Genome-wide association study identification of novel loci associated with airway responsiveness in chronic obstructive pulmonary disease

Nadia N. Hansel, Peter D. Pare, Nicholas Rafaels, Don D. Sin, Andrew Sandford, Denise Daley, Candelaria Vergara, Lili Huang, W. Mark Elliott, Chris D. Pascoe, Bryna A. Arsenault, Dirkje S. Postma, H. Marike Boezen, Yohan Bosse, Maarten Van Den Berge, Pieter S. Hiemstra, Michael H. Cho, Augusto A. Litonjua, David Sparrow, Carole OberRobert A. Wise, John Connett, Enid R. Neptune, Terri H. Beaty, Ingo Ruczinski, Rasika A. Mathias, Kathleen C. Barnes

Research output: Contribution to journalArticlepeer-review

Abstract

Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P<9.57× 10-8). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57×10-8,P<4.6×10-6). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for SGCD (P = 2.57×10-9) and MYH15 (P = 1.62×10-6), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness.

Original languageEnglish (US)
Pages (from-to)226-234
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume53
Issue number2
DOIs
StatePublished - Aug 1 2015

Keywords

  • Airway reactivity
  • Bronchial responsiveness
  • COPD
  • eQTL
  • δ-Sarcoglycan

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Genome-wide association study identification of novel loci associated with airway responsiveness in chronic obstructive pulmonary disease'. Together they form a unique fingerprint.

Cite this