BACKGROUND: Toll-like receptors (TLRs) are structurally and functionally related and play important roles in the innate and adaptive immune system. By genome scanning, evidence of linkage between chromosome Xp22 and asthma and related atopic disorders has previously been obtained. Xp22 harbours the TLR7 and TLR8 genes. METHODS: The involvement of TLR7 and TLR8 in the aetiology of asthma and related disorders was investigated 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 nine 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. The 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 (eg, p = 0.00012 in asthma, combined sample, additive model). CONCLUSION: The results provide strong evidence that TLR7 and 8 may confer susceptibility to asthma and related atopic disorders and highlight these receptors as interesting targets for individualised, causally directed treatment.
BACKGROUND: Toll-like receptors (TLRs) are structurally and functionally related and play important roles in the innate and adaptive immune system. By genome scanning, evidence of linkage between chromosome Xp22 and asthma and related atopic disorders has previously been obtained. Xp22 harbours the TLR7 and TLR8 genes. METHODS: The involvement of TLR7 and TLR8 in the aetiology of asthma and related disorders was investigated 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 nine 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. The 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 (eg, p = 0.00012 in asthma, combined sample, additive model). CONCLUSION: The results provide strong evidence that TLR7 and 8 may confer susceptibility to asthma and related atopic disorders and highlight these receptors as interesting targets for individualised, causally directed treatment.
Authors: Rachel Lubong Sabado; Anna Pavlick; Sacha Gnjatic; Crystal M Cruz; Isabelita Vengco; Farah Hasan; Meredith Spadaccia; Farbod Darvishian; Luis Chiriboga; Rose Marie Holman; Juliet Escalon; Caroline Muren; Crystal Escano; Ethel Yepes; Dunbar Sharpe; John P Vasilakos; Linda Rolnitzsky; Judith Goldberg; John Mandeli; Sylvia Adams; Achim Jungbluth; Linda Pan; Ralph Venhaus; Patrick A Ott; Nina Bhardwaj Journal: Cancer Immunol Res Date: 2015-01-29 Impact factor: 11.151
Authors: Nicholas W Lukacs; Joost J Smit; Sumanta Mukherjee; Susan B Morris; Gabriel Nunez; Dennis M Lindell Journal: J Immunol Date: 2010-07-12 Impact factor: 5.422
Authors: Teresa Requena; Irene Gazquez; Antonia Moreno; Angel Batuecas; Ismael Aran; Andres Soto-Varela; Sofia Santos-Perez; Nicolas Perez; Herminio Perez-Garrigues; Alicia Lopez-Nevot; Eduardo Martin; Ricardo Sanz; Paz Perez; Gabriel Trinidad; Marta E Alarcon-Riquelme; Roberto Teggi; Laura Zagato; Miguel A Lopez-Nevot; Jose A Lopez-Escamez Journal: Immunogenetics Date: 2013-02-01 Impact factor: 2.846
Authors: Holly D Clifford; Stephanie T Yerkovich; Siew-Kim Khoo; Guicheng Zhang; John Upham; Peter N Le Souëf; Peter Richmond; Catherine M Hayden Journal: Immunogenetics Date: 2011-09-23 Impact factor: 2.846
Authors: Timothy M Bahr; Grant J Hughes; Michael Armstrong; Rick Reisdorph; Christopher D Coldren; Michael G Edwards; Christina Schnell; Ross Kedl; Daniel J LaFlamme; Nichole Reisdorph; Katerina J Kechris; Russell P Bowler Journal: Am J Respir Cell Mol Biol Date: 2013-08 Impact factor: 6.914