Abstract
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.
Highlights
chronic obstructive pulmonary disease (COPD) is expected to be the third leading cause of worldwide mortality and the fifth leading cause of morbidity by the year 2020 [1]
The genome-wide association analyses of the COPD casecontrol status in the Bergen cohort identified several significant associations, including three single nucleotide polymorphisms (SNPs) on chromosome 5 that reached the level of genome-wide significance (Table S1)
We have demonstrated and replicated genetic associations between SNPs at the CHRNA3/5 locus and COPD in four study populations
Summary
COPD is expected to be the third leading cause of worldwide mortality and the fifth leading cause of morbidity by the year 2020 [1]. Cigarette smoking is the major risk factor for COPD but smokers show considerable variation in their risk of developing airflow obstruction. Familial aggregation studies suggest a strong genetic component to this risk [2,3,4,5,6,7,8]. The only proven genetic risk factor for COPD is severe deficiency of a1-antitrypsin [9], which is present in only 1–2% of individuals with COPD. This suggests that other genes have yet to be identified that predispose smokers to airflow obstruction. We report the first genome wide association study (GWAS) for COPD. Our primary discovery sample was a case-control population collected from Bergen, Author Summary
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