Rhinovirus wheezing illness and genetic risk of childhood-onset asthma

Minal Calışkan, Yury A Bochkov, Eskil Kreiner-Møller, Klaus Bønnelykke, Michelle M Stein, Gaixin Du, Hans Bisgaard, Daniel J Jackson, James E Gern, Robert F Lemanske Jr, Dan L Nicolae, Carole Ober, Minal Calışkan, Yury A Bochkov, Eskil Kreiner-Møller, Klaus Bønnelykke, Michelle M Stein, Gaixin Du, Hans Bisgaard, Daniel J Jackson, James E Gern, Robert F Lemanske Jr, Dan L Nicolae, Carole Ober

Abstract

Background: Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts.

Methods: We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Finally, we examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs).

Results: The 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Moreover, the expression levels of ORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs, as compared with unstimulated PBMCs. The expression of these genes was associated with 17q21 variants in both conditions, although the increase with exposure to HRV was not genotype-specific.

Conclusions: Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. The expression levels of both genes increased in response to HRV stimulation, although the relative increase was not associated with the 17q21 genotypes. (Funded by the National Institutes of Health.).

Figures

Figure 1. Effects of 17q21 Genotype on…
Figure 1. Effects of 17q21 Genotype on Asthma and Human Rhinovirus (HRV) Wheezing Illnesses in the Childhood Origins of Asthma (COAST) Cohort
Panel A shows the prevalence of asthma according to 17q21 genotype, and Panel B shows the mean number of HRV wheezing illnesses in the first 3 years of life according to 17q21 genotype. Sample sizes for each genotype group are shown in parentheses under the horizontal axis. T bars in Panel B indicate standard errors. Panel C shows the prevalence of asthma among the children according to the whether they had at least one HRV wheezing illness in the first 3 years of life or no HRV wheezing illness. The dashed horizontal line shows the overall prevalence of asthma among children in the COAST cohort. P = 0.006 for the main effect of this single-nucleotide polymorphism (SNP) among children who had at least one HRV wheezing illness in the first 3 years of life, and P = 0.70 among children who did not have an HRV wheezing illness; P = 0.004 for the interaction between the rs7216389 SNP and HRV wheezing illness with respect to the development of asthma. Panel D shows the odds-ratio estimates for asthma risk associated with the three genotypes at rs7216389 among children who had at least one HRV wheezing illness in the first 3 years of life, and Panel E, the odds-ratio estimates among children who did not have any HRV wheezing illnesses in the first 3 years of life. In Panels D and E, the odds ratios are shown relative to the reference group — the children with the CC genotype who did not have any HRV wheezing illnesses. The sample size of each genotype group is shown in parentheses under the horizontal axis in both panels, and I bars indicate 95% confidence intervals.
Figure 2. Effects of 17q21 Genotype on…
Figure 2. Effects of 17q21 Genotype on Asthma and HRV Wheezing Illnesses in the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) Cohort
Panel A shows the prevalence of asthma among children in the COPSAC cohort, according to whether they had at least one HRV wheezing illness in the first 3 years of life or no HRV wheezing illnesses. The dashed horizontal line shows the overall prevalence of asthma among children in the COPSAC cohort. Panel B shows the odds-ratio estimates for asthma risk associated with the three genotypes at rs7216389 among children who had at least one HRV wheezing illness in the first 3 years of life, and Panel C, the odds-ratio estimates for asthma risk associated with the three rs7216389 genotypes among children who did not have any HRV wheezing illnesses in the first 3 years of life. In both panels, the odds ratios were relative to the reference group — children with the CC genotype who did not have any HRV wheezing illnesses. In Panels B and C, the numbers in parentheses under the horizontal axis are the numbers of participants with a given genotype. I bars in Panels B and C indicate 95% confidence intervals.
Figure 3. Expression of IKZF3 , GSDMB…
Figure 3. Expression of IKZF3, GSDMB, and ORMDL3 in Peripheral-Blood Mononuclear Cells (PBMCs) from the Adult Participants
Relative expression levels are shown in unstimulated (U) and HRV-stimulated (HRV) PBMCs. Expression of IKZF3 was measured in 96 paired samples, and expression of GSDMB and ORMDL3 in 97 paired samples. Each circle corresponds to an individual participant. The horizontal lines show the mean expression levels. As compared with the expression of IKZF3, GSDMB, and ORMDL3 in unstimulated cells, the mean expression of these genes in HRV-stimulated cells was increased by a factor of 1.01, 1.29, and 2.17, respectively.
Figure 4. Association between rs7216389 Genotype and…
Figure 4. Association between rs7216389 Genotype and Expression of 17q21 Genes in Unstimulated and HRV-Stimulated PBMCs
Relative expression levels of IKZF3, GSDMB, and ORMDL3 are shown according to 17q21 genotype in unstimulated and HRV-stimulated PBMCs. The sample size of each genotype group is shown in parentheses under the horizontal axis. Each circle corresponds to an individual participant. The horizontal lines show the mean expression levels. The P values indicate the significance of the association between the number of T alleles and gene expression.

