Genome-wide gene-by-smoking interaction study of chronic obstructive pulmonary disease

Woori Kim, Dmitry Prokopenko, Phuwanat Sakornsakolpat, Brian D. Hobbs, Sharon M. Lutz, John E. Hokanson, Louise V. Wain, Carl A. Melbourne, Nick Shrine, Martin D. Tobin, Edwin K. Silverman, Michael H. Cho, Terri H. Beaty

Research output: Contribution to journalArticlepeer-review


Risk of chronic obstructive pulmonary disease (COPD) is determined by both cigarette smoking and genetic susceptibility, but little is known about gene-by-smoking interactions. We performed a genome-wide association analysis of 179,689 controls and 21,077 COPD cases from UK Biobank subjects of European ancestry recruited from 2006 to 2010, considering genetic main effects and gene-by-smoking interaction effects simultaneously (2-degrees-of-freedom (df) test) as well as interaction effects alone (1-df interaction test). We sought to replicate significant results in COPDGene (United States, 2008.2010) and SpiroMeta Consortium (multiple countries, 1947.2015) data. We considered 2 smoking variables: 1) ever/never and 2) current/noncurrent. In the 1-df test, we identified 1 genome-wide significant locus on 15q25.1 (cholinergic receptor nicotinic β4 subunit, or CHRNB4) for ever- and current smoking and identified PI∗Z allele (rs28929474) of serpin family A member 1 (SERPINA1) for ever-smoking and 3q26.2 (MDS1 and EVI1 complex locus, or MECOM) for current smoking in an analysis of previously reported COPD loci. In the 2-df test, most of the significant signals were also significant for genetic marginal effects, aside from 16q22.1 (sphingomyelin phosphodiesterase 3, or SMPD3) and 19q13.2 (Egl-9 family hypoxia inducible factor 2, or EGLN2). The significant effects at 15q25.1 and 19q13.2 loci, both previously described in prior genome-wide association studies of COPD or smoking, were replicated in COPDGene and SpiroMeta. We identified interaction effects at previously reported COPD loci; however, we failed to identify novel susceptibility loci.

Original languageEnglish (US)
Pages (from-to)875-885
Number of pages11
JournalAmerican journal of epidemiology
Issue number5
StatePublished - 2021


  • Chronic obstructive pulmonary disease
  • Gene-by-smoking interaction
  • Gene-environment interaction
  • Genome-wide association study
  • Smoking

ASJC Scopus subject areas

  • Epidemiology


Dive into the research topics of 'Genome-wide gene-by-smoking interaction study of chronic obstructive pulmonary disease'. Together they form a unique fingerprint.

Cite this