Respiratory problems in Children 1.4X more likely if poor Vitamin D receptor
Vitamin D receptor polymorphisms are associated with severity of wheezing illnesses and asthma exacerbations in children
Journal of Steroid Biochemistry and Molecular Biology April 2020, https://doi.org/10.1016/j.jsbmb.2020.105692
Katharine Leitera, Kimberley Franksa,b, Meredith L Borlanda,c, Laura Colemana,b, Leesa Harrisa,b, Peter N. Le Souefa,b, Ingrid A. Lainga,b,*
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Wheezing and asthma exacerbations are a leading cause of hospitalisations for children in developed countries [1]. Asthma is a multifactorial disease caused by a complex interaction of genetic predisposition and environmental exposures. A significant proportion of the inter-individual risk for developing asthma is due to genetic differences [2-4]. Numerous studies have identified loci, candidate genes, and single nucleotide polymorphisms (SNPs) which show linkage and association with asthma development [5-8]. However, limited studies have evaluated the association between these isolated genetic variations and mechanisms of acute wheeze and asthma.
There has been increasing interest in the role of vitamin D in wheezing and asthma. Vitamin D, a fat-soluble nutrient widely recognised for its role in bone health, also plays a role in immune regulation [9]. Its biological effects, including regulation of helper T-cell development and subsequent cytokine secretion profiles, are achieved through the regulation of gene expression, which is mediated by the vitamin D receptor (VDR) [8]. The VDR gene is located on chromosome 12, region q13-23: a region commonly linked to asthma in genomewide linkage analyses [10].
Family-based cohort studies have identified VDR genetic variants that are strongly associated with asthma traits in particular populations [7,8]. Such findings suggest that the VDR locus harbours variants that Single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene have shown linkage and association with asthma development in multiple cohort studies. However, the majority of investigations have focused on asthma phenotypes in cohorts with stable disease. We investigated the relationship between VDR SNPs and the frequency and severity of acute episodes of wheeze/asthma in a cohort of Australian children, as the ability to identify children at risk of more severe exacerbations could lead to personalized and improved genotype-specific treatment pathways. We successfully genotyped five SNPs of the VDR gene (rs2525046, rs9729, rs1544410 (BsmI), rs22239179, and rs2228570 (FokI)) in 657 children presenting to a tertiary children's hospital with acute asthma, bronchiolitis, or a wheezing illness. The relationships between VDR SNPs and exacerbation severity scores, 2-agonist use, and frequency of respiratory exacerbations were analysed using multiple regression. The rs2525046 (FokI) CT genotype was associated with higher VDR mRNA intensity levels (p = 0.007) compared to the CC genotype. A trend towards significance (p = 0.056) was identified between the rs2525046 TT genotype and higher VDR mRNA intensity levels compared to the CC genotype. Children with rs2228570 AA genotype had higher exacerbation severity scores (p = 0.001) and poorer 2-agonist treatment response (doses at 6h:p = 0.009 and 12h:p = 0.033) compared to those with the GG genotype. Children with rs1544410 (BsmI) TT genotype had lower exacerbation severity scores (p = 0.005) compared to those with the CC genotype. Children with rs2228570 GA genotype presented to and/or were admitted to hospital more times since birth with respiratory (p = 0.011) and wheezing (p = 0.021) illnesses than children with the GG genotype. No associations were identified between rs9729, rs2525046 and r2239179 polymorphisms and acute wheezing/asthma variables. These findings suggest that genetic variants at the VDR locus may play a role in acute wheeze/asthma severity in children.