TLR4基因多态性与慢性胃炎幽门螺杆菌感染无相关性

目的:研究我国湖北汉族人群TLR4基因 Asp299Gly多态性与慢性浅表性胃炎及幽门螺杆(H pylori)感染的关系．方法:采用病例-对照研究和多聚酶链反应-限制性片段长度多态性(PCR-RFLP)方法,检测 115例慢性浅表性胃炎患者115例和正常对照者2644例的TLR4等位基因Asp299Gly基因型分布．结果:慢性浅表性胃炎患者的H pylori阳性率 89．6％,显著高于正常对照组61．7％(P<0．000 1, OR=5．319．95％CI:2．784-10．162)．在H pylori 感染相关性的慢性胃炎组和正常对照组中 TLR4基因Asp299Gly基因型所有个体均为 AA纯合子,未发现的突变型,其基因型、等位基因以及携带者频率总体分布无显著性差异．结论:TLR4基因Asp299Gly基因多态性与H pylori相性慢性胃炎无明显相关性．     

CD14及Toll样受体4基因多态性与大肠癌的相关性研究

目的探讨我国湖北汉族人Toll样受体（TLR）4基因Asp299Gly和CD14 C-260T基因多态性分布与大肠癌的相关性。方法采用聚合酶链反应限制性片段长度多态性（PCR—RFLP）方法，检测110例大肠癌患者及160例正常对照者TLR4基因Asp299Gly及CD14 C-260T基因型及等位基因频率的分布。结果大肠癌组CD14 C-260T基因型与正常对照组比较，差异有统计学意义（P〈0．05）。正常对照组CC基因型的频率为15．6%，明显低于大肠癌组的31．8％（P=0．0027，OR=0．3968，95％CI=0．2209～0．7129）；正常对照组中CT基因型的频率为48．1％，明显高于大肠癌组的30．9％（P=0．0056，OR=2．074，95%CI=1．246～3．452）。所有样本中均未发现TLR4基因Asp299Gly的突变型。结论CD14 C-260T基因多态性与中国湖北汉族大肠癌显著相关，而TLR4基因Asp299Gly多态性与大肠癌无关。     

Toll样受体4基因多态性与消化性溃疡和幽门螺杆菌感染的相关性研究

背景：幽门螺杆菌（H．pylori）感染是消化性溃疡的主要病因。脂多糖（LPS）通过TOU样受体（TLR）4激活核因子（NF）-KB，在抗感染免疫应答中起启动和调节作用。TLR4基因发生Asp299Gly突变可中断TLR4介导LPS信号传导。目的：研究我国湖北省汉族人群TLR4基因Asp299Gly多态性与消化性溃疡和肌pylori感染的关系。方法：采用病例对照研究和聚合酶链反应-限制性片段长度多态性（PCR-RFLP）法．检测126例消化性溃疡患者和264名正常对照者的TLR4等位基因Asp299Gly基因型分布。结果：消化性溃疡者肌pylori阳性率（90．5％）显著高于正常对照组（61．7％）（P〈0．0001，OR=5．889，95％CI：3．089-11．216）。在H．pylori感染相关性消化性溃疡组和正常对照组中均未发现TLR4基因Asp299Gly的突变型，其基因型、等位基因以及携带者频率总体分布无显著性差异。结论：本研究未能显示TLR4基因Asp299Gly基因多态性与H.pylori感染、H．pylori相关性消化性溃疡形成有相关性。     

