Journal article
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, Vol.56(3), pp.332-341
03/2017
DOI: 10.1165/rcmb.2016-0172OC
PMCID: PMC5359539
PMID: 27854507
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
. 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
). 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
) 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.
Details
- Title: Subtitle
- Sex-Based Genetic Association Study Identifies CELSR1 as a Possible Chronic Obstructive Pulmonary Disease Risk Locus among Women
- Creators
- Megan Hardin - Brigham and Women's HospitalMichael H Cho - Brigham and Women's HospitalSunita Sharma - University of Colorado DenverKimberly Glass - 1 Channing Division of Network Medicine and.Peter J Castaldi - 1 Channing Division of Network Medicine and.Merry-Lynn McDonald - 1 Channing Division of Network Medicine and.Hugues Aschard - Harvard UniversityJody Senter-Sylvia - 1 Channing Division of Network Medicine and.Kelan Tantisira - Brigham and Women's HospitalScott T Weiss - Brigham and Women's HospitalCraig P Hersh - Brigham and Women's HospitalJarrett D Morrow - Brigham and Women's HospitalDavid Lomas - University College LondonAlvar Agusti - Hospital Clínic de BarcelonaPer Bakke - University of BergenAmund Gulsvik - Oslo University HospitalGeorge T O'Connor - Boston UniversityJosée Dupuis - Boston UniversityJohn Hokanson - Colorado School of Public HealthJames D Crapo - National Jewish HealthTerri H Beaty - Johns Hopkins UniversityNan Laird - Harvard UniversityEdwin K Silverman - Brigham and Women's HospitalDawn L DeMeo - Brigham and Women's HospitalCOPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points Investigators
- Contributors
- Eric A Hoffman (Contributor) - University of Iowa, Radiology
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory cell and molecular biology, Vol.56(3), pp.332-341
- DOI
- 10.1165/rcmb.2016-0172OC
- PMID
- 27854507
- PMCID
- PMC5359539
- ISSN
- 1044-1549
- eISSN
- 1535-4989
- Grant note
- U01 HL089897 / NHLBI NIH HHS R01 HL089856 / NHLBI NIH HHS R01 HL124233 / NHLBI NIH HHS HHSN268201500001I / NHLBI NIH HHS R01 HL130883 / NHLBI NIH HHS R01 HL113264 / NHLBI NIH HHS HHSN268201500001C / NHLBI NIH HHS R01 HL126596 / NHLBI NIH HHS U01 HL089856 / NHLBI NIH HHS P01 HL105339 / NHLBI NIH HHS S10 OD018526 / NIH HHS R01 HL089438 / NHLBI NIH HHS R00 HL121087 / NHLBI NIH HHS R01 HL089897 / NHLBI NIH HHS K12 HL120004 / NHLBI NIH HHS
- Language
- English
- Date published
- 03/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Internal Medicine
- Record Identifier
- 9984318702802771
Metrics
16 Record Views