Genetic Variations in IL28B and Allergic Disease in Children

Environmental changes affecting the relationship between the developing immune system and microbial exposure have been implicated in the epidemic rise of allergic disease in developed countries. While early developmental differences in T cell function are well-recognised, there is now emerging evidence that this is related to developmental differences in innate immune function. In this study we sought to examine if differences associated with innate immunity contribute to the altered immune programming recognised in allergic children. Here, we describe for the first time, the association of carriage of the T allele of the tagging single nucleotide polymorphism rs12979860 3 kb upstream of IL28B, encoding the potent innate immune modulator type III interferon lambda (IFN-λ3), and allergy in children (p = 0.004; OR 4.56). Strikingly, the association between rs12979860 genotype and allergic disease is enhanced in girls. Furthermore, carriage of the T allele at rs12979860 correlates with differences in the pro-inflammatory profile during the first five years of life suggesting this contributes to the key differences in subsequent innate immune development in children who develop allergic disease. In the context of rising rates of disease, these immunologic differences already present at birth imply very early interaction between genetic predisposition and prenatal environmental influences

IL-1B and TNF cytokine production with age in peripheral blood mononuclear cells from individuals with C/C or C/T,T/T genotype stimulated with TLR agonists.

<p>Plots are scaled to span ∼90% of the data range. Differences between groups with p-values<0.05 are annotated: CB measures of rs12979860 genotype C/T, T/T vs C/C amongst females (*: P≤0.01) and males (#: P≤0.01); average linear trend of profiles of C/T,T/T vs C/C amongst females (†: P≤0.01, ††: P≤0.001) and males (‡: P≤0.01, ‡‡: P<0.001).</p

Variation at tagging SNP rs12979860 confers risk for allergic disease.

<p><b>a.</b> Carriage of the T allele of rs12979860 is over-represented in children with allergic disease (cohort 1, n = 70) (p = 0.004). This relationship is also observed for children with IgE-mediated food allergy (Cohort 2, n = 60) (p = 0.04 dominant model). For both cohorts, the frequency of the different genotypes varies between disease and control subjects (p = 0.02; cohort 1 and cohort 2). <b>b.</b> Odds ratio (OR; 95% CI) for carriage of T allele of rs12979860 and allergic disease and for HCV persistence. Odds ratio values for HCV cohorts are from di Iulio et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030607#pone.0030607-diIulio1" target="_blank">[20]</a> and Tillman et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030607#pone.0030607-Tillmann1" target="_blank">[28]</a>. ORs for allergic disease and food allergy adjusted for gender. ORs for HCV cohorts adjusted for HBV co-infection in all cohorts and gender in the multiple source cohort.</p

Carriage of the T allele of rs12979860 is associated with clinical presentation of allergic disease.

<p>Proportion of infants in cohort 1 that are sensitised, have doctor-diagnosed atopic dermatitis, asthma or IgE-mediated food allergy at 1, 2.5 or 5 years of age, with C/C (n = 35, black bars) or C/T, T/T (n = 35, grey bars) genotype. OR = odds-ratio. *P<0.05, **P<0.01 and ***P<0.001 versus age-matched C/C genotype.</p

Gender differences in the association between carriage of the T allele of rs12979860 and allergic disease.

<p><b>a.</b> Interaction between gender and carriage of the T allele of rs12979860 for sensitization (top panel) and atopic dermatitis (bottom panel) in cohort 1 in individuals with C/C (n = 35, black bars) or C/T,T/T (n = 35, grey bars) genotype. *P<0.05 and **P<0.001 versus females with C/C genotype. <b>b.</b> Trends in sensitization (top panel) and atopic dermatitis (bottom panel) levels with age relative to rs12979860 genotype. *P<0.05 versus proportion of sensitised females with C/C genotype and †P<0.05 versus C/T,T/T genotype in females with atopic dermatitis. OR = odds ratio.</p