浙江汉族人群Toll样受体4基因多态性与幽门螺杆菌相关消化性溃疡的关系

背景：幽门螺杆菌（H.pylori）感染是消化性溃疡的主要病因,然而其致病性存在个体差异,可能与宿主遗传易感性和先天性免疫机制有关。Toll样受体（TLR）在机体的先天性抗感染免疫中起重要作用。目的：探讨浙江汉族人群TLR4基因Asp299Gly多态性与H.pylori相关消化性溃疡的关系。方法：以聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法检测118例浙江汉族消化性溃疡患者和210名健康对照者的TLR4基因Asp299Gly等位基因和基因型;行快速尿素酶试验和血清H.pyloriIgG检测判断H.pylori感染情况。结果：本组浙江汉族人群TLR4基因Asp299Gly均为AA纯合子基因型,未见突变基因型AG和GG。消化性溃疡组H.pylori感染率为94.9%,显著高于正常对照组的62.4%（P=0.000）;两组Asp299Gly基因型频率差异无统计学意义。结论：浙江汉族人群TLR4基因Asp299Gly多态性与H.pylori相关消化性溃疡无相关性。     

TLR4基因Asp299Gly及TLR2基因Arg753Glu、Arg677Trp多态性与中国湖北汉族炎症性肠病无相关性

目的:研究TLR4基因Asp299Gly及LTLR2基因 Arg753Glu及Arg677Trp多态性在中国汉族人群中的分布,探讨其与炎症性肠病的相关性．方法:采用聚合酶链反应-限制性片段长度多态性方法,检测120例中国湖北汉族炎症性肠病患者与110例正常对照者TLR4 基因ASp299Gly及TLR2基因Arg753Glu及 Arg677Trp基因型,分析该基因多态性与炎症性肠病以及临床亚型的相关性．结果:炎症性肠病患者和健康对照者均未检测出TLR4基因ASp299Gly及TLR2基因 Arg753Glu及Arg677Trp突变型．结论:TLR4基因Asp299Gly及TLR2基因 Arg753Glu及Arg677Trp基因多态性与中国湖北汉族人群炎症性肠病的易感性无相关性．     

TLR4和TNF-α基因多态性与支气管哮喘的相关性研究

目的探讨Toll样受体4和肿瘤坏死因子-α基因多态性与支气管哮喘的关系。方法采用病例对照研究和PCR-DNA测序的方法,检测50例支气管哮喘患者和30例对照组的TLR4的Asp299Gly和TNF-308的基因多态性。结果 （1）在支气管哮喘和健康对照组间,未发现TLR4Asp299Gly突变型。（2）支气管哮喘和正常对照组间未发现存在TNF-308G-A替换多态性。结论 （1）TLR4Asp299Gly基因多态性与支气管哮喘的易感性不相关,TNF-α基因多态性与支气管哮喘的易感性无相关性。     

TLR2、TLR4和NOD2/CARD15基因多态性与溃疡性结肠炎相关性的meta分析

背景:近年我国溃疡性结肠炎(UC)的患病率明显增高,Toll样受体2(TLR2)、TLR4和NOD2/CARD15基因多态性与UC的发生、发展可能密切相关。目的:探讨TLR2、TLR4和NOD2/CARD15基因多态性对UC发生的影响。方法:计算机检索Pub Med、中国生物医学文献、中国知网、万方数据库、重庆维普等数据库中所有TLR2、TLR4和NOD2/CARD15基因多态性与UC相关性的研究。按照纳入与排除标准筛选文献、评价质量并提取数据,采用Rev Man 5.3软件进行meta分析。结果:共纳入15项研究。Meta分析结果显示,TLR2 Arg753Gln基因多态性与UC发生风险无关(P 0.05)。除隐性模型外,TLR4 Asp299Gly基因多态性可显著增加UC的发生风险(P 0.05),TLR4 Thr399Ile基因超显性模型可导致UC风险增加(P 0.05),但显性模型和隐性模型与UC无关(P 0.05)。NOD2/CARD15(Arg702Trp、Gly908Arg、Leu1007fsins C)基因多态性均与UC无关(P 0.05)。结论:NOD2/CARD15(Arg702Trp、Gly908Arg、Leu1007fsins C)、TLR2(Arg753Gln)与UC发生风险无关,TLR4(Asp299Gly、Thr399Ile)可增加UC的发生风险。     

