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。     

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．     

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.     

Lack of association of single nucleotide polymorphisms in toll-like receptors 2 and 4 with enthesitis-related arthritis category of juvenile idiopathic arthritis in Indian population

Toll-like receptors 2 and 4 are over expressed in patients with enthesitis-related arthritis and cause increased production of pro-inflammatory cytokines. This aberrant functioning could be due to polymorphisms in TLR2 and TLR4. Hence, we genotyped ERA patients for Arg753Gln and Arg677Trp polymorphism in TLR2 gene and Asp299Gly and Thr399Ile polymorphism in TLR4 gene. DNA was extracted from blood from ERA patients and healthy controls. All four polymorphisms were studied by PCR–RFLP method. 200 healthy controls and 97 ERA patients were enrolled. All healthy controls and patients had wild-type allele for Arg753Gln and Arg677Trp TLR2 polymorphism. Regarding TLR4, Asp299Gly polymorphism A allele frequency was 90 % in controls and 96 % in patients (OR 2.7, 95 % CI 0.81–8.8). GG homozygous genotype was detected in one healthy control and was absent from patients. The TLR4 Thr399Ileu variant was not detected in patients. Out of 200 healthy controls, 10 were heterozygous (5 %) and only one was homozygous for rare variant (0.5 %). Polymorphisms in TLR2 and TLR4 are not associated with ERA.     

A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease

Human Toll-like receptor 4 (TLR4) transduces proinflammatory cytokine release by human cells in response to lipopolysaccharide (LPS). This study tested the hypothesis that, if TLR4 is rate limiting for a successful response to bacterial LPS in humans, a human gene polymorphism that results in the amino acid substitution Asp299Gly and causes reduced expression and function of TLR4 should influence susceptibility to or severity of natural gram-negative infection. The allele frequency of the Asp299Gly polymorphism was 5.9% among 879 blood donors, 6.5% among 1047 patients with microbiologically proven meningococcal disease, and 4.1% among 86 patients who died of meningococcal disease. No significant differences were observed, including those analyzed after stratification of the infected population by age and by meningococcal serogroup. Therefore, this functional TLR4 polymorphism does not influence susceptibility to or severity of meningococcal disease.     

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.     

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 hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction.

AIM: Toll-like receptor 4 (TLR4) is a receptor for bacterial lipopolysaccharide (LPS) and heat shock protein essential for innate immunity. Recent studies imply that TLR4 polymorphisms might affect atherogenesis. In this study we investigated the impact of LPS-hypo-responsive TLR4 variants on the risk of myocardial infarction (MI). METHODS AND RESULTS: Using TaqMan PCR technology, we determined the prevalence of the Asp299Gly and Thr399Ile polymorphisms in the TLR4 gene, and their association with MI in a study of 1213 survivors of a first MI and 1561 controls from the Stockholm region. The frequency was 0.096 for carriers of both 299Gly and 399Ile, and 0.006 for carriers of 399Ile alone. Carriers of both 299Gly and 399Ile were more frequent among the male cases than the male controls (10.7% vs 7.9%, p = 0.004). Compared with wild-type carriers, men with the 299Gly and the 399Ile TLR4 genotype had an increased risk of MI (OR [95% CI]: 1.4 [1.0;1.9]) whereas no association was observed for women. Furthermore a synergistic interaction was found between the TLR4 polymorphism and smoking in men. CONCLUSION: The association found between TLR4 genotype and risk of MI suggests that TLR4 genetic variants could potentially affect the susceptibility to MI and that TLR4-mediated innate immunity is implicated in the pathogenesis of MI.     

