Polymorphisms of Toll-like Receptor 3 (TLR3), TNF Receptor-associated Factor 6 (TRAF6), and Heme Oxygenase-1 (HO-1) are Associated with Clinical Severity of Severe Acute Respiratory Syndrome
Date Issued
2005
Date
2005
Author(s)
Tsai, Wan-Yu
DOI
en-US
Abstract
Background – Patients with severe acute respiratory syndrome (SARS) exhibits signs and symptoms of respiratory and systemic infection that follows with clinical course of varying severity, including death due to acute respiratory distress syndrome (ARDS). In addition to advanced age, comorbidity, and high viral load, genetic predisposition has been postulated to influence the immune response and clinical course. This study aims to identify potential genetic effectors involved in the pathogenesis of SARS.
Method – This is a population-based case-control study that enrolled 108 unrelated laboratory-confirmed SARS patients and 333 healthy Taiwanese as reference. Gene products that are known or predicted to be involved in host response were selected for study of polymorphism. SARS patients are divided into 3 groups based on the duration of illness as index for severity: <15 days for mild, 15~28 days for intermediate, and >28 days for severe case.
Result – Clinical severity was significantly associated with certain genotype of three SNPs: a nonsynonymous substitution in the coding region of Toll-like receptor 3, TLR3(L412F) and in the promoter regions of TNF receptor-associated factor 6- TRAF6 (A-9423C) and heme oxygenase-1 - HO-1(T-495A). TLR3 is directly upstream to TRAF6 in the interferon-inducing pathway, and the joint effect of TLR3 or TRAF6 in the pathway was considered, termed TLR3-TRAF6. The severe SARS patients had 4.06-folds (95% CI=1.69~9.74, p=0.002) increased odds of possessing any susceptible genotypes of TLR3-TRAF6 (TLR3(6300T/T), TRAF6(-9423C/C) or (A/C)) and 2.77-folds (95% CI=1.69~9.74, p=0.002) of possessing susceptible genotype of HO-1 (HO-1(-495A/A) or (A/T)) than patients with shorter clinical course in a cumulative logit model. This genetic effect is more profound for the younger SARS patients (<40 yr) than the elder group.
Conclusion - TLR3 recognizes double-stranded RNA, and together with TRAF6, activates interferon production; HO-1 can protect tissues from immune-mediated injury. Along with our previous report of two interferon-γ- inducible genes, FGL2 - a prothrombinase and CXCL10 - a chemokine activating TH1 response, our results strongly support the hypothesis that genetic predisposition to certain host responses participate in the pathogenesis of severe SARS-CoV infection. Identifying pathways participating in viral pathogenesis can provide insights to formulating therapeutic interventions for SARS, and probably ARDS from other causes.
Subjects
嚴重急性呼吸道症候群
嚴重程度
病程
單一核苷
酸多型性
SARS
severity
pathogenesis
duration of illness
SNP
Toll-like receptor 3
TNF receptor-associated factor 6
Heme oxygenase-1
Type
thesis
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