A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci

摘要: There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor severe deficiency alpha(1)-antitrypsin, which present 1-2% individuals with COPD. We conducted a genome-wide association study (GWAS) homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) evaluated top 100 single nucleotide polymorphisms (SNPs) family-based International Genetics Network (ICGN; 1891 Caucasian 606 pedigrees) study. that showed replication were further 389 subjects US National Emphysema Treatment Trial (NETT) 472 controls Normative Aging Study (NAS) then fourth 949 127 extended pedigrees Boston Early-Onset population. Logistic regression models adjustments covariates used analyze populations. Family-based analyses for diagnosis lung function family Two SNPs at alpha-nicotinic acetylcholine receptor (CHRNA 3/5) locus identified They unambiguous ICGN analysis NETT combined p-values 1.48 x 10(-10), (rs8034191) 5.74 10(-10) (rs1051730). Furthermore, these significantly associated both C allele rs8034191 SNP was estimated have population attributable 12.2%. hedgehog interacting protein (HHIP) on chromosome 4 also consistently replicated, but did not reach significance levels. Genome-wide significant HHIP Framingham Heart (Wilk et al., companion article this issue PLoS Genetics; doi:10.1371/journal.pgen.1000429). CHRNA 3/5 loci make contribution CHRNA3/5 same has been implicated cancer.