Genetic association of circadian clock genes and the risk of childhood asthma

Background: Asthma is a chronic respiratory disease characterized by diurnal oscillations of symptoms severity with the highest intensity at 4 a.m. and improvement at 4 p.m. The underlying cause may be central circadian clock dysregulation that also controls the target tissues such as lungs. We hypothesized that altered circadian regulation in asthma may result from circadian clock genes variants. This study aimed to investigate the possible association of genetic variants of core circadian clock genes and asthma risk in the population of Polish children. Methods: In the study we included 165 asthmatic patients and 138 healthy children. Asthma diagnosis was based on GINA 2006 guidelines. In the control group, asthma and allergic disease were excluded based on clinical examination and lung function testing. Genotyping was performed for 32 polymorphisms in CLOCK, BMAL1, PER3, and TIMELESS genes using real-time PCR with TaqMan genotyping assays. Statistical calculations were performed in Statistica 12 and linkage disequilibrium was analysed using Haploview 4.2. Results: Three SNPs in TIMELESS (rs10876890, rs2291739, rs11171856), were significantly associated with asthma. Moreover, haplotype analysis showed that two TIMELESS haplotypes (TTTT and CTAC) were also associated with asthma risk, although after multiple testing correction only TTTT haplotype showed significant association with childhood asthma. Conclusions: We have shown for the first time that TIMELESS may be a novel candidate gene for childhood asthma and thus indicating that circadian oscillation in symptoms severity may be genetically predisposed.