The lack of genetic association of the Toll-like receptor 2 (TLR2) Arg753Gln and Arg677Trp polymorphisms with rheumatic heart disease

Acute rheumatic fever (ARF) is a non-suppurative inflammatory disease after group A, beta haemolytic streptococcal pharyngitis. Certain individuals can develop ARF. This finding implies variability in host predisposition to ARF. A variety of studies have linked specific genetic markers with ARF or rheumatic heart disease (RHD) as a sequelae of ARF. For this purpose, we aimed to search the role of polymorphisms in Toll-like receptor-2 and -4 (TLR2 and TLR4) gene in Turkish patients with RHD. This study included a total 84 patients with RHD, ages ranging between 18 and 65, 25 male and 59 female, fulfilling the revised classification criteria of Jones. One hundred forty healthy unrelated persons were selected as a control group. Genotype analysis: DNA was extracted from whole blood. TLR4 gene (Asp 299Gly and Thr399Ile) and TLR2 gene (Arg753Gln and Arg677Trp) polymorphisms were genotyped by the previously reported method. Statistical analysis: binary logistic regression models were used. Results were expressed as odds ratios (OR) with corresponding 95% confidence intervals (95% CI). Significant level was predefined at 0.05. There was a significant difference for carrying Ile allele in the 399 position in the patients compared to healthy controls (OR = 5.26, 95% CI, 1.40-19.73, p = 0.014). In the TLR4 gene, Asp 299Gly polymorphism did not reach to a statistically significant value (OR = 3.02). We found no Arg753Gln polymorphism of the TLR2 gene in the patient group. There were three heterozygote samples in the healthy group. We did not detect Arg677Trp polymorphism of the TLR2 gene in both patient and control groups.     

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．     

Non-high density lipoprotein cholesterol is the best discriminator of myocardial infarction in young individuals

Stroke is one of the leading causes of death in the world. Most stroke patients are classified as having ischemic stroke. The causes of ischemic stroke are very diverse. Atherosclerosis resulting in cerebral or carotid arterial stenosis/occlusion plays the most important role in the occurrence of ischemic stroke. Inflammatory processes or immune responses are involved in the formation of atherosclerosis. Toll-like receptor 4 (TLR4) is a member of the toll-like receptor (TLR) family. TLRs are pattern-recognition receptors, which initiate innate immune responses after interaction with pattern-specific ligands. A polymorphism of the TLR4 gene, Asp299Gly, is associated with an increased risk for coronary heart diseases in Caucasian populations. In this study, we explored the complete coding regions of TLR4 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), Single-strand conformation polymorphism (SSCP), and sequencing and found obvious ethnic differences. There was no Asp299Gly polymorphism among the ethnic Chinese examined in this study. We found only one polymorphism on intron 1 (A119C) among our samples. The allele frequencies of 119A were 0.0256 and 0.0022 among the patients and controls, respectively. The odds ratio of 119A of TLR4 in ischemic stroke was 11.71 (95% CI: 1.52–90.01). This polymorphism was significantly associated with ischemic stroke. These data possibly implicate TLR4 as an important genetic factor for stroke in ethnic Chinese populations despite the rarity of the Asp299Gly polymorphism.     

CD14 C(-159)T polymorphism is a risk factor for development of pulmonary tuberculosis

BACKGROUND: Neither the expression of CD14 and Toll-like receptor 4 (TLR4) on monocytes' surface nor the mutations CD14 -159TT and TLR4 Asp299Gly have yet been evaluated as risk factors for development of pulmonary tuberculosis (TB) in the Mexican population. METHODS: Level of membrane CD14 (mCD14) and membrane TLR4 (mTLR4) were determined by flow cytometry, in 104 patients with pulmonary TB (before and after treatment), 67 household contacts, and 114 healthy control subjects. Genotype/allele frequencies in CD14 -159 and TLR4 Asp299Gly were obtained by polymerase chain reaction-restriction-fragment length polymorphism. Levels of soluble CD14 (sCD14) in sera were quantified by ELISA. RESULTS: Higher levels of mCD14/sCD14 and mTLR4 were observed in the patients and the household contacts than in the control subjects (P<.05) and decreased in the patients after the infection was resolved. The frequency of the CD14 -159TT genotype was higher in the patients than in the control subjects (35.6% vs. 12.3%, respectively). Patients who were homozygous for allele T of the CD14 promoter gene had a significantly higher risk for development of pulmonary TB, with an odds ratio of 2.267 (95% confidence interval, 1.5%-3.3%). Levels of sCD14 or mCD14 were not associated with the CD14 -159TT genotype (P>.05).CONCLUSIONS: No association between TLR4 Asp299Gly and pulmonary TB was found. CD14 -159TT is a risk factor for development of pulmonary TB, whereas mCD14/sCD14 and mTLR4 are possible biomarkers for the prognosis for TB disease.CLINICAL TRIAL PROTOCOL ID: SA1168-05.     

