Association analysis identifies TLR7 and TLR8 as novel risk genes in asthma and related disorders
- Mette Nyegaard ( )
- Annette Haagerup ( )
- Jørgen Vestbo ( )
- Torben A Kruse ( )
- Anders D Børglum ( )
- Published Online First 5 August 2008
Background: Toll-like receptors (TLRs) are structurally and functionally related and play important roles in the innate and adaptive immune system. By genome scanning, we have previously obtained evidence of linkage between chromosome Xp22 and asthma and related atopic disorders. Xp22 harbours the TLR7 and TLR8 genes.
Methods: We investigated the involvement of TLR7 and TLR8 in the aetiology of asthma and related disorders by a family based association analysis of two independently ascertained family samples comprising 540 and 424 individuals from 135 and 100 families, respectively. Ten affected individuals from families showing evidence of linkage to Xp22 were screened for sequence variations in TLR7 and 8, and 9 single nucleotide polymorphisms (SNPs) identified were tested for association.
Results: In both samples, significant associations were observed for single SNPs and haplotypes of both TLR7 and 8 in all four phenotypes investigated, asthma, rhinitis, atopic dermatitis and increased specific IgE. Most significant association was seen for rs2407992 (TLR8) in asthma (p=0.00023, sample A and B combined, recessive model). In TLR7, rs179008 showed the strongest association. Both rs179008 and rs2407992 are of putative functional significance, potentially affecting TLR7 processing and TLR8 splicing, respectively. Haplotypes comprising the major alleles of these two SNPs were overtransmitted to the affected offspring (e.g. p=0.00012 in asthma, combined sample, additive model).
Conclusion: The results presented, provide strong evidence that TLR7 and 8 may confer susceptibility to asthma and related atopic disorders and highlight these receptors as interesting targets for individualized, causally directed treatment.