Wurfel Mark M, Gordon Anthony C, Holden Tarah D, Radella Frank, Strout Jeanna, Kajikawa Osamu, Ruzinski John T, Rona Gail, Black R Anthony, Stratton Seth, Jarvik Gail P, Hajjar Adeline M, Nickerson Deborah A, Rieder Mark, Sevransky Jonathan, Maloney James P, Moss Marc, Martin Greg, Shanholtz Carl, Garcia Joe G N, Gao Li, Brower Roy, Barnes Kathleen C, Walley Keith R, Russell James A, Martin Thomas R
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
Am J Respir Crit Care Med. 2008 Oct 1;178(7):710-20. doi: 10.1164/rccm.200803-462OC. Epub 2008 Jul 17.
Polymorphisms affecting Toll-like receptor (TLR)-mediated responses could predispose to excessive inflammation during an infection and contribute to an increased risk for poor outcomes in patients with sepsis.
To identify hypermorphic polymorphisms causing elevated TLR-mediated innate immune cytokine and chemokine responses and to test whether these polymorphisms are associated with increased susceptibility to death, organ dysfunction, and infections in patients with sepsis.
We screened single-nucleotide polymorphisms (SNPs) in 43 TLR-related genes to identify variants affecting TLR-mediated inflammatory responses in blood from healthy volunteers ex vivo. The SNP associated most strongly with hypermorphic responses was tested for associations with death, organ dysfunction, and type of infection in two studies: a nested case-control study in a cohort of intensive care unit patients with sepsis, and a case-control study using patients with sepsis, patients with sepsis-related acute lung injury, and healthy control subjects.
The SNP demonstrating the most hypermorphic effect was the G allele of TLR1(-7202A/G) (rs5743551), which associated with elevated TLR1-mediated cytokine production (P < 2 x 10(-20)). TLR1(-7202G) marked a coding SNP that causes higher TLR1-induced NF-kappaB activation and higher cell surface TLR1 expression. In the cohort of patients with sepsis TLR1(-7202G) predicted worse organ dysfunction and death (odds ratio, 1.82; 95% confidence interval, 1.07-3.09). In the case-control study TLR1(-7202G) was associated with sepsis-related acute lung injury (odds ratio, 3.40; 95% confidence interval, 1.59-7.27). TLR1(-7202G) also associated with a higher prevalence of gram-positive cultures in both clinical studies.
Hypermorphic genetic variation in TLR1 is associated with increased susceptibility to organ dysfunction, death, and gram-positive infection in sepsis.
影响Toll样受体（TLR）介导反应的多态性可能使个体在感染期间易发生过度炎症反应，并增加脓毒症患者预后不良的风险。
识别导致TLR介导的先天性免疫细胞因子和趋化因子反应升高的超显性多态性，并测试这些多态性是否与脓毒症患者死亡、器官功能障碍及感染易感性增加相关。
我们筛选了43个TLR相关基因中的单核苷酸多态性（SNP），以识别影响健康志愿者离体血液中TLR介导的炎症反应的变异。在两项研究中测试了与超显性反应关联最密切的SNP与死亡、器官功能障碍及感染类型的相关性：一项在重症监护病房脓毒症患者队列中的巢式病例对照研究，以及一项使用脓毒症患者、脓毒症相关急性肺损伤患者和健康对照受试者的病例对照研究。
表现出最强超显性效应的SNP是TLR1（-7202A/G）（rs5743551）的G等位基因，其与TLR1介导的细胞因子产生增加相关（P < 2 × 10^(-20)）。TLR1（-7202G）是一个编码SNP，可导致更高的TLR1诱导的核因子κB激活及更高的细胞表面TLR1表达。在脓毒症患者队列中，TLR1（-7202G）预示着更差的器官功能障碍和死亡（比值比，1.82；95%置信区间，1.07 - 3.09）。在病例对照研究中，TLR1（-7202G）与脓毒症相关急性肺损伤相关（比值比，3.40；95%置信区间，1.59 - 7.27）。在两项临床研究中，TLR1（-7202G）还与革兰氏阳性菌培养物的更高患病率相关。
TLR1中的超显性基因变异与脓毒症患者器官功能障碍、死亡及革兰氏阳性菌感染的易感性增加相关。
