Association analysis identifies TLR7 and TLR8 as novel risk genes in asthma and related disorders

Abstract

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.

Toll-like Receptor 7 Rapidly Relaxes Human Airways

“…Respiratory viruses cause airway hyperreactivity (an abnormal tendency to contract) (5,6) and asthma exacerbations (7). A role for TLR7 in the development of virus-induced airway hyperreactivity has been proposed, because TLR7 activation causes a proinflammatory type 1 T-helper cell (Th1) immune response (8) and because TLR7 polymorphisms have been associated with asthma (9). In patients with asthma, however, TLR7 responses were reduced (10).…”

TOLL-LIKE RECEPTOR 7 GENE Gln11Leu MISSENSEMUTATION AND SUSCEPTIBILITY TO PSORIASIS

“…В диагностике псориатического артрита использовали крите-рии CASPAR (Классификация критериев псо-риатического артрита -ClASsification criteria for Psoriatic ARthritis) [35], рентгенографическое исследование суставов и позвоночника, а также анализ крови для определения ревматоидного фактора в крови пациента и исключения ревма-тоидного артрита.…”

“…В соответствии с предлагаемой ролью этого рецептора TLR7 в различных иммуноопосредо-ванных заболеваниях, полиморфные варианты TLR7 гена были ассоциированы со многими за-болеваниями, в том числе с заболеванием Грейв-са [45], системной красной волчанкой [18,40], бронхиальной астмой [35], рассеянным склеро-зом [19] и витилиго [44]. Какие-либо опублико-ванные данные по результатам ассоциаций гена TLR7 с псориазом отсутствуют.…”

“…M ller-Larsen и соавт. при ис-следовании больных с бронхиальной астмой ев-ропейского происхождения идентифицировали ассоциацию SNP rs179008 гена TLR7 с заболева-нием (OR = 1,53, Р = 0,0004) [35]. Была обнару-жена ассоциация rs179008 гена TLR7 (OR = 1,25, Р = 0,03) с временем прогрессирования забо-левания у больных рассеянным склерозом ев-ропейского происхождения [19].…”

“…M ller-Larsen и соавт. in silico установили, что замена Gln11 на Leu приводит к укорачиванию N-региона и удлинению H-региона TLR7, что может влиять на посттрансляционную модифи-кацию белка [35]. Определенные миссенс-му-тации влияют на гидрофобность белка, его во-дородные, электростатические и сульфидные связи.…”