title: The association of Toll-like receptor 4 gene polymorphisms with the development of emphysema in Japanese subjects: a case control study.
abstract: BACKGROUND
  The principal role of Toll-like receptor 4 (TLR4) is the induction of immune responses to lipopolysaccharides. Previously, mice deficient in the TLR4 gene exhibited up-regulation of the NADPH oxidase system in the lungs. This resulted in increased oxidant generation and elastolytic activity, which led to pulmonary emphysema. It was suggested that TLR4 might maintain constitutive lung integrity by modulating oxidant generation. We investigated whether single nucleotide polymorphisms (SNPs) in the TLR4 gene were associated with the emphysema phenotype in Japanese subjects with chronic obstructive pulmonary disease (COPD).
  
  
  RESULTS
  Seven SNPs in the TLR4 gene (rs10759930, rs1927914, rs12377632, rs2149356, rs11536889, rs7037117, and rs7045953) were genotyped with allelic discrimination assays. The frequencies of SNPs were compared between 106 patients with the emphysema phenotype of COPD and 137 healthy smokers. We found that the positivity of the individuals with the major G allele of rs11536889 was significantly less in the emphysema group than the control group (p = 0.019). The frequencies of the minor C allele and the distribution of the CC genotype as well as the frequency of the major haplotype that carried the minor C allele of rs11536889 were all significantly higher in the emphysema group than the control group (p = 0.0083, 0.019, and 0.004, respectively). Furthermore, the strength of the association of the CC genotype with the emphysema phenotype was in an odds ratio of 2.60 with 95% confidence intervals from 1.17 to 5.78. However, these significances were not apparent after adjust for age and smoking history by logistic regression. No associations were observed between the rs11536889 and the low attenuation area score, the forced expiratory volume, and the carbon monoxide diffusion capacity in the emphysema group.
  
  
  CONCLUSIONS
  The minor C allele of the rs11536889 SNP in the TLR4 gene is likely associated with the risk of developing emphysema in the Japanese population.
authors.affiliation: First Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Ito
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hanaoka
authors.forename: Yunden
authors.initials: Y
authors.lastname: Droma
authors.forename: Nobumitsu
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Masanori
authors.initials: M
authors.lastname: Yasuo
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kitaguchi
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Horiuchi
authors.forename: Kayoko
authors.initials: K
authors.lastname: Ikegawa
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Katsuyama
authors.forename: Keishi
authors.initials: K
authors.lastname: Kubo
authors.forename: Masao
authors.initials: M
authors.lastname: Ota
mesh_terms: D000368:Aged; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D004646:Emphysema / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005260:Female; D005541:Forced Expiratory Volume; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000235:genetics* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4