Identification of Sex-Specific Genetic Polymorphisms Associated with Asthma in Middle-Aged and Older Canadian Adults: An Analysis of CLSA Data

Abstract

Purpose

Asthma is a chronic heterogeneous respiratory disease resulting from a complex interplay between genetic variations and environmental exposures. There are sex disparities in the prevalence and severity of asthma in males and females. Asthma prevalence is higher in males during childhood but increases in females in adulthood. The mechanisms underlying these sex differences are not well understood; nevertheless, genetic variations, hormonal changes, and environmental influences are thought to play important roles. This study aimed to identify sex-specific genetic variants associated with asthma using CLSA genomic and questionnaire data.

Methods

First, we conducted a genome-wide SNP-by-sex interaction analysis on 23,323 individuals, examining 416,562 single nucleotide polymorphisms (SNPs) after quality control, followed by sex-stratified survey logistic regression of SNPs with interaction p-value less than 10^¯5.

Results

Out of the 49 SNPs with interaction p-value less than 10⁻⁵, a sex-stratified survey logistic regression showed that five male-specific SNPs (rs6701638, rs17071077, rs254804, rs6013213, and rs2968822) in/near KIF26B, NMBR, PEPD, RTN4, and NFATC2 loci, and three female-specific SNPs (rs2968801, rs2864052, and rs9525931) in/near RTN4, and SERP2 loci were significantly associated with asthma after Bonferroni correction. An SNP (rs36213) in the EPHB1 gene was significantly associated with an increased risk of asthma in males [OR=1.35, 95% CI (1.14, 1.60)] but with a reduced risk of asthma in females [OR=0.84, 95% CI (0.76, 0.92)] after Bonferroni correction.

Conclusion

We discovered novel sex-specific genetic markers in/near the KIF26B, RTN4, EPHB1, NMBR, SERP2, PEPD, and NFATC2 genes that could potentially shed light on the sex differences in asthma susceptibility in males and females. Future mechanistic studies are required to understand better the underlying sex-related pathways of the identified loci in asthma development.

Keywords:

• asthma
• single nucleotide polymorphism
• sex-specific
• CLSA

Data Sharing 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.

Ethics 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). This study was also conducted following the principles of the Declaration of Helsinki, and ethical approval was obtained from the University of Alberta Health Research Ethics Board (Pro00091377_REN3) and Memorial University Health Research Ethics Board (HREB # 2019.072).

Acknowledgment

This research was made possible using the data/biospecimens collected by the Canadian Longitudinal Study on Aging (CLSA). 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 and Labrador, Nova Scotia, Quebec, Ontario, Manitoba, Alberta, and British Columbia. 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.

Disclosure

The authors declare no conflicts of interest in this work.

Additional information

Funding

The Canadian Institutes of Health Research (CIHR) Catalyst Grant provided funding for this project (ACD 162989).