Genetic and Environmental Determinants of Childhood Asthma Phenotypes

• Main Author: Tang, Man Fung
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2016
• Subjects: Epidemiology; Genetics; Medicine; Philosophy of Science
• ISBN: 1369410425; 9781369410426

Allergic diseases including asthma and eczema are the results of complex interplay between many genetics and environmental factors. This thesis focused on potential contribution of predisposition factors to both susceptibility and clinical endpoints of asthma and other allergic diseases in Chinese children. A large-scale meta-analysis of genome-wide association studies (GWASs) in Europeans by the GABRIEL Consortium identified 10 asthma susceptibility loci. The first part of this thesis extended these findings to the relationship with lung function in three independent cohorts of Chinese subjects – school-age children (903 asthmatics vs 1205 controls), adults (479 asthmatics vs 746 controls) and preschool children (1341 subjects). The associations of IL13_rs1295686 and GSDMB_rs2305480 for early-onset asthma were replicated in cohorts of school-age children and adults. In meta-analyses, the association between common minor allele of GSDMB_rs2305480 and reduced FEV1%, FVC% and FEV1 /FVC among asthmatics were detected. Beside single-locus effect, gene-gene interaction between SNPs implicating SLC22A5, IL13, GSDMB and SMAD3 was found to modulate spirometric parameters including FEV1%, FVC% and FEV1/FVC among patients. Besides, this thesis investigated longitudinal changes in spirometric indices and fractional exhaled nitric oxide concentration (FeNO), and their possible determinants in a cohort of 188 asthmatic children aged 6-12 years with 5 years of follow-up. Patients had significant annual decline in FVC%, but annual increase in FEV1/FVC and FEF25-75%. Males had higher FEV1% compared to females, but no significant gender disparity in longitudinal change in any spirometric indices. Patients receiving inhaled corticosteroid treatment and with higher BMI had better prognosis, as manifested by less rapid decline in FVC% and more rapid increase in FEV1% per year. Passive household smoking, presence of eczema, family allergic history and atopy were not associated with serial lung function changes. Regarding FeNO, patients had significant annual increase in FeNO. Body height was positively associated with FeNO, but negatively associated with its longitudinal change. FeNO of patients increasd more quickly with increasing total number of asthma exacerbation per year. Atopic patients had higher FeNO than non-atopic patients in any single year, but there was no significant atopic status disparity in longitudinal change in FeNO. Gender, passive smoking in household, degree of asthma control, ICS treatment ever, presence of eczema and BMI were not associated with serial FeNO change. Genetic analysis included the 10 asthma loci and further explored region of chromosome 17q21. GSDMB_rs2305480 and SMAD3_rs744910 were associated with annual growth in FEV1/FVC. IL33_rs1342326 appeared to be a candidate gene for longitudinal lung function and F eNO changes, which should be further examined due to low minor allele frequency. To conclude, this thesis identifies environmental and genetic determinants for various childhood allergy phenotypes, such as asthma, spirometric indices and FeNO, providing new insight into pathogenesis of this prevalent disease.