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

By S. Pillai, D. Ge, G. Zhu, Xiangyang Kong, K. Shianna, A. Need, Sheng Feng, C. Hersh, P. Bakke, A. Gulsvik and 8 more. PLoS Genetics, 2009

803 citations recorded by the source corpus.

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.

Subfields: Genetics, Physiology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/280b6e9675e7ecfdf6bd96fd21ec2c2f6d8a5c07

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Citations in the corpus

• Genetic Epidemiology of COPD (COPDGene) Study Design (2010, neutral): “Pillai et al., in addition to the association with HHIP, also found two SNPs in a genomic region containing the α-nicotinic acetylcholine receptor (CHRNA 3/5) that associated strongly with COPD in a case-control design, and associated with lung function as well.”
• Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function (2014, background): “Both mucus hyperplasia and squamous metaplasia are seen in the condition known as chronic obstructive pulmonary disease (COPD).”
• Genome-wide association studies: what do they teach us about asthma and chronic obstructive pulmonary disease? (2009, methodology): “Second, the commonly used multistage GWA approach, using very stringent P values in the identification cohort, might result in missing relevant and potentially promising findings that Figure 2. Study design of the first genome-wide association study on chronic obstructive pulmonary disease (COPD) ( ”
• Uncovering the roles of rare variants in common disease through whole-genome sequencing (2010, methodology): “This assumption has controlled much of the follow-up research, in which the focus has generally been on resequencing in the linkage disequilibrium block defined by common variant”