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Genetic background is thought to be one of the risk factors for development of COPD. Recently, it has been proposed that the innate immune system is involved in the pathophysiology of COPD. We hypothesized that polymorphisms in the nucleotide-binding and oligomerization domain(NOD)1andNOD2genes would be associated with the pathogenesis of COPD. In addition, the associations between these single nucleotide polymorphisms (SNPs) and phenotypes of COPD were analysed.Japanese COPD patients (n= 228) and non-COPD smokers (n= 101) were recruited from the outpatient clinic at Kyoto University Hospital, Kyoto, Japan. At entry into the study, a blood sample was taken and a pulmonary function test was performed. Genotyping was performed for 6 selected tag SNPs ofNOD1and 5 tag SNPs ofNOD2. Further investigations were performed for SNP that were associated with COPD, including baseline gene expression, the relative proportions of splicing variants in whole blood, responses to ligand and enhancement of gene expression in peripheral blood neutrophils stimulated with pro-inflammatory cytokines.The distribution ofNOD2rs1077861 genotypes differed between Japanese COPD patients and non-COPD smokers (P= 0.036). This SNP was also associated with a lower FEV1 % predicted (57.2 ± 1.8 for TT vs 50.8 ± 2.3 for TA/AA,P= 0.03) and DLCO/VA (2.89 ± 0.1 in TT vs 2.53 ± 0.14 in TA/AA,P= 0.036) in COPD patients.NOD2gene expression after stimulation with 10 ng/mL of tumour necrosis factor-α for 4 h, was increased to a greater extent in TA/AA genotype than in TT genotype peripheral blood neutrophils (P= 0.015).TheNOD2rs1077861 SNP may influence the development and progression of COPD in Japanese subjects.