The role of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn's disease

BACKGROUND: We investigated the influence of 2 common Toll-like receptor 4 (TLR4) polymorphisms on susceptibility and disease characteristics of Crohn's disease (CD). METHODS: Genomic DNA from 204 patients with CD and 199 unrelated controls was analyzed for the presence of 2 single nucleotide polymorphisms in the TLR4 gene, resulting in the amino acid substitutions Asp299Gly and Thr399Ile. In addition, the carrier status for the 3 common CD-associated CARD15/NOD2 gene mutations, Arg702Trp, Gly908Arg, and 1007fs, was determined. The frequency of the different genotypes was compared, and a detailed genotype-phenotype correlation was performed. RESULTS: An almost 2-fold increase in the frequency of the TLR4 Asp299Gly phenotype was observed in patients with CD (14.2%) compared with healthy controls (7.5%, P = 0.038, odds ratio = 2.03). The prevalence of a stricturing phenotype was increased in patients heterozygous for 1 of the TLR4 polymorphisms studied (Asp299Gly, 34.5%; Thr399Ile, 36.7%) compared with patients with wild-type TLR4 (17.1% and 16.7%; P = 0.04 and 0.02, respectively). The presence of the Asp299Gly polymorphism in the absence of CARD15/NOD2 mutations was a particularly strong predictor of the stricturing disease phenotype that was present in 47.4% of the patients with Asp299Gly+/NOD2- compared with 10.1% of the patients with the Asp299Gly-/NOD2+ status (P = 0.0009; P = 0.0004 for Thr399Ile+/NOD2- versus Thr399Ile-/NOD2+). In contrast, there was a trend toward a higher prevalence of the penetrating phenotype in the TLR4-/NOD2+ group (71.6%) compared with the TLR4+/NOD2- group (47.4%, P = 0.059). CONCLUSIONS: The TLR4 Asp299Gly polymorphism is a risk factor for CD. TLR4 and CARD15/NOD2 mutations may contribute to distinct disease phenotypes.     

The Asp299Gly Toll-like receptor 4 polymorphism in advanced aortic atherosclerosis

BACKGROUND: Recently, the common Asp299Gly polymorphism of the Toll-like receptor 4 (TLR-4) was found to be associated with a reduced incidence of acute myocardial infarction and carotid atherosclerosis. As TLR-4 signalling is causally involved in atherogenesis, the polymorphism was postulated to impart protection from atherosclerosis. To explore a potential atheroprotective effect, we studied the association between the Asp299Gly polymorphism and atherosclerosis in hypertensive patients undergoing angiography for suspected renovascular disease. METHODS: 140 hypertensive subjects underwent intraarterial digital subtraction angiography, during which the presence of atherosclerotic lesions was assessed at the level of the abdominal aorta and renal arteries. Extensiveness of disease was classified as follows: atherosclerosis confined to the abdominal aorta, unilateral renal artery stenosis or bilateral renal artery stenosis. Subsequently, genotyping for the +896 A>G (Asp299Gly) single nucleotide polymorphism was performed in all patients. In statistical analyses 17 patients were excluded because of incomplete data (n=3) or a diagnosis of fibromuscular disease (n=14). RESULTS: 21 patients were found heterozygous for the 299Gly allele, whereas none of the subjects were 299Gly homozygous (299Gly allele frequency 7.8%). The prevalence of the 299Gly allele in atherosclerotic patients was not different from the prevalence observed in subjects without atherosclerotic lesions (16.9 vs 15.5%, p=0.83). Moreover, 299Gly carriership was not associated with the extensiveness of (advanced) aortic atherosclerosis (p=0.64). CONCLUSION: Our results suggest that the Asp299Gly TLR-4 receptor polymorphism is not associated with the prevalence nor extensiveness of (advanced) aortic atherosclerosis.     

