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.Allergic disorders such as asthma, rhinitis and atopic dermatitis constitute a high incidence global health problem that affects an increasing number of individuals who are often faced with a considerable loss in quality of life. When possible, the typical countermeasure is to avoid contact with known allergens. When this is not possible, however, the only option is medical treatment, which currently aims at modulating general immunological/inflammatory responses, often at the price of adverse side effects. A more focused treatment is dependent on a more detailed knowledge of the aetiology of the diseases.The diseases are complex and depend on multiple poorly defined environmental as well as genetic factors. The genetic component, which is poly-or oligogenic in nature, is considerable, as evidenced by several family and twin studies.

Atopic dermatitis (AD) is a common, itchy skin disease of complex inheritance characterized by dermal and epidermal inflammation. The heritability is considerable and well documented. To date, four genome scans have examined the AD phenotype, showing replicated linkage at 3p26-22, 3q13-21 and 18q11-21. Our previous AD scan showed evidence of linkage to loci at 3p and 18q, and furthermore at 4p15-14. In order to further investigate the genetic basis of AD, we collected and analysed a new Danish family sample consisting of 130 AD sib pair families (555 individuals including 295 children with AD). AD was diagnosed after clinical examination, AD severity was scored and specific IgE was determined. A linkage scan of chromosome 3, 4 and 18 was performed using 91 microsatellite markers. Linkage analyses were performed of dichotomous phenotypes and semi-quantitative traits including the AD severity score. We analysed the novel AD sample alone and together with the previously examined sample. AD severity showed a maximum Z-score of 3.7 at 4q22.1 suggesting the localization of a novel gene for AD severity. A maximum MOD score of 4.6 was obtained at 3p24 for the AD phenotype, providing the first significant linkage of AD at this locus. A maximum MLS score of 3.3 was obtained at 3q21 for IgE-associated AD, and evidence of linkage was also obtained at 3p22.2-21.31, 3q13, 4q35, and 18q12. The results presented should provide a firm basis for gene-targeting studies of AD and related disorders.

Allergic rhinitis (AR) is a complex disorder with a polygenic, multifactorial aetiology. Twin studies have found the genetic contribution to be substantial. We collected and clinically characterised a sample consisting of 127 Danish nuclear families with at least two siblings suffering from AR or allergic conjunctivitis including 540 individuals (286 children and 254 parents). A whole-genome linkage scan, using 424 microsatellite markers, was performed on both this sample and an earlier collected sample consisting of 130 families with atopic dermatitis and other atopic disorders. A third sib-pair family sample, which was previously collected and genotyped, was added to the analysis increasing the total sample size to 357 families consisting of 1508 individuals. In total, 190 families with AR was included. The linkage analysis software Genehunter NPL, Genehunter MOD, and Genehunter Imprinting were used to obtain nonparametric and parametric linkage results. Family-based association analysis of positional candidate SNPs was carried out using the FBAT program. We obtained genome-wide significant linkage to a novel AR locus at 1p13 and suggestive linkage to two novel regions at 1q31-q32 and 20p12, respectively. Family-based association analysis of SNPs in the candidate locus DNND1B/CRB1 at 1q31 showed no significant association and could not explain the linkage signal observed. Suggestive evidence of linkage was also obtained at three AR loci previously reported (2q14-q23, 2q23, and 12p13) and indication of linkage was observed at a number of additional loci. Likely maternal imprinting was observed at 2q23, and possible maternal imprinting at 3q28.