Abstract
BACKGROUND: Sex differences related to immune responses can influence atopic manifestations in childhood asthma. While genome-wide association studies have investigated a sex-specific genetic architecture of the immune response, gene-by-sex interactions have not been extensively analysed for atopy-related markers including allergy skin tests, IgE and eosinophils in asthmatic children. METHODS: We performed a genome-wide gene-by-sex interaction analysis for atopy-related markers using whole-genome sequencing data based on 889 trios from the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) and 284 trios from the Childhood Asthma Management Program (CAMP). We also tested the findings in UK Biobank participants with self-reported childhood asthma. Furthermore, downstream analyses in GACRS integrated gene expression to disentangle observed associations. RESULTS: Single nucleotide polymorphism (SNP) rs1255383 at 10q11.21 demonstrated a genome-wide significant gene-by-sex interaction (p(interaction)=9.08×10(-10)) for atopy (positive skin test) with opposite direction of effects between females and males. In the UK Biobank participants with a history of childhood asthma, the signal was consistently observed with the same sex-specific effect directions for high eosinophil count (p(interaction)=0.0058). Gene expression of ZNF33B (zinc finger protein 33B), located at 10q11.21, was moderately associated with atopy in girls, but not in boys. CONCLUSIONS: We report SNPs in/near a zinc finger gene as novel sex-differential loci for atopy-related markers with opposite effect directions in females and males. A potential role for ZNF33B should be studied further as an important driver of sex-divergent features of atopy in childhood asthma.