Sex-specific genetic determinants of Asthma-COPD phenotype in middle-aged and older Canadian adults: an analysis of CLSA data

Asthma is a chronic respiratory disease affecting both children and adults, while chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease most often associated with smoking and is usually seen in middle-aged and older adults. Asthma-COPD phenotype is a newly found phenotype of chronic obstructive airway disease exhibiting features of both asthma and COPD. Patients with coexisting asthma and COPD are more likely than those with COPD or asthma alone to have poorer quality of life, more frequent exacerbation of respiratory symptoms, rapid lung function decline, higher mortality, and greater healthcare utilization. Many recent population studies have found that females have a higher prevalence of asthma-COPD phenotype and COPD than males. In addition, the prevalence of asthma is higher in males during childhood but increases in females in puberty and adulthood. Although it is unclear what causes sex differences in the risk of asthma-COPD phenotype, COPD, and asthma, it is widely believed that genetic, environmental risk factors, and gene-environmental interactions play an important role. This study used the Canadian Longitudinal Study on Aging (CLSA) data (Baseline Comprehensive and Genomic datasets) to examine sex-specific genetic risk factors for asthma-COPD phenotype, COPD, and asthma in middle-aged and older Canadian adults. The study cohort consisted of 26,622 participants genotyped using the Affymetrix U.K. Biobank Axiom array from the Comprehensive Cohort of 30,097 adults aged 45 to 85. Participants were grouped into four mutually exclusive categories (asthma-COPD phenotype, COPD, asthma, and control). Asthma and COPD were defined as positive responses to the survey questions: "Has a doctor ever told you that you have asthma?" and "Has a doctor told you that you have/had any of the following: emphysema, chronic bronchitis, chronic obstructive pulmonary disease (COPD), or chronic changes in the lungs due to smoking?" respectively. Participants who answered "yes" to self-reported physician-diagnosed asthma and COPD were classified as having asthma-COPD phenotype. The control subjects were those who responded "no" to a self-reported physician diagnosis of asthma and COPD. The association between genetic markers and the outcomes ( asthma-COPD phenotype, COPD, and asthma) was assessed in 2 phases. First, A genome-wide SNP by sex interaction test was conducted using multivariate logistic regression under the additive inheritance model to identify SNPs with significant interaction with sex at the level of 10-5. Second, a sex-stratified multivariate survey logistic regression was performed using SNPs with interaction p-values less than 10-5 to identify male and female-specific polymorphisms associated with asthma-COPD phenotype, COPD, and asthma. A total of 416,562 SNPs were examined after GWAS quality control. Seven male-specific SNPs (rs11799559, rs3821479, rs77800494, rs11061082, rs926718, rs1884882, and rs1051169) in/near SMYD3, FHIT, ZNF608, RIMBP2, ZNF133, BPIFB1, and S100B respectively were significantly associated with asthma-COPD phenotype. No SNP was significantly associated with asthma-COPD phenotype in females. Eight polymorphisms (rs13326145, rs56334611, rs6816344, rs17039240, rs6935314, rs13225543, rs12869252, and rs6090327) near MAGI1, COX18, OSTC, ELOVL5, C7orf72 FGF14, and NKAIN4 genes respectively were significantly associated with COPD in males. In addition, four polymorphisms (rs12025895, rs10931835, rs220806, and rs77625370) in/near CAMTA1, SATB2, PDE10A, and LINC00908 genes were significantly associated with COPD amongst females. Five polymorphisms (rs6701638, rs17071077, rs254804, rs6013213, and rs2968822) in/near KIF26B, NMBR, PEPD, RTN4, and NFATC2 loci, were significantly associated with asthma in males. In contrast, three SNPs (rs2968801, rs2864052, and rs9525931) in/near RTN4 and SERP2 loci were significantly associated with asthma in females. These results suggest a sexually dimorphic association between these polymorphisms and asthma-COPD phenotype, COPD, and asthma. It provides further evidence of the distinct pathogenesis of the three diseases since no overlapping SNP was identified. Further functional studies will help determine the roles these variants/genes play in the pathogenesis of asthma-COPD phenotype, COPD, and asthma, thus, potentially paving the way for better disease endotyping and precision medicine.

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