The 15q24/25 susceptibility variant for lung cancer and chronic obstructive pulmonary disease is associated with emphysema.
BACKGROUND
Genome-wide association studies have identified genetic variants in the nicotinic acetylcholine receptor (nAChR) on chromosome 15q24/25 as a risk for nicotine dependence, lung cancer, and chronic obstructive pulmonary disease (COPD). Assessment of bronchial obstruction by spirometry, typically used for diagnosing COPD, fails, however, to detect emphysema.


OBJECTIVE
To determine the association of the 15q24/25 locus with emphysema.


METHODS
The rs1051730 variant on 15q24/25 was genotyped in two independent white cohorts of 661 and 456 heavy smokers. Participants underwent pulmonary function tests and computed tomography (CT) of the chest, and took questionnaires assessing smoking behavior and health status.


RESULTS
The rs1051730 A-allele correlated with reduced FEV(1) and with increased susceptibility for bronchial obstruction with a pooled odds ratio (OR) of 1.33 (95% confidence interval [CI] = 1.11-1.61; P = 0.0026). In both studies a correlation between the rs1051730 A-allele and lung diffusing capacity (Dl(CO)) and diffusing capacity per unit alveolar volume (Kco) was observed. Consistently, the rs1051730 A-allele conferred increased risk for emphysema as assessed by CT (P = 0.0097 and P = 0.019), with a pooled OR of 1.39 (CI = 1.15-1.68; P = 0.00051). Visual emphysema scores and scores based on densities quantified on CT were more pronounced in A-allele carriers, indicating that rs1051730 correlates with the severity of emphysema.


CONCLUSIONS
The 15q24/25 locus in nAChR is associated with the presence and severity of emphysema. This association was independent of pack-years smoking, suggesting that nAChR is causally involved in alveolar destruction as a potentially shared pathogenic mechanism in lung cancer and COPD.
Lambrechts
Diether
D
Vesalius Research Center, K.U. Leuven, Leuven, Belgium. diether.lambrechts@vib-kuleuven.be
Buysschaert
Ian
I
Zanen
Pieter
P
Coolen
Johan
J
Lays
Natacha
N
Cuppens
Harry
H
Groen
Harry J M
HJ
Dewever
Walter
W
van Klaveren
Rob J
RJ
Verschakelen
Johny
J
Wijmenga
Cisca
C
Postma
Dirkje S
DS
Decramer
Marc
M
Janssens
Wim
W
D000483:Alleles; D001980:Bronchi / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics*; D011656:Pulmonary Emphysema / Q000209:etiology / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*; D012129:Respiratory Function Tests; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics; D014057:Tomography, X-Ray Computed
D011978:Receptors, Nicotinic