Journal Article

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

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

2015

Overview

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.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Asthma / Chromosome 9 / Chromosomes / Chronic obstructive pulmonary disease / Endothelium / Epithelium / Gene expression / Genetic diversity / Genetic Predisposition to Disease / Genome-wide association studies / Genome-Wide Association Study / Genomes / Humans / Immunohistochemistry / Lung diseases / Mortality / mRNA / Myosin Heavy Chains - genetics / Myosin Heavy Chains - metabolism / Original Research / Polymorphism, Single Nucleotide / Pulmonary Disease, Chronic Obstructive - genetics / Pulmonary Disease, Chronic Obstructive - metabolism / Quantitative Trait Loci / Regression analysis / Respiratory function / Respiratory system / Respiratory tract diseases / Risk / Sarcoglycans - genetics / Sarcoglycans - metabolism / Single-nucleotide polymorphism / Smooth muscle