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Sex-Based Genetic Association Study Identifies CELSR1 as a Possible Chronic Obstructive Pulmonary Disease Risk Locus among Women

Hardin, M; Cho, MH; Sharma, S; Glass, K; Castaldi, PJ; McDonald, M-L; Aschard, H; ... COPDGene and Evaluation of COPD Longitudinally to Identify Predi; + view all (2017) Sex-Based Genetic Association Study Identifies CELSR1 as a Possible Chronic Obstructive Pulmonary Disease Risk Locus among Women. American Journal of Respiratory Cell and Molecular Biology , 56 (3) pp. 332-341. 10.1165/rcmb.2016-0172OC. Green open access

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Abstract

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 genome-wide significance for an interaction with sex (P = 1.24 × 10-7). 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 = 3.32 × 10-7) 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.

Type: Article
Title: Sex-Based Genetic Association Study Identifies CELSR1 as a Possible Chronic Obstructive Pulmonary Disease Risk Locus among Women
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1165/rcmb.2016-0172OC
Publisher version: https://doi.org/10.1165/rcmb.2016-0172OC
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: chronic obstructive pulmonary disease, genetics, genome-wide association study, growth and development, sex, Aged, Alleles, Cadherins, Demography, Female, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Lung, Male, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Risk Factors
UCL classification: UCL
UCL > Provost and Vice Provost Offices > VP: Health
URI: https://discovery.ucl.ac.uk/id/eprint/10066409
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