Methods: 23 SNPs of five vitamin D pathway genes were genotyped in 914 asthmatic children and 1442 non-allergic controls. Genotypic and haplotypic associations with asthma phenotypes (diagnosis, spirometric indices, total IgE and eosinophil percentage) were analysed by multivariate regression. Generalised multifactor dimensionality reduction (GMDR) was used to detect epistatic interactions between SNPs for asthma phenotypes.
Results: The genotyping efficiency was ≥ 97%, and all SNPs followed Hardy-Weinberg equilibrium among the controls. Several SNPs of CYP27A1, CYP27B1, GC and CYP2R1 were associated with asthma or spirometric indices, although only the association between FEV1 and CYP2R1 rs7935792 passed Bonferroni correction (P = 2.73 x 10-4). Patients with CC genotype of rs7935792 had higher FEV1 than those with the other two genotypes. Asthma was associated with an at-risk haplotype of CYP27A1, formed by rs645163 and rs13406831, with odds ratio (OR) 1.22 and 95% confidence interval (CI) 1.03-1.44 (P = 0.021). The MAF of CYP2R1 haplotype AGGATA was higher among asthmatics (0.017) than controls (0.005) (OR 2.57, 95% CI 1.13-5.84; P = 0.024). FEV1 was associated with GAGAG and GATAG haplotypes of CYP2R1, with the latter association being significant after Bonferroni correction (ß = 13.37, P = 4.83 x 10-4). The TA haplotype of CYP27B1 was associated with FEV1/FVC (ß = 2.11, P = 0.031). CYP27A1 did not form any haplotype block, whereas no significant haplotypic association was found between GC and VDR and spirometric indices. GMDR failed to identify any epistatic interaction that modulated asthma or spirometric indices.
Conclusions: Several SNPs and haplotypes of CYP2R1 are associated with asthma diagnosis and FEV1 in children. Asthma is also modestly associated with a CYP27A1 haplotype. These two 25-hydroxylase genes may be genetic determinants for asthma phenotypes in children.
Funding: General Research Funds (469908, 470909 and 477110), Hong Kong Research Grants Council; Research Committee Group Research Scheme (3110087) and Direct Grant for Research (2013.2.033), CUHK