中国大陆汉族人群类风湿关节炎与HLA-DRB1*0401基因的相关性分析

目的 探讨中国大陆汉族人群类风湿关节炎(RA)与人类白细胞抗原(HLA)-DRB1*0401基因的关联情况。方法 检索已发表的有关中国大陆汉族人群RA患者和HLA-DRB1*0401的文献，进行Meta分析。结果 国内7项研究共578例RA患者和743例正常对照，DRB1*0401基因亚型是中国大陆汉族人群RA的关联基因(OR=2．66，P=0．004)。结论 Meta分析证实DRB1*0401与中国大陆汉族人群RA有相关性，样本大小对基因关联分析有重要影响。     

Toll样受体4基因多态性与HBV相关原发性肝癌易感性及预后的关系

目的探讨分析Toll样受体4(TLR4)基因多态性与HBV相关原发性肝癌易感性之间的关系以及对患者预后的影响。方法选取2015年6月-2017年7月北京中医药大学东直门医院合作的北京佑安医院收治的HBV相关肝癌患者106例作为肝癌组,同期北京中医药大学东直门医院收治的慢性乙型肝炎患者120例作为乙型肝炎组以及健康对照受试者100例作为对照组。收集各组受试者的血液标本,检测3组受试者TLR4 D299G、T399I以及A896G多态性位点基因型,并分析不同基因型肝癌患者术后复发情况。计量资料多组间比较采用方差分析,进一步两两比较采用LSD-t检验;计数资料两组比较采用χ2检验,多组间比较采用Kruskal-Wallis H秩和检验。采用非条件logistic回归模型及相对危险度近似估计值比值比(OR)估计各研究因素与HBV相关原发性肝癌发病风险的关系;生存分析绘制Kaplan-Meier曲线,生存曲线比较采用log-rank检验。结果 3组受试者TLR4 D299G位点以及TLR4 A896G位点基因型及等位基因分布差异均无统计学意义(χ2=1. 436、1. 949、1. 851、2. 599,P值均 0. 05);而3组受试者TLR4 T399I位点基因型和等位基因比较差异均具有统计学意义(χ2=11. 654、14. 995,P值均0. 001),其中肝癌组T等位基因频率明显高于乙型肝炎组及对照组(P 0. 05)。非条件logistic回归模型显示,TLR4 T399I CC基因型OR[95%可信区间(95%CI)]为1. 682(1. 109～2. 243),P=0. 027、TLR4 T399I TT基因型OR(95%CI)为2. 103(1. 347～2. 896),P 0. 001; TLR4 T399I T等位基因OR(95%CI)为1. 872(1. 192～2. 374),P=0. 002。TLR4 D299G位点以及TLR4 A896G位点不同基因型肝癌患者术后无复发生存情况无明显差异(χ2=0. 022、0. 471,P值均 0. 05)。TLR4 T399I位点CC基因型肝癌患者术后无复发生存情况明显优于CT+TT基因型(χ2=6. 781,P 0. 05)。结论 TLR4 T399I位点基因多态性与HBV相关原发性肝癌易感性密切相关,该位点T基因携带可能是肿瘤发生以及预后不良的重要因素。     

中国汉族人群类风湿性关节炎与HLA-DQ基因多态性和HLA-DR-DQ连锁性的关系

目的 评价中国汉族人群类风湿性关节炎(RA)与HLA-DQ基因多态性和HLA-DR-DQ连锁性的关联情况.方法 以RA组和对照组(正常人)各HLA-DQ、HLA-DR-DQ等位基因频数分布的OR值为统计量.全面检索已发表的有关中国汉族人群RA和HLA-DQ的文献,应用Me-ta分析对基因分型研究结果进行汇总分析.结果 四项研究共入选348例RA患者和162名正常者进行对照,经Meta分析中国汉族人群RA的易感基因有HLA-DQA1*0301(OR=1.820,P=0.01)、DQB1*0401(OR=4.807,P＜0.01).DR4.DQA1*0301(OR=8.437,P=0.024)、DR4-DQB1*0401(OR=3.215,P＜0.01)在中国汉族人群RA中有连锁性并且是RA的危险基因型.HLA.DOA1*0102(OR=0.352,P=0.040)、DQB1*0602(OR=0.404,P=0.01)、DQB1*0604(OR=0,P＜0.05)是中国汉族人群RA的保护基因.结论 DQA1*0301、DQB1*0401是中国汉族人群RA的易感基因,其中DR4-DQA1*0301和DQB1*0401与DR4相连锁是RA的危险基因型,DQA1*0102、DQB1*0602和DQB1*0604是中国汉族人群RA的保护基因.     

