Level and course of FEV1 in relation to polymorphisms in NFE2L2 and KEAP1 in the general population
Mateusz Siedlinski
2
Dirkje S Postma
1
Jolanda MA Boer
0
Gerrit van der Steege
3
Jan P Schouten
2
Henriette A Smit
0
H Marike Boezen
2
0
National Institute for Public Health and the Environment
,
Bilthoven
,
The Netherlands
1
Department of Pulmonology, University Medical Center Groningen, University of Groningen
,
Groningen
,
The Netherlands
2
Department of Epidemiology, University Medical Center Groningen, University of Groningen
,
Groningen
,
The Netherlands
3
Department of Medical Genetics, University Medical Center Groningen, University of Groningen
,
Groningen
,
The Netherlands
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.
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Background
The mortality and morbidity of Chronic Obstructive
Pulmonary Disease (COPD) has been increasing over the
past decades and the disease is a fundamental medical
and economical problem in Western societies [1]. A
genetic predisposition is thought to play a crucial role in
the onset of COPD and the heritability of lung function
loss that precedes COPD development has been clearly
established [2,3]. Several polymorphisms have been
identified in association with level of lung function, but
subsequent studies have failed to replicate these reported
associations [4,5]. So far, only a small subset of
polymorphisms has been consistently replicated in their
association with COPD development or lung function decline
across independent studies or populations [6-11].
Nuclear Factor (Erythroid-derived 2)-Like 2 (NFE2L2 or
NRF2) regulates the transcription of numerous
antioxidant enzymes in response to oxidant injury, via direct
binding to the antioxidant responsive element in the
target gene [12-15]. It therefore is a potent candidate gene for
excess lung function loss and COPD development.
Kelch-like ECH-associated protein-1 (KEAP1) is a
cytosolic repressor of NFE2L2. Oxidative stress causes
disruption of the KEAP1-NFE2L2 complex, translocation of
NFE2L2 to the nucleus and subsequent induction of the
expression of antioxidant genes [16]. It has been shown
that Nfe2l2 protects mice against elastase-induced [17]
and tobacco-induced [18] emphysema. Additionally, the
expression pattern of both KEAP1 and NFE2L2 is different
in COPD patients as compared to healthy never- or
former- smokers [19,20] and the expression of
NFE2L2regulated antioxidant genes is lower in COPD subjects
than in non-diseased controls [21]. Three new
polymorphisms have been discovered in the promoter region of
NFE2L2, but these were not associated with COPD in a
Japanese population [22]. One study showed that one of
these polymorphisms decreases NFE2L2 expression in
vitro and is associated with development of acute lung
injury in a Caucasian population [23]. So far no studies
have investigated the role of NFE2L2 or KEAP1
polymorphisms in relation to the longitudinal course of lung
function in the general population.
Therefore, in the current study we investigated whether
NFE2L2 or KEAP1 polymorphisms affect the level and
longitudinal course of FEV1 (Forced Expiratory Volume in
1 second), both being important risks for COPD [24]. In
order to assure consistency of results, we performed this
study in two prospective and independent
populationbased cohorts.
Metho (...truncated)