Sex-Specific Genetic Determinants of Asthma-COPD Phenotype and COPD in Middle-Aged and Older Canadian Adults: An Analysis of CLSA Data

Abstract

The etiology of sex differences in the risk of asthma-COPD phenotype and COPD is still not completely understood. Genetic and environmental risk factors are commonly believed to play an important role. This study aims to identify sex-specific genetic markers associated with asthma-COPD phenotype and COPD using the Canadian Longitudinal Study on Aging (CLSA) Baseline Comprehensive and Genomic data. There were a total of 1,415 COPD cases. Out of them, 504 asthma-COPD phenotype cases were identified. 20,524 participants without a diagnosis of asthma and COPD served as controls. We performed genome-wide SNP-by-sex interaction analysis. SNPs with an interaction p-value < 10⁻⁵ were included in a sex-stratified multivariable logistic regression for asthma-COPD phenotype and COPD outcomes. 18 and 28 SNPs had a significant interaction term p-value < 10⁻⁵ with sex in the regression analyses of asthma-COPD phenotype and COPD outcomes, respectively. Sex-stratified multivariable analysis of asthma-COPD phenotype showed that 7 SNPs in/near SMYD3, FHIT, ZNF608, RIMBP2, ZNF133, BPIFB1, and S100B loci were significant in males. Sex-stratified multivariable analysis of COPD showed that 8 SNPs in/near MAGI1, COX18, OSTC, ELOVL5, C7orf72 FGF14, and NKAIN4 were significant in males, and 4 SNPs in/near genes CAMTA1, SATB2, PDE10A, and LINC00908 were significant in females. An SNP in the ZPBP gene was associated with COPD in both males and females. Identification of sex-specific loci associated with asthma-COPD phenotype and COPD may offer valuable evidence toward a better understanding of the sex-specific differences in the pathophysiology of the diseases.

Keywords:

• Asthma-COPD phenotype
• chronic obstructive pulmonary disease
• sex
• polymorphisms
• CLSA

Acknowledgment

This research was made possible using the data/biospecimens collected by the Canadian Longitudinal Study on Aging (CLSA). This research has been conducted using CLSA’s Baseline Comprehensive Dataset version 4.0 and Genomics Dataset version 3.0, under Application Number 19CA006. The CLSA is led by Drs. Parminder Raina, Christina Wolfson, and Susan Kirkland. The opinions expressed in this manuscript are solely those of the author and do not represent those of the Canadian Longitudinal Study on Aging.

Ethical approval

This CLSA project received ethics approval at two levels. Consent to participate was obtained for all participants under the CLSA harmonized multi-university ethics process approved by the Hamilton Integrated Research Ethics Board (HiREB), Hamilton Health Sciences/McMaster University. Simon Fraser University (SFU) was a participating institution in the CLSA data collection, and the SFU Office of Research Services Ethics Committee reviewed all consent material prior to data collection (SFU ORS #2018s0139). Ethics approval for the current study was obtained from the University of Alberta Health Research Ethics Board (Pro00091377_REN3) and Memorial University Health Research Ethics Board (HREB # 2019.072).

Disclaimer

The opinions expressed in this manuscript are the author’s own and do not reflect the views of the Canadian Longitudinal Study on Aging.

Disclosure statement

The authors declare no conflicts of interest.

Data availability statement

The datasets used in this study are not readily available. Data are only available from the Canadian Longitudinal Study on Aging (www.clsa-elcv.ca) for researchers who meet the criteria for access to de-identified CLSA data.

Additional information

Funding

The Canadian Institutes of Health Research (CIHR) Catalyst Grant provided funding for this project (ACD 162989). This was also supported by The Government of Canada provides funding for the Canadian Longitudinal Study on Aging (CLSA) through the Canadian Institutes of Health Research (CIHR) under grant reference: LSA 94473 and the Canada Foundation for Innovation, as well as the following provinces, Newfoundland, Nova Scotia, Quebec, Ontario, Manitoba, Alberta, and British Columbia.