Association between Toll-like receptor 4 and inflammatory bowel disease

BACKGROUND: The human Toll-like receptor 4 (TLR4) participates in the innate response. Recently, the TLR4 variant Asp299Gly has been described to affect the response of this receptor to lipopolysaccharide. As such, there is a potentially important role of TLR4 in the pathogenesis of inflammatory bowel disease (IBD). We studied the involvement of TLR4 in IBD in a large population of Dutch patients with IBD and in family-based controls. METHODS: In 781 IBD cases and 315 controls, genotyping was performed forAsp299Gly and Thr399Ile variants and for 4 microsatellite markers flanking TLR4. Association analysis and the were applied. In addition, interaction of TLR4 with the caspase recruitment domain containing protein 15 gene (CARD15) was studied in patients with Crohn's disease (CD). RESULTS: The haplotype sharing statistic showed association at microsatellite marker D9S1864 with IBD (P = 0.0019), and in particular with CD (P = 0.0025) and at TLR406 with ulcerative colitis (UC; P = 0.027). No association was found for Asp299Gly and Thr399Ile. However, the frequencies of both variant allele carriers were higher among CD cases with a disease onset > or = 40 years than among controls. No evidence for interaction between TLR4 and CARD15 was found. CONCLUSIONS: Haplotype analysis shows that TLR4 is associated with both CD and UC. The Asp299Gly and Thr399Ile variants do not show an association with CD, UC, or IBD as a group, indicating that these polymorphisms are likely not the causal ones. We propose that the 2 polymorphisms are in linkage with (the) disease susceptibility variant(s) located elsewhere on TLR4.     

Has toll-like receptor 4 been prematurely dismissed as an inflammatory bowel disease gene? Association study combined with meta-analysis shows strong evidence for association

OBJECTIVES: Published association studies of the TLR4 Asp299Gly polymorphism and inflammatory bowel disease (IBD) in caucasian populations have inconsistent results. We tested two TLR4 variants for association with IBD in the New Zealand caucasian population and assessed the cumulative evidence for association of TLR4 Asp299Gly and IBD. METHODS: The TLR4 Asp299Gly and Thr399Ile polymorphisms were genotyped and tested for case-control frequency differences in a New Zealand white cohort of 389 Crohn's disease (CD) patients, 405 ulcerative colitis (UC) patients, and 416 population controls. Meta-analysis using a random effects model was performed to test whether 299Gly carriage was associated with UC, CD, or phenotypes of CD patients. RESULTS: There were no significant allele or genotype frequency differences between cases and controls or between CD phenotypes in our New Zealand data. Meta-analysis did not identify any significant associations between CD phenotypes and 299Gly carriage. However, meta-analysis demonstrated significantly higher 299Gly carrier frequencies in CD patients (odds ratio 1.45, 95% CI 1.11-1.90) and in IBD patients (odds ratio 1.36, 95% CI 1.01-1.84) compared to controls. CONCLUSIONS: The meta-analysis provides evidence that Asp299Gly is associated with CD and IBD in whites. Only the Asp299Gly polymorphism has been consistently genotyped in previous TLR4 studies with IBD patients, therefore other TLR4 variants with stronger associations with IBD may exist. Additional well-powered studies of Asp299Gly and other TLR4 variants are urgently needed.     

