TY - JOUR
T1 - Sex-based genetic association study identifies celsr1 as a possible chronic obstructive pulmonary disease risk locus among women
AU - the COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points Investigators
AU - Hardin, Megan
AU - Cho, Michael H.
AU - Sharma, Sunita
AU - Glass, Kimberly
AU - Castaldi, Peter J.
AU - McDonald, Merry Lynn
AU - Aschard, Hugues
AU - Senter-Sylvia, Jody
AU - Tantisira, Kelan
AU - Weiss, Scott T.
AU - Hersh, Craig P.
AU - Morrow, Jarrett D.
AU - Lomas, David
AU - Agusti, Alvar
AU - Bakke, Per
AU - Gulsvik, Amund
AU - O’connor, George T.
AU - Dupuis, Josée
AU - Hokanson, John
AU - Crapo, James D.
AU - Beaty, Terri H.
AU - Laird, Nan
AU - Silverman, Edwin K.
AU - Demeo, Dawn L.
AU - Make, Barry
AU - Regan, Elizabeth
AU - Lange, Christoph
AU - Santorico, Stephanie
AU - Hansel, Nadia
AU - Wan, Emily
AU - Hetmanski, Jacqueline
AU - Parker, Margaret
AU - Foreman, Marilyn
AU - Hobbs, Brian
AU - Busch, Robert
AU - El-Boueiz, Adel
AU - Qiao, Dandi
AU - Halper-Stromberg, Eitan
AU - Begum, Ferdouse
AU - Won, Sungho
AU - Lutz, Sharon
AU - Lynch, David A.
AU - Coxson, Harvey O.
AU - Han, Meilan K.
AU - Hoffman, Eric A.
AU - Humphries, Stephen
AU - Wise, Robert
AU - Brown, Robert
AU - Horton, Karen
AU - Putcha, Nirupama
PY - 2017/3/1
Y1 - 2017/3/1
N2 - Chronic obstructive pulmonary disease (COPD) is a complex disease with strong environmental and genetic influences and sexually dimorphic features. Although genetic risk factors for COPD have been identified, much of the heritability remains unexplained. Sex-based genetic association studies may uncover additional COPD genetic risk factors. We studied current and former smokers from COPD case-control cohorts (COPDGene non-Hispanic whites and African Americans, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, and Genetics of Chronic Obstructive Lung Disease). COPD was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity less than 0.70 and forced expiratory volume in 1 second percent predicted less than 80. Testing was performed across all cohorts and combined in a meta-analysis adjusted for age, pack-years, and genetic ancestry. We first performed genome-wide single-nucleotide polymorphism (SNP)- by-sex interaction testing on the outcome of COPD affection status. We performed sex-stratified association testing for SNPs with interaction P less than 10-6. We examined over 8 million SNPs in four populations, including 6,260 subjects with COPD (40.6% female) and 5,269 smoking control subjects (47.3% female). The SNP rs9615358 in the cadherin gene CELSR1 approached genomewide significance for an interaction with sex (P = 1.24310-7). In the sex-stratified meta-analysis, this SNP was associated with COPD among females (odds ratio, 1.37 [95% confidence interval, 1.25-1.49]; P = 3.32310-7) but not males (odds ratio, 0.90 [95% confidence interval, 0.79-1.01]; P = 0.06). CELSR1 is involved in fetal lung development. In a human fetal lung tissue dataset, we observed greater CELSR1 expression in female compared with male samples. This SNP-by-sex genome-wide association analysis identified the fetal lung development gene, CELSR1, as a potential sex-specific risk factor for COPD. Identifying sex-specific genetic risk factors may reveal new insights into sexually dimorphic features of COPD.
AB - Chronic obstructive pulmonary disease (COPD) is a complex disease with strong environmental and genetic influences and sexually dimorphic features. Although genetic risk factors for COPD have been identified, much of the heritability remains unexplained. Sex-based genetic association studies may uncover additional COPD genetic risk factors. We studied current and former smokers from COPD case-control cohorts (COPDGene non-Hispanic whites and African Americans, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, and Genetics of Chronic Obstructive Lung Disease). COPD was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity less than 0.70 and forced expiratory volume in 1 second percent predicted less than 80. Testing was performed across all cohorts and combined in a meta-analysis adjusted for age, pack-years, and genetic ancestry. We first performed genome-wide single-nucleotide polymorphism (SNP)- by-sex interaction testing on the outcome of COPD affection status. We performed sex-stratified association testing for SNPs with interaction P less than 10-6. We examined over 8 million SNPs in four populations, including 6,260 subjects with COPD (40.6% female) and 5,269 smoking control subjects (47.3% female). The SNP rs9615358 in the cadherin gene CELSR1 approached genomewide significance for an interaction with sex (P = 1.24310-7). In the sex-stratified meta-analysis, this SNP was associated with COPD among females (odds ratio, 1.37 [95% confidence interval, 1.25-1.49]; P = 3.32310-7) but not males (odds ratio, 0.90 [95% confidence interval, 0.79-1.01]; P = 0.06). CELSR1 is involved in fetal lung development. In a human fetal lung tissue dataset, we observed greater CELSR1 expression in female compared with male samples. This SNP-by-sex genome-wide association analysis identified the fetal lung development gene, CELSR1, as a potential sex-specific risk factor for COPD. Identifying sex-specific genetic risk factors may reveal new insights into sexually dimorphic features of COPD.
KW - Chronic obstructive pulmonary disease
KW - Genetics
KW - Genome-wide association study
KW - Growth and development
KW - Sex
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U2 - 10.1165/rcmb.2016-0172OC
DO - 10.1165/rcmb.2016-0172OC
M3 - Article
C2 - 27854507
AN - SCOPUS:85014755225
SN - 1044-1549
VL - 56
SP - 332
EP - 341
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 3
ER -