References

    1. Moffatt MF, Kabesch M, Liang L, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. 2007;448:470–3.
    1. Akhabir L, Sandford AJ. Genomewide association studies for discovery of genes involved in asthma. Respirology. 2011;16:396–406.
    1. Ober C, Yao TC. The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev. 2011;242:10–30.
    1. Bouzigon E, Corda E, Aschard H, et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med. 2008;359:1985–94.
    1. Halapi E, Gudbjartsson DF, Jonsdottir GM, et al. A sequence variant on 17q21 is associated with age at onset and severity of asthma. Eur J Hum Genet. 2010;18:902–8.
    1. Moffatt MF, Gut IG, Demenais F, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010;363:1211–21.
    1. Bisgaard H, Bønnelykke K, Sleiman PM, et al. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am J Respir Crit Care Med. 2009;179:179–85.
    1. Wu H, Romieu I, Sienra-Monge JJ, Li H, del Rio-Navarro BE, London SJ. Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma. Allergy. 2009;64:629–35.
    1. Flory JH, Sleiman PM, Christie JD, et al. 17q12-21 Variants interact with smoke exposure as a risk factor for pediatric asthma but are equally associated with early-onset versus late-onset asthma in North Americans of European ancestry. J Allergy Clin Immunol. 2009;124:605–7.
    1. Smit LA, Bouzigon E, Pin I, et al. 17q21 Variants modify the association between early respiratory infections and asthma. Eur Respir J. 2010;36:57–64.
    1. van der Valk RJ, Duijts L, Kerkhof M, et al. Interaction of a 17q12 variant with both fetal and infant smoke exposure in the development of childhood asthma-like symptoms. Allergy. 2012;67:767–74.
    1. Verlaan DJ, Ge B, Grundberg E, et al. Targeted screening of cis-regulatory variation in human haplotypes. Genome Res. 2009;19:118–27.
    1. Murphy A, Chu JH, Xu M, et al. Mapping of numerous disease-associated expression polymorphisms in primary peripheral blood CD4+ lymphocytes. Hum Mol Genet. 2010;19:4745–57.
    1. Ober C, Vercelli D. Gene-environment interactions in human disease: nuisance or opportunity? Trends Genet. 2011;27:107–15.
    1. Sykes A, Johnston SL. Etiology of asthma exacerbations. J Allergy Clin Immunol. 2008;122:685–8.
    1. Johnston SL, Pattemore PK, Sanderson G, et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ. 1995;310:1225–9.
    1. Bisgaard H, Hermansen MN, Bønnelykke K, et al. Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study. BMJ. 2010;341:c4978.
    1. Kotaniemi-Syrjänen A, Vainionpää R, Reijonen TM, Waris M, Korhonen K, Korppi M. Rhinovirus-induced wheezing in infancy — the first sign of childhood asthma? J Allergy Clin Immunol. 2003;111:66–71.
    1. Hyvärinen MK, Kotaniemi-Syrjänen A, Reijonen TM, Korhonen K, Korppi MO. Teenage asthma after severe early childhood wheezing: an 11-year prospective follow-up. Pediatr Pulmonol. 2005;40:316–23.
    1. Jackson DJ, Gangnon RE, Evans MD, et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med. 2008;178:667–72.
    1. Lemanske RF., Jr The Childhood Origins of Asthma (COAST) study. Pediatr Allergy Immunol. 2002;13(Suppl 15):38–43.
    1. Bisgaard H, Pipper CB, Bønnelykke K. Endotyping early childhood asthma by quantitative symptom assessment. J Allergy Clin Immunol. 2011;127(5):1155.e2–1164.e2.
    1. DiFranza JR, Aligne CA, Weitzman M. Prenatal and postnatal environmental tobacco smoke exposure and children’s health. Pediatrics. 2004;113:1007–15.
    1. Hirota T, Harada M, Sakashita M, et al. Genetic polymorphism regulating ORM1-like 3 (Saccharomyces cerevisiae) expression is associated with childhood atopic asthma in a Japanese population. J Allergy Clin Immunol. 2008;121:769–70.
    1. Cantero-Recasens G, Fandos C, Rubio-Moscardo F, Valverde MA, Vicente R. The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum Mol Genet. 2010;19:111–21.
    1. Miller M, Tam AB, Cho JY, et al. ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6. Proc Natl Acad Sci U S A. 2012;109:16648–53.
    1. Trujillo-Alonso V, Maruri-Avidal L, Arias CF, López S. Rotavirus infection induces the unfolded protein response of the cell and controls it through the non-structural protein NSP3. J Virol. 2011;85:12594–604.
    1. Carl-McGrath S, Schneider-Stock R, Ebert M, Rocken C. Differential expression and localisation of gasdermin-like (GSDML), a novel member of the cancer-associated GSDMDC protein family, in neoplastic and non-neoplastic gastric, hepatic, and colon tissues. Pathology. 2008;40:13–24.
    1. Saeki N, Usui T, Aoyagi K, et al. Distinctive expression and function of four GSDM family genes (GSDMA-D) in normal and malignant upper gastrointestinal epithelium. Genes Chromosomes Cancer. 2009;48:261–71.

Source: PubMed

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