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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Hardin, M; Cho, MH; Sharma, S; Glass, K; Castaldi, PJ; McDonald, M-L; Aschard, H; Senter-Sylvia, J; Tantisira, K; Weiss, ST; Hersh, CP; Morrow, JD; Lomas, D; Agusti, A; Bakke, P; Gulsvik, A; O'Connor, GT; Dupuis, J; Hokanson, J; Crapo, JD; Beaty, TH; Laird, N; Silverman, EK; DeMeo, DL; COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points Investigators,

Published Date

  • March 2017

Published In

Volume / Issue

  • 56 / 3

Start / End Page

  • 332 - 341

PubMed ID

  • 27854507

Pubmed Central ID

  • PMC5359539

Electronic International Standard Serial Number (EISSN)

  • 1535-4989

Digital Object Identifier (DOI)

  • 10.1165/rcmb.2016-0172OC

Language

  • eng

Conference Location

  • United States