Research

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

Mateusz Siedlinski¹ , Dirkje S Postma² , Jolanda MA Boer³ , Gerrit van der Steege⁴ , Jan P Schouten¹ , Henriette A Smit³ and H Marike Boezen¹

¹  Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

²  Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

³  National Institute for Public Health and the Environment, Bilthoven, The Netherlands

⁴  Department of Medical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

author email corresponding author email

Respiratory Research 2009, 10:73doi:10.1186/1465-9921-10-73

Published:	11 August 2009

Abstract

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 (FEV₁) 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 FEV₁ measurements during 3 surveys, respectively 7 FEV₁ measurements during 8 surveys were present. Linear Mixed Effect models were used to test cross-sectional and longitudinal genetic effects on repeated FEV₁ measurements.

Results

In the Vlagtwedde-Vlaardingen cohort SNP rs11085735 in KEAP1 was associated with a higher FEV₁ level (p = 0.02 for an additive effect), and SNP rs2364723 in NFE2L2 was associated with a lower FEV₁ level (p = 0.06). The associations were even more significant in the pooled cohort analysis. No significant association of KEAP1 or NFE2L2 SNPs with FEV₁ 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 FEV₁ in the general population. It additionally shows that NFE2L2 and KEAP1 variations are unlikely to play a role in the longitudinal course of FEV₁ in the general population.