Pillai, SG;
Ge, D;
Zhu, G;
Kong, X;
Shianna, KV;
Need, AC;
Feng, S;
... ICGN Investigators; + view all
(2009)
A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci.
PLoS Genet
, 5
(3)
e1000421.
10.1371/journal.pgen.1000421.
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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.
| Type: | Article |
|---|---|
| Title: | A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pgen.1000421 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pgen.1000421 |
| Language: | English |
| Additional information: | © 2009 Pillai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The Bergen and ICGN populations were funded by GlaxoSmithKline. SGP, GZ, XK, AR and WA are employees of GlaxoSmithKline. The NETT/NAS and Boston Early-Onset COPD replication studies were supported by U.S. National Institutes of Health grants R01HL075478, U01HL089856, P01HL083069, R01HL084323, and K08HL080242. The National Emphysema Treatment Trial was supported by the National Heart, Lung, and Blood Institute (N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, N01HR76119), Centers for Medicare and Medicaid Services, and the Agency for Healthcare Research and Quality. The Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the US Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Boston, MA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | Carrier Proteins, Case-Control Studies, Chromosomes, Human, Pair 4, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Membrane Glycoproteins, Norway, Pedigree, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Regression Analysis, Risk Factors, Smoking |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > VP: Health |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1382097 |
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