NFE2L2 pathway polymorphisms and lung function decline in chronic obstructive pulmonary disease.
An oxidant-antioxidant imbalance in the lung contributes to the development of chronic obstructive pulmonary disease (COPD) that is caused by a complex interaction of genetic and environmental risk factors. Nuclear erythroid 2-related factor 2 (NFE2L2 or NRF2) is a critical molecule in the lung's defense mechanism against oxidants. We investigated whether polymorphisms in the NFE2L2 pathway affected the rate of decline of lung function in smokers from the Lung Health Study (LHS)(n = 547) and in a replication set, the Vlagtwedde-Vlaardingen cohort (n = 533). We selected polymorphisms in NFE2L2 in genes that positively or negatively regulate NFE2L2 transcriptional activity and in genes that are regulated by NFE2L2. Polymorphisms in 11 genes were significantly associated with rate of lung function decline in the LHS. One of these polymorphisms, rs11085735 in the KEAP1 gene, was previously shown to be associated with the level of lung function in the Vlagtwedde-Vlaardingen cohort but not with decline of lung function. Of the 23 associated polymorphisms in the LHS, only rs634534 in the FOSL1 gene showed a significant association in the Vlagtwedde-Vlaardingen cohort with rate of lung function decline, but the direction of the association was not consistent with that in the LHS. In summary, despite finding several nominally significant polymorphisms in the LHS, none of these associations were replicated in the Vlagtwedde-Vlaardingen cohort, indicating lack of effect of polymorphisms in the NFE2L2 pathway on the rate of decline of lung function.
UBC James Hogg Research Centre, Providence Heart + Lung Institute, St. Paul's Hospital, Vancouver, British Columbia, Canada. andrew.sandford@hli.ubc.ca
Andrew J
AJ
Sandford
Deepti
D
Malhotra
H Marike
HM
Boezen
Mateusz
M
Siedlinski
Dirkje S
DS
Postma
Vivien
V
Wong
Loubna
L
Akhabir
Jian-Qing
JQ
He
John E
JE
Connett
Nicholas R
NR
Anthonisen
Peter D
PD
Paré
Shyam
S
Biswal
D000328:Adult; D015331:Cohort Studies; D003710:Demography; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008168:Lung / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology*; D012129:Respiratory Function Tests; D015398:Signal Transduction / Q000235:genetics*; D012907:Smoking / Q000235:genetics
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human