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. 2016 Jan;46(1):112-24.
doi: 10.1111/cea.12642.

Genetic associations with viral respiratory illnesses and asthma control in children

D A Loisel  1   2 , G Du  1 , T S Ahluwalia  3   4 , C J Tisler  5 , M D Evans  6 , R A Myers  1 , R E Gangnon  6   7 , E Kreiner-Møller  3 , K Bønnelykke  3 , H Bisgaard  3 , D J Jackson  5 , R F Lemanske Jr  5   8 , D L Nicolae  1   9   10 , J E Gern  5 , C Ober  1
Affiliations

Genetic associations with viral respiratory illnesses and asthma control in children

D A Loisel et al. Clin Exp Allergy. 2016 Jan.

Abstract

Background: Viral respiratory infections can cause acute wheezing illnesses in children and exacerbations of asthma.

Objective: We sought to identify variation in genes with known antiviral and pro-inflammatory functions to identify specific associations with more severe viral respiratory illnesses and the risk of virus-induced exacerbations during the peak fall season.

Methods: The associations between genetic variation at 326 SNPs in 63 candidate genes and 10 phenotypes related to viral respiratory infection and asthma control were examined in 226 children enrolled in the RhinoGen study. Replication of asthma control phenotypes was performed in 2128 children in the Copenhagen Prospective Study on Asthma in Childhood (COPSAC). Significant associations in RhinoGen were further validated using virus-induced wheezing illness and asthma phenotypes in an independent sample of 122 children enrolled in the Childhood Origins of Asthma (COAST) birth cohort study.

Results: A significant excess of P values smaller than 0.05 was observed in the analysis of the 10 RhinoGen phenotypes. Polymorphisms in 12 genes were significantly associated with variation in the four phenotypes showing a significant enrichment of small P values. Six of those genes (STAT4, JAK2, MX1, VDR, DDX58, and EIF2AK2) also showed significant associations with asthma exacerbations in the COPSAC study or with asthma or virus-induced wheezing phenotypes in the COAST study.

Conclusions: We identified genetic factors contributing to individual differences in childhood viral respiratory illnesses and virus-induced exacerbations of asthma. Defining mechanisms of these associations may provide insight into the pathogenesis of viral respiratory infections and virus-induced exacerbations of asthma.

Keywords: allergic sensitization; asthma; children; cold symptoms; genetic association; human rhinovirus; viral respiratory illness; wheezing.

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Figures

Figure 1
Figure 1
Histogram of frequency of P values below defined significant thresholds for 326 SNPs obtained from permutation analysis (n=10,000 runs). The observed number of P values below each threshold is shown in red. (A) Distribution of permutation P values < 0.05. Three hundred and eight of the 10,000 permutations (3.08%) contained more P values <0.05 than the number observed. (B) Distribution of permutation P values < 0.01. Five hundred and fifty of the 10,000 permutations (5.5%) contained more P values <0.01 than the number observed. (C) Distribution of P values <0.001. Two thousand, two hundred and twenty-one of the 10,000 permutations (22.01%) contained more P values <0.001 than that observed.
Figure 2
Figure 2
Q-Q plots of the four RhinoGen phenotypes showing an enrichment of small P values. In each plot (A-D), the observed -log(P value) and expected -log(P value) are plotted.
Figure 3
Figure 3
SNP associations with RhinoGen, COPSAC, and COAST phenotypes. STAT4 rs4853546 genotype association with asthma (P=0.031) in RhinoGen (A) and asthma exacerbations (P=0.024) in COPSAC (B). JAK2 rs3780375 genotype association with mean number of illnesses (P=0.019) in RhinoGen (C) and wheezing illnesses (P=0.012) in COAST (D). MX1 rs469390 genotype association with viral asthma symptom burden (P=0.031) in RhinoGen (E) and asthma exacerbations (P=8.8x10−4) in COPSAC (F). DDX58 rs10813831 genotype association with loss of asthma control (P=0.0055) in RhinoGen (G) and asthma at age 6 years (P=0.035) in COAST (H). Error bars show standard error of means or proportions. Total number of individuals is indicated beneath each genotype class.
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