Toll-like receptor polymorphisms and rheumatoid arthritis: a systematic review

The aim of this study was to determine whether toll-like receptor (TLR) polymorphisms confer susceptibility to rheumatoid arthritis (RA) and influence the clinical characteristics of RA. The authors conducted a systematic review on associations between TLR polymorphisms and RA susceptibility and clinical findings. Meta-analysis was performed if at least three comparisons of an issue were available. A total of 14 studies were included in this systematic review, which included European and Asian studies. Meta-analysis of five European studies showed no association between the TLR4 Asp299Gly (rs4986790) polymorphism and RA (OR for the minor allele = 0.907, 95 % CI = 0.755–1.088, p = 0.291). Furthermore, none of these studies found any association between the polymorphism and clinical characteristics. A significant difference between TLR9 rs187084 allele frequencies in RA patients and controls was found in one Turkish study (p = 0.003), and a moderate association between RF positivity and TLR8 rs5741883 was found in an European study (p = 0.001). The numbers of guanine–thymine [(GT)_n] repeats in intron II of the TLR2 gene were found a significantly higher S-allele frequency in Korean patients with RA than in controls (30.3 vs. 23.0 %, p = 0.03). This meta-analysis shows lack of an association between the TLR4 Asp299Gly polymorphism and RA. However, our finding suggests the possibility that TLR polymorphisms are associated with the development and clinical characteristics of RA. Because of a paucity of data of the TLR polymorphisms, case–control studies are required to determine whether TLR2, 4, 8, 9 polymorphisms contribute to RA susceptibility or severity in more than 2,000 patients and controls.     

Lack of association of TLR4 gene Asp299Gly and Thr399Ile polymorphisms with rheumatoid arthritis in Chinese Han population of Yunnan Province

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of synovium and subsequent joint destruction. Recently, genetic polymorphisms within the toll-like receptor 4 (TLR4) genes have been reported to be associated with RA. To analyze the association between the genetic polymorphisms within TLR4 gene and the susceptibility to RA in Chinese people, two functional variants, Asp299Gly and Thr399Ile, in the TLR4 gene were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and direct sequencing techniques from 213 RA patients and 247 ethnically matched controls. None polymorphisms of Asp299Gly and Thr399Ile were detected in all RA cases and controls, which indicates that there is no relevance between these two SNPs and RA in the Chinese Han population. Further studies with extended single nucleotide polymorphisms (SNP) should be performed.     

The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia

SETTING: Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide. Studies in a murine model of pulmonary TB have identified a role for Toll-like receptor 4 (TLR4) in the development of chronic lung infection with Mycobacterium tuberculosis. The Asp299Gly polymorphism in the human TLR4 gene is associated with in vivo hyporesponsiveness to lipopolysaccharide (LPS) in Caucasians. OBJECTIVE: To determine whether TLR4 Asp299Gly influences LPS responses or susceptibility to pulmonary TB in humans in a Gambian population sample. DESIGN: We compared whole blood monokine responses to LPS in 245 healthy blood donors stratified by TLR4 Asp299Gly genotype to assess whether this polymorphism was functional in this population. A case-control study of 640 subjects was conducted to investigate whether TLR4 Asp299Gly was associated with TB. RESULTS: LPS-induced tumour necrosis factor, interleukin-1 beta and interleukin-10 production was not influenced by TLR4 Asp299Gly genotype. There was no association between TLR4 Asp299Gly and TB. CONCLUSION: Our data suggest that TLR4 Asp299Gly has no influence on monocyte LPS responses or susceptibility to TB in Gambians and could be an ancient neutral polymorphism.     