TLR4 mutations (Asp299Gly and Thr399Ile) are not associated with ankylosing spondylitis

BACKGROUND: Immunoregulatory genes and Gram negative gut bacteria are thought to be important in disease expression in ankylosing spondylitis (AS). OBJECTIVE: To compare the frequency of two common and functional TLR4 mutations (Asp299Gly, and Thr399Ile) between patients with AS and HLA-B27 healthy controls. METHODS: The TLR4 genotypes of patients and healthy HLA-B27 controls were determined using allele-specific PCR and restriction fragment length polymorphism analysis. Asp299Gly genotype was determined in 193 patients and 125 HLA-B27 positive controls and Thr399Ile genotype in 184 patients and 113 HLA-B27 controls. Allele frequencies were compared using a chi(2) test of association. RESULTS: 29/193 (15%) patients with AS had a polymorphism in the Asp299 site compared with 18/125 (14.4%) healthy HLA-B27 controls. Of the patients genotyped for the Thr399Ile allele, 29/184 (15.8%) carried the polymorphism compared with 19/113 (16.8%) HLA-B27 controls. No significant difference between the frequencies of the Asp299Gly genotype or the Thr399Ile genotype between patients with AS and healthy HLA-B27 controls was found. No significant difference in allele frequency was found at either site. CONCLUSION: Two common TLR4 polymorphisms, which cause a functional deficiency in host immune response to Gram negative bacteria, are not overrepresented in patients with AS.     

The toll-like receptor 4 Asp299Gly variant and tuberculosis susceptibility in HIV-infected patients in Tanzania

Toll-like receptor 4 (TLR4) plays an important role in the pattern recognition of Mycobacterium tuberculosis, and polymorphisms in the TLR4 gene influence the function of the receptor. We therefore investigated in a cohort of HIV-infected Tanzanian patients whether the Asp299Gly TLR4 polymorphism is associated with the development of active tuberculosis. We found a greater risk of developing active tuberculosis as well as a reduction in CD4 T-cell counts in patients with the Asp299Gly TLR4 polymorphism.     

Polymorphisms in toll-like receptor genes and susceptibility to pulmonary aspergillosis

Toll-like receptors (TLRs) are important components of innate immunity. We investigated the association between polymorphisms in the TLR2, TLR4, and TLR9 genes and susceptibility to noninvasive forms of pulmonary aspergillosis. A significant association was observed between allele G on Asp299Gly (TLR4) and chronic cavitary pulmonary aspergillosis (odds ratio [OR], 3.46; P =.003). Susceptibility to allergic bronchopulmonary aspergillosis was associated with allele C on T-1237C (TLR9) (OR, 2.49; P =. 043). No particular polymorphism was associated with severe asthma with fungal sensitization. These findings reinforce the importance of innate immunity in the pathogenesis of different forms of aspergillosis.     

Lack of genetic association of the Toll-like receptor 4 (TLR4) Asp299Gly and Thr399Ile polymorphisms with spondylarthropathies in a Hungarian population

OBJECTIVES: Bacteria have long been suggested as aetiological factors in the genetically susceptible host in spondylarthropathies, including ankylosing spondylitis (AS) and reactive arthritis (ReA). Variability of the Toll-like receptor 4 (TLR4) gene has been shown to play a role in the inflammatory response to certain bacterial infections. We investigated whether TLR4 Asp299Gly and Thr399Ile polymorphisms contribute to the genetic background of spondylarthropathies in a cohort of Hungarian patients with AS and ReA. METHODS: DNA was obtained from patients with AS (n=138), ReA (n=91) and ethnically matched healthy controls (n=140). Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism analysis and the results were confirmed by direct sequencing. RESULTS: No significant differences in allele or genotype frequencies were observed between controls and either the AS patients or the ReA patients. Clinical characteristics of these groups were unrelated to the presence of any of these polymorphisms. CONCLUSIONS: Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms do not contribute to disease susceptibility in either AS or ReA. Functional abnormalities of the TLR4 signalling pathway suggested in spondylarthropathies seem not to be genetically determined by these two common polymorphisms.