NKG2D gene variation and susceptibility to viral bronchiolitis in childhood

Abstract

<div lang="en" class="abs"><p class="abs_header">Abstract</p><p><em>Background:</em> Genetic factors associated with bronchiolitis are inadequately characterized. We therefore inspected a selected subpopulation of our previous genome-wide association study (GWAS) of bronchiolitis for overlap with known quantitative trait loci (QTLs) to identify susceptibility loci that potentially affect mRNA and protein levels.</p><p><em>Methods:</em> GWAS included a Finnish–Swedish case–control population (<em>n</em> = 187), matched for age and site. We integrated GWAS variants (<em>p</em> < 10−⁴) with QTL data. We subsequently verified allele-specific expression of identified QTLs by flow cytometry. Association of the resulting candidate loci with bronchiolitis was tested in three additional cohorts from Finland and Denmark (<em>n</em> = 1201).</p><p><em>Results:</em> Bronchiolitis-susceptibility variant rs10772271 resided within QTLs previously associated with <em>NKG2D</em> (NK group 2, member D) mRNA and protein levels. Flow cytometric analysis confirmed the association with protein level in NK cells. The GWAS susceptibility allele (A) of rs10772271 (odds ratio [OR] = 2.34) corresponded with decreased NKG2D expression. The allele was nominally associated with bronchiolitis in one Finnish replicate (OR = 1.50), and the other showed directional consistency (OR = 1.43). No association was detected in Danish population.</p><p><em>Conclusions:</em> The bronchiolitis GWAS susceptibility allele was linked to decreased NKG2D expression in the QTL data and in our expression analysis. We propose that reduced <em>NKG2D</em> expression predisposes infants to severe bronchiolitis.</p></div>