title: A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci.
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 alpha(1)-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 alpha-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 x 10(-10), (rs8034191) and 5.74 x 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.
authors.affiliation: Genetics Division, GlaxoSmithKline Research and Development, Research Triangle Park, NC, USA. sreekumar.g.pillai@gsk.com
authors.forename: Sreekumar G
authors.initials: SG
authors.lastname: Pillai
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhu
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Kong
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Anna C
authors.initials: AC
authors.lastname: Need
authors.forename: Sheng
authors.initials: S
authors.lastname: Feng
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.forename: Andreas
authors.initials: A
authors.lastname: Ruppert
authors.forename: Karin C
authors.initials: KC
authors.lastname: Lødrup Carlsen
authors.forename: Allen
authors.initials: A
authors.lastname: Roses
authors.forename: Wayne
authors.initials: W
authors.lastname: Anderson
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002894:Chromosomes, Human, Pair 4; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D009664:Norway; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics*; D012044:Regression Analysis; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D044465:White People
chemical_list: D002352:Carrier Proteins; C117596:HHIP protein, human; D008562:Membrane Glycoproteins