Association of toll-like receptor 4 variants and ankylosing spondylitis: a case-control study

OBJECTIVE: Functional single nucleotide polymorphisms within the ectoplasmic domain of the Toll-like receptor 4 (TLR4) gene have been shown to result in an endotoxin-hyporesponsive phenotype and aberrant signal transduction for bacterial agonists. TLR4 is in proximity to a genome-wide linkage peak in 9q32-33. Given the proposed function and location of TLR4, we examined the association of 2 functional variants of TLR4 in patients with ankylosing spondylitis (AS) in Newfoundland. METHODS: In total, 101 AS patients and 100 ethnically matched controls were genotyped, using the Sequenom MassArray platform, for 2 functional variants in the TLR4 gene: Asp299Gly (A/G polymorphism) and Thr399Ile (C/T polymorphism). RESULTS: The minor allele frequency for the Asp299Gly variant (G) was significantly higher in AS cases compared to controls (7.5% vs 2.6%, respectively; OR 3.10, p = 0.037). The minor allele frequency for the Thr399Ile variant (T) for cases and controls was 7.4% vs 3.0% (OR 2.59, p = 0.071). Haplotype analysis using Haploview noted a higher proportion of GT in the cases (for GT, chi-squared p = 0.023). CONCLUSION: Given the functional role of TLR4 variants in the innate immune system, larger studies are now warranted to elucidate the association of TLR4 variants in AS.     

Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis

BACKGROUND AND AIMS: Elicitation of an innate immune response to bacterial products is mediated through pattern recognition receptors (PRRs) such as the toll-like receptors (TLRs) and the NODs. The recently characterised Asp299Gly polymorphism in the lipopolysaccharide (LPS) receptor TLR4 is associated with impaired LPS signalling and increased susceptibility to Gram negative infections. We sought to determine whether this polymorphism was associated with Crohn's disease (CD) and/or ulcerative colitis (UC). METHODS: Allele frequencies of the TLR4 Asp299Gly polymorphism and the three NOD2/CARD15 polymorphisms (Arg702Trp, Gly908Arg, and Leu1007fsinsC) were assessed in two independent cohorts of CD patients (cohort 1, n = 334; cohort 2, n = 114), in 163 UC patients, and in 140 controls. A transmission disequilibrium test (TDT) was then performed on 318 inflammatory bowel disease (IBD) trios. RESULTS: The allele frequency of the TLR4 Asp299Gly polymorphism was significantly higher in CD (cohort 1: 11% v 5%, odds ratio (OR) 2.31 (95% confidence interval (CI) 1.28-4.17), p = 0.004; and cohort 2: 12% v 5%, OR 2.45 (95% CI 1.24-4.81), p = 0.007) and UC patients (10% v 5%, OR 2.05 (95% CI 1.07-3.93), p = 0.027) compared with the control population. A TDT on 318 IBD trios demonstrated preferential transmission of the TLR4 Asp299Gly polymorphism from heterozygous parents to affected children (T/U: 68/34, p = 0.01). Carrying polymorphisms in both TLR4 and NOD2 was associated with a genotype relative risk (RR) of 4.7 compared with a RR of 2.6 and 2.5 for TLR4 and NOD2 variants separately. CONCLUSION: We have reported on a novel association of the TLR4 Asp299Gly polymorphism with both CD and UC. This finding further supports the genetic influence of PRRs in triggering IBD.     

No evidence for involvement of the toll-like receptor (TLR) 4 gene Asp299Gly and Thr399Ile polymorphisms in susceptibility to primary gouty arthritis

Previous studies demonstrated that toll-like receptor (TLR) 4 was involved in the development of autoinflammatory disease including gouty arthritis (GA). TLR4 functional gene Asp299Gly and Thr399Ile polymorphisms play a role in some autoinflammatory disease susceptibility. We undertook this study to analyze the association between the genetic polymorphisms within TLR4 gene and the susceptibility to GA in Chinese Han people. Two functional variants, Asp299Gly and Thr399Ile, in the TLR4 gene were genotyped using 5′ exonuclease TaqMan^® technology from 218 male GA patients and 226 ethnically matched controls. None polymorphisms of Asp299Gly and Thr399Ile were detected in all GA cases and controls, which indicates that there is no evidence for involvement of the TLR4 gene Asp299Gly and Thr399Ile polymorphisms in susceptibility to primary GA in the Chinese Han population. Further studies with extended single nucleotide polymorphisms should be performed.