| Summary: | <p>Abstract</p> <p>Background</p> <p>An Nrf2-dependent response is a central protective mechanism against oxidative stress. We propose that particular genetic variants of the <it>Nrf2 </it>gene may be associated with a rapid forced expiratory volume in one second (FEV<sub>1</sub>) decline induced by cigarette smoking.</p> <p>Methods</p> <p>We conducted a retrospective cohort study of 915 Japanese from a general population. Values of annual decline in FEV<sub>1 </sub>were computed for each individual using a linear mixed-effect model. Multiple clinical characteristics were assessed to identify associations with annual FEV<sub>1 </sub>decline. Tag single-nucleotide polymorphisms (SNPs) in the <it>Nrf2 </it>gene (rs2001350, rs6726395, rs1962142, rs2364722) and one functional SNP (rs6721961) in the <it>Nrf2 </it>promoter region were genotyped to assess interactions between the <it>Nrf2 </it>polymorphisms and smoking status on annual FEV<sub>1 </sub>decline.</p> <p>Results</p> <p>Annual FEV<sub>1 </sub>decline was associated with smoking behavior and inversely correlated with FEV<sub>1</sub>/FVC and FEV<sub>1 </sub>% predicted. The mean annual FEV<sub>1 </sub>declines in individuals with rs6726395 G/G, G/A, or A/A were 26.2, 22.3, and 20.8 mL/year, respectively, and differences in these means were statistically significant (p<sub>corr </sub>= 0.016). We also found a significant interaction between rs6726395 genotype and smoking status on the FEV<sub>1 </sub>decline (p for interaction = 0.011). The haplotype rs2001350T/rs6726395A/rs1962142A/rs2364722A/rs6721961T was associated with lower annual decline in FEV<sub>1 </sub>(p = 0.004).</p> <p>Conclusions</p> <p>This study indicated that an Nrf2-dependent response to exogenous stimuli may affect annual FEV<sub>1 </sub>decline in the general population. It appears that the genetic influence of <it>Nrf2 </it>is modified by smoking status, suggesting the presence of a gene-environment interaction in accelerated decline in FEV<sub>1</sub>.</p>
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