Investigation of the effect of childhood asthma related genetic traits on disease phenotype

Asthma is the most common inflammatory disease of childhood. Genetic- epigenetic mechanisms and environmental risk factors have the main role in disease development. In this study GWAS (Genome-Wide Association Studies) confirmed 7 genetic loci (IL18R1 rs3771166, IL33 rs1342326, SMAD3 rs744910, GSDMA rs3894194, IL2RB rs2284033, ORMDL3/GSDMB rs2305480 and RAD50 rs6871536) were investigated for their relationship with childhood asthma. Distribution of the risk alleles was genotyped by KASP (Competitive Allele-Specific PCR) technology, in individuals (n=920), selected with ISAAC (International Study on Asthma and Allergies in Children) Phase II questionnaire. Results were evaluated using 114 different clinical and personal characteristics of the Turkish pediatric group. According to the results of single variant-association analysis; rs6871536, rs2284033, rs2305480 variants were found to be risk factors for asthma-related phenotypes. PheWAS (Phenome Wide Association Study) analysis revealed 44 different phenotypic associations for 6 of investigated variants (except IL33 rs1342326). GTEx (Genotype-Tissue Expression) data were used to determine the effect of investigated alleles on gene expression in 48 different tissues, relevant for asthma and lung function. It was observed that the investigated loci associated with 237 eQTL and affect the transcriptional regulation of many genes. A PRS (Polygenic Risk Score) was calculated to determine the combined effect of genetic variants and, the interaction was observed between RAD50 rs6871536 and IL2RB rs2284033. This study generated novel data regarding the genetics of asthma and its comorbidities, providing a genetic characterization of loci associated with asthma. Key Words: Asthma phenotypes, Asthma genetics, PheWAS, GTEx, Genotypephenotype correlation.