Shibahara, Shigeki
AU - Sasaki, Hidetada
N1 - Funding Information:
We thank Drs. Munehiko Ishii, Masaharu Sugiyama, Ryo Kikuchi, Hideki Nakazawa, Kiyoshi Zayasu, Kazuhiko Satoh, Shigeru Itabashi, Akio Kanda, Mizue Monma, Mitsutoshi Shinkawa, and Hidenori Takahashi for samples, and we thank Mr. G. Crittenden for English corrections. This work was supported in part by a Grant-in-Aid for Exploratory Research (to M. Y.) and a Grant-in-Aid for Scientific Research on Priority Areas (to S. S.), both from the Japanese Ministry of Education, Science, Sports, and Culture.
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
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U2 - 10.1086/302729
DO - 10.1086/302729
M3 - Article
C2 - 10631150
AN - SCOPUS:0033925281
VL - 66
SP - 187
EP - 195
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -