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Background  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  Nfe2l2 -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 1 ) in the general population.    Methods  Five  NFE2L2  and three  KEAP1  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 1  measurements during 3 surveys, respectively 7 FEV 1  measurements during 8 surveys were present. Linear Mixed Effect models were used to test cross-sectional and longitudinal genetic effects on repeated FEV 1  measurements.    Results  In the Vlagtwedde-Vlaardingen cohort SNP rs11085735 in  KEAP1  was associated with a higher FEV 1  level (p = 0.02 for an additive effect), and SNP rs2364723 in  NFE2L2  was associated with a lower FEV 1  level (p = 0.06). The associations were even more significant in the pooled cohort analysis. No significant association of  KEAP1  or  NFE2L2  SNPs with FEV 1  decline was observed.    Conclusion  This is the first genetic study on variations in key antioxidant transcriptional regulators  KEAP1  and  NFE2L2  and lung function in a general population. It identified 2 SNPs in  NFE2L2  and  KEAP1  which affect the level of FEV 1  in the general population. It additionally shows that  NFE2L2  and  KEAP1  variations are unlikely to play a role in the longitudinal course of FEV 1  in the general population.

Level and course of FEV1 in relation to polymorphisms in NFE2L2 and KEAP1 in the general population