A Genome-Wide association study in chronic obstructive pulmonary disease (COPD)

Identification of two major susceptibility loci

Sreekumar G. Pillai, Dongliang Ge, Guohua Zhu, Xiangyang Kong, Kevin V. Shianna, Anna C. Need, Sheng Feng, Craig P. Hersh, Per Bakke, Amund Gulsvik, Andreas Ruppert, Karin C.Lødrup Carlsen, Allen Roses, Wayne Anderson, Stephen Israel Rennard, David A. Lomas, Edwin K. Silverman, David B. Goldstein

Research output: Contribution to journalArticle

458 Citations (Scopus)

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. Copyright:

Original languageEnglish (US)
JournalPLoS genetics
Volume5
Issue number3
DOIs
StatePublished - Mar 1 2009

Fingerprint

Genome-Wide Association Study
respiratory tract diseases
Chronic Obstructive Pulmonary Disease
genome
loci
Hedgehog Proteins
polymorphism
single nucleotide polymorphism
Single Nucleotide Polymorphism
Erinaceidae
lung function
Population
Emphysema
Pedigree
pedigree
Lung
protein
Logistic Models
Genome
Social Adjustment

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

A Genome-Wide association study in chronic obstructive pulmonary disease (COPD) : Identification of two major susceptibility loci. / Pillai, Sreekumar G.; Ge, Dongliang; Zhu, Guohua; Kong, Xiangyang; Shianna, Kevin V.; Need, Anna C.; Feng, Sheng; Hersh, Craig P.; Bakke, Per; Gulsvik, Amund; Ruppert, Andreas; Carlsen, Karin C.Lødrup; Roses, Allen; Anderson, Wayne; Rennard, Stephen Israel; Lomas, David A.; Silverman, Edwin K.; Goldstein, David B.

In: PLoS genetics, Vol. 5, No. 3, 01.03.2009.

Research output: Contribution to journalArticle

Pillai, SG, Ge, D, Zhu, G, Kong, X, Shianna, KV, Need, AC, Feng, S, Hersh, CP, Bakke, P, Gulsvik, A, Ruppert, A, Carlsen, KCL, Roses, A, Anderson, W, Rennard, SI, Lomas, DA, Silverman, EK & Goldstein, DB 2009, 'A Genome-Wide association study in chronic obstructive pulmonary disease (COPD): Identification of two major susceptibility loci', PLoS genetics, vol. 5, no. 3. https://doi.org/10.1371/journal.pgen.1000421
Pillai, Sreekumar G. ; Ge, Dongliang ; Zhu, Guohua ; Kong, Xiangyang ; Shianna, Kevin V. ; Need, Anna C. ; Feng, Sheng ; Hersh, Craig P. ; Bakke, Per ; Gulsvik, Amund ; Ruppert, Andreas ; Carlsen, Karin C.Lødrup ; Roses, Allen ; Anderson, Wayne ; Rennard, Stephen Israel ; Lomas, David A. ; Silverman, Edwin K. ; Goldstein, David B. / A Genome-Wide association study in chronic obstructive pulmonary disease (COPD) : Identification of two major susceptibility loci. In: PLoS genetics. 2009 ; Vol. 5, No. 3.
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