Variants in the 15q24/25 locus associate with lung function decline in active smokers.
Genetic variation in nicotinic acetylcholine receptor subunit genes (nAChRs) is associated with lung function level and chronic obstructive pulmonary disease (COPD). It is unknown whether these variants also predispose to an accelerated lung function decline. We investigated the association of nAChR susceptibility variants with lung function decline and COPD severity. The rs1051730 and rs8034191 variants were genotyped in a population-based cohort of 1,226 heavy smokers (COPACETIC) and in an independent cohort of 883 heavy smokers, of which 653 with COPD of varying severity (LEUVEN). Participants underwent pulmonary function tests at baseline. Lung function decline was assessed over a median follow-up of 3 years in COPACETIC. Current smokers homozygous for the rs1051730 A-allele or rs8034191 G-allele had significantly greater FEV(1)/FVC decline than homozygous carriers of wild-type alleles (3.3% and 4.3%, p = 0.026 and p = 0.009, respectively). In the LEUVEN cohort, rs1051730 AA-carriers and rs8034191 GG-carriers had a two-fold increased risk to suffer from COPD GOLD IV (OR 2.29, 95% confidence interval [CI] = 1.11-4.75; p = 0.025 and OR = 2.42, 95% [CI] = 1.18-4.95; p = 0.016, respectively). The same risk alleles conferred, respectively, a five- and four-fold increased risk to be referred for lung transplantation because of end-stage COPD (OR = 5.0, 95% [CI] = 1.68-14.89; p = 0.004 and OR = 4.06, 95% [CI] = 1.39-11.88; p = 0.010). In Europeans, variants in nAChRs associate with an accelerated lung function decline in current smokers and with clinically relevant COPD.
Division of Heart and Lungs, Department of Respiratory Medicine, University Medical Center, Utrecht, The Netherlands. fmohamedhoesein@gmail.com
Firdaus A A
FA
Mohamed Hoesein
Els
E
Wauters
Wim
W
Janssens
Harry J M
HJ
Groen
Joanna
J
Smolonska
Cisca
C
Wijmenga
Dirkje S
DS
Postma
H Marike
HM
Boezen
Pim A
PA
De Jong
Marc
M
Decramer
Jan-Willem J
JW
Lammers
Diether
D
Lambrechts
Pieter
P
Zanen
D000368:Aged; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D005260:Female; D005540:Forced Expiratory Flow Rates / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000235:genetics* / Q000503:physiopathology*; D019966:Substance-Related Disorders / Q000150:complications / Q000235:genetics / Q000503:physiopathology
D021122:Protein Subunits; D011978:Receptors, Nicotinic; D009538:Nicotine