Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes

rs5743836 was genotyped in two family-based cohorts of children with asthma and a case-control study of adult asthmatics. Association analyses were performed using chi square, family-based and population-based testing. A luciferase assay was performed to investigate whether rs5743836 genotype influences TLR9 promoter activity.Contrary to prior reports, rs5743836 was not associated with asthma in any of the three cohorts. Marginally significant associations were found with FEV1 and FVC (p = 0.003 and p = 0.008, respectively) in one of the family-based cohorts, but these associations were not significant after correcting for multiple comparisons. Higher promoter activity of the CC genotype was demonstrated by luciferase assay, confirming the functional importance of this variant.Although rs5743836 confers regulatory effects on TLR9 transcription, this variant does not appear to be an important asthma-susceptibility locus.Asthma is a public health problem of considerable importance with over 300 million people affected worldwide[1]. Asthma is likely due to genetic and environmental determinants that are poorly understood. Although primarily a disorder resulting from TH2 cell mediated inflammation, significant interest is developing in investigating innate immunity in the search to understand the pathogenesis of this disease[2].Toll-like receptors (TLRs) are evolutionarily conserved components of the innate immune system that act to directly recognize pathogen-derived elements, including viral and bacterial DNA, lipopolysaccharides, and proteoglycans. They provide a crucial link between the recognition of pathogens by the innate immune system and subsequent activation of adaptive immunity, inducing maturation of antigen presenting cells and differentiation of T cells. TLR9 is expressed in plasmacytoid dendritic cells, B cells, CD3+CD4+ T cells and pulmonary epithelial cells[3], and recognizes bacterial unmethylated cytosine-guanine dinucleotide (CpG) motifs and viral an