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Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis.

Publication ,  Journal Article
Cho, MH; McDonald, M-LN; Zhou, X; Mattheisen, M; Castaldi, PJ; Hersh, CP; Demeo, DL; Sylvia, JS; Ziniti, J; Laird, NM; Lange, C; Litonjua, AA ...
Published in: Lancet Respir Med
March 2014

BACKGROUND: The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies. METHODS: We combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5 × 10(-7) in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p<5 × 10(-8)). FINDINGS: Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38 × 10(-14)), FAM13A (p=1·12 × 10(-14)), and HHIP (p=1·57 × 10(-12)). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25 × 10(-9)). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4 × 10(-9)). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p<0·01). We also identified associations at two additional loci: MMP12 (overall joint meta-analysis p=2·6 × 10(-9)) and TGFB2 (overall joint meta-analysis p=8·3 × 10(-9)). INTERPRETATION: We have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in α-1 antitrypsin increase the risk of COPD. FUNDING: US National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs.

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Published In

Lancet Respir Med

DOI

ISSN

2213-2600

Publication Date

March 2014

Volume

2

Issue

3

Start / End Page

214 / 225

Location

England

Related Subject Headings

  • Pulmonary Disease, Chronic Obstructive
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Genetic Loci
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
  • 1199 Other Medical and Health Sciences
  • 1117 Public Health and Health Services
  • 1103 Clinical Sciences
 

Citation

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Cho, M. H., McDonald, M.-L., Zhou, X., Mattheisen, M., Castaldi, P. J., Hersh, C. P., … NETT Genetics, ICGN, ECLIPSE and COPDGene Investigators, . (2014). Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. Lancet Respir Med, 2(3), 214–225. https://doi.org/10.1016/S2213-2600(14)70002-5
Cho, Michael H., Merry-Lynn N. McDonald, Xiaobo Zhou, Manuel Mattheisen, Peter J. Castaldi, Craig P. Hersh, Dawn L. Demeo, et al. “Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis.Lancet Respir Med 2, no. 3 (March 2014): 214–25. https://doi.org/10.1016/S2213-2600(14)70002-5.
Cho MH, McDonald M-LN, Zhou X, Mattheisen M, Castaldi PJ, Hersh CP, et al. Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. Lancet Respir Med. 2014 Mar;2(3):214–25.
Cho, Michael H., et al. “Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis.Lancet Respir Med, vol. 2, no. 3, Mar. 2014, pp. 214–25. Pubmed, doi:10.1016/S2213-2600(14)70002-5.
Cho MH, McDonald M-LN, Zhou X, Mattheisen M, Castaldi PJ, Hersh CP, Demeo DL, Sylvia JS, Ziniti J, Laird NM, Lange C, Litonjua AA, Sparrow D, Casaburi R, Barr RG, Regan EA, Make BJ, Hokanson JE, Lutz S, Dudenkov TM, Farzadegan H, Hetmanski JB, Tal-Singer R, Lomas DA, Bakke P, Gulsvik A, Crapo JD, Silverman EK, Beaty TH, NETT Genetics, ICGN, ECLIPSE and COPDGene Investigators. Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. Lancet Respir Med. 2014 Mar;2(3):214–225.
Journal cover image

Published In

Lancet Respir Med

DOI

ISSN

2213-2600

Publication Date

March 2014

Volume

2

Issue

3

Start / End Page

214 / 225

Location

England

Related Subject Headings

  • Pulmonary Disease, Chronic Obstructive
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Genetic Loci
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
  • 1199 Other Medical and Health Sciences
  • 1117 Public Health and Health Services
  • 1103 Clinical Sciences