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

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 10Results: 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. 5.