| Summary: | <p>Abstract</p> <p>Background</p> <p>The metabolism of xenobiotics plays an essential role in smoking related lung function loss and development of Chronic Obstructive Pulmonary Disease. Nuclear Factor Erythroid 2-Like 2 (NFE2L2 or NRF2) and its cytosolic repressor Kelch-like ECH-associated protein-1 (KEAP1) regulate transcription of enzymes involved in cellular detoxification processes and <it>Nfe2l2</it>-deficient mice develop tobacco-induced emphysema. We assessed the impact of Single Nucleotide Polymorphisms (SNPs) in both genes on the level and longitudinal course of Forced Expiratory Volume in 1 second (FEV<sub>1</sub>) in the general population.</p> <p>Methods</p> <p>Five <it>NFE2L2 </it>and three <it>KEAP1 </it>tagging SNPs were genotyped in the population-based Doetinchem cohort (n = 1,152) and the independent Vlagtwedde-Vlaardingen cohort (n = 1,390). On average 3 FEV<sub>1 </sub>measurements during 3 surveys, respectively 7 FEV<sub>1 </sub>measurements during 8 surveys were present. Linear Mixed Effect models were used to test cross-sectional and longitudinal genetic effects on repeated FEV<sub>1 </sub>measurements.</p> <p>Results</p> <p>In the Vlagtwedde-Vlaardingen cohort SNP rs11085735 in <it>KEAP1 </it>was associated with a higher FEV<sub>1 </sub>level (p = 0.02 for an additive effect), and SNP rs2364723 in <it>NFE2L2 </it>was associated with a lower FEV<sub>1 </sub>level (p = 0.06). The associations were even more significant in the pooled cohort analysis. No significant association of <it>KEAP1 </it>or <it>NFE2L2 </it>SNPs with FEV<sub>1 </sub>decline was observed.</p> <p>Conclusion</p> <p>This is the first genetic study on variations in key antioxidant transcriptional regulators <it>KEAP1 </it>and <it>NFE2L2 </it>and lung function in a general population. It identified 2 SNPs in <it>NFE2L2 </it>and <it>KEAP1 </it>which affect the level of FEV<sub>1 </sub>in the general population. It additionally shows that <it>NFE2L2 </it>and <it>KEAP1 </it>variations are unlikely to play a role in the longitudinal course of FEV<sub>1 </sub>in the general population.</p>
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