肿瘤坏死因子相关凋亡诱导配体基因多态性及单倍型与溃疡性结肠炎易感性相关性研究

[目的]探讨肿瘤坏死因子相关凋亡诱导配体(Trail) (G1525A、C1595T)基因多态性及单倍型与溃疡性结肠炎(UC)易感性的关系.[方法]收集252例UC患者和775例正常对照者(HC),采用直接测序法检测Trail (G1525A、C1595T)等位基因及基因型,并做单倍型分析.[结果]与HC组相比,UC组Trail GI525A变异等位基因(A)和基因型(GA+AA)的频率明显减低(35.52％ VS 55.94％,P＜0.01;41.27％ VS 79.74％,P＜0.01) ;Trail C1595T变异基因型(CT+TT)的频率UC组亦明显降低(70.23％ VS 80.52％,P＜0.01).单倍型分析发现Trail (G1525A、C1595T)完全连锁(D’=0.979,r2=0.810).与HC组比较,GC、GT单倍型UC组明显增高(46.56％VS 36.77％,P＜0.01;13.36％ VS 7.54％,P＜0.01);而AC、AT单倍型明显降低(0.64％ VS 10.22％,P＜0.01;39.44％ VS 45.47％,P＜0.01).[结论]Trail(G1525A、C1595T)基因多态性及单倍型与UC易感性相关,此2位点基因变异对UC可能具有保护作用.     

Tumour necrosis factor polymorphisms and susceptibility to follicular lymphoma

Follicular lymphoma is characterized in 85% of patients by the presence of a t(14;18) chromosomal translocation that results in overproduction of BCL2. In this study the distribution of high and low expressing TNF alleles at the TNF (-308) and LTalpha (+252) polymorphic sites in 121 patients with follicular lymphoma and 88 control individuals has been analysed. A reduction in high expressing haplotypes in patients compared to normal controls was found (P = 0.055), with no significant difference observed in response rate or overall survival between patients with high or low expressing haplotypes. These results suggest that the TNF locus, or an adjacent locus within the MHC region, is an important genetic risk factor in this disease.     

Human leukocyte antigen class I region single-nucleotide polymorphisms are associated with leprosy susceptibility in Vietnam and India

Experimental evidence suggested the existence of unidentified leprosy susceptibility loci in the human leukocyte antigen (HLA) complex. To identify such genetic risk factors, a high-density association scan of a 1.9-mega-base (Mb) region in the HLA complex was performed. Among 682 single-nucleotide polymorphisms (SNPs), 59 were associated with leprosy (P <.01) in 198 Vietnamese single-case leprosy families. Genotyping of these SNPs in an independent sample of 292 Vietnamese single-case leprosy families replicated the association of 12 SNPs (P <.01). Multivariate analysis of these 12 SNPs showed that the association information could be captured by 2 intergenic HLA class I region SNPs (P = 9.4 × 10??)-rs2394885 and rs2922997 (marginal multivariate P = 2.1 × 10?? and P = .0016, respectively). SNP rs2394885 tagged the HLA-C*15:05 allele in the Vietnamese population. The identical associations were validated in a third sample of 364 patients with leprosy and 371 control subjects from North India. These results implicated class I alleles in leprosy pathogenesis.     

Analysis of tumor necrosis factor-alpha, lymphotoxin-alpha, tumor necrosis factor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by chronic inflammation that is associated with structural damage of the lung and fibrosis. Although the etiology of IPF is unknown, it is likely to involve an interaction between environmental and multiple genetic components. Animal models of pulmonary fibrosis have shown that proinflammatory mediators are critical at both the inflammatory and fibrotic stages of the disease. Genetic variants exist in genes encoding proinflammatory mediators, as well as in genes encoding their receptors, which makes these genes candidates for the pathogenesis of IPF. In the present study, we examined 12 biallelic polymorphisms in the genes for tumor necrosis factor (TNF)-alpha (+488[G/A], -238[G/A], -308[G/A]), lymphotoxin (LT)-alpha (+720[C/A], +365[C/G], and +249[A/G], determining haplotypes LT-alpha1 to LT-alpha4), tumor necrosis factor-receptor 2 (TNF-RII) (gb:M32315: 676[T/G], 1663[A/G], 1668[T/G], 1690[C/T]), and interleukin- (IL)-6 (promoter -174[G/C], intron 4[A/G]). We also examined the haplotypes determined by the three biallelic polymorphisms in each of the TNF-alpha and LT-alpha genes. As compared with a normal control population, the IPF group showed no significant deviations in genotype, allele, or haplotype frequencies. Surprisingly, in the IPF population, but not in the control population, an increased frequency of cocarriage of the IL-6 intron 4G and the TNF-RII 1690C alleles was observed, despite the location of the two genes on different chromosomes. Moreover, using impairment of carbon monoxide transfer (DL(CO)) adjusted for duration of dyspnea as a marker of rapidity of disease progression, we found that the IL-6 intron 4GG genotype was the only genotype independently associated with lower DL(CO) levels. These findings, if independently confirmed, will be the first to suggest that disease progression in IPF may be linked to a particular genetic marker or to functional polymorphisms in other genes near that marker.     

Clinical characteristics and treatment outcome of infants with non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL) is rarely observed during infancy and data on its incidence, characteristics and outcome are scarce. The present study aimed to assess the prevalence, clinical presentation and treatment results of all infants who were diagnosed with NHL between October 1986 and December 2002 among 2084 patients treated according to the NHL-BFM (Berlin-Frankfurt-Münster) multicentre trials 86, 90 and 95. We identified 20 (1%) infants with NHL including five with T-cell lymphoblastic lymphoma (T-cell LBL), seven with precursor B-cell LBL (pB-cell LBL), two with a mature Burkitt neoplasm, five with anaplastic large cell lymphoma (ALCL) and one with peripheral T-cell lymphoma (PTCL). The PTCL patient, 3/7 pB-cell LBL and 1/5 ALCL patients relapsed. One patient each from the T-cell LBL and Burkitt lymphoma groups suffered from a second malignancy and one patient each with ALCL and Burkitt leukaemia died from treatment-related toxicity. The 5-year event-free survival rate was 53 +/- 12% for the 20 cases. This study has provided preliminary evidence that infants with NHL have a dismal prognosis and showed that infant NHL differed to lymphomas in older patients with respect to the distribution of gender, histopathologic subtypes as well as the ratio of T- to pB-cell LBL and the frequency of relapses of pB-cell LBL.     

Genome‐wide association study of genetic predictors of anti–tumor necrosis factor treatment efficacy in rheumatoid arthritis identifies associations with polymorphisms at seven loci

Objective

Anti–tumor necrosis factor (anti‐TNF) agents are successful therapies in rheumatoid arthritis (RA); however, inadequate response occurs in 30–40% of patients treated. Knowledge of the genetic factors that influence response may facilitate personalized therapy. The purpose of this study was to identify genetic predictors of response to anti‐TNF therapy in RA and to validate our findings in independent cohorts.

Methods

Data from genome‐wide association (GWA) studies were available from the Wellcome Trust Case Control Consortium for 566 anti‐TNF–treated RA patients. Multivariate linear regression analysis of changes in the Disease Activity Score in 28 joints at 6 months was conducted at each single‐nucleotide polymorphism (SNP) using an additive model. Associated markers (P < 10⁻³) were genotyped in 2 independent replication cohorts (n = 379 and n = 341), and a combined analysis was performed.

Results

Of 171 successfully genotyped markers demonstrating association with treatment response in the GWA data, 7 were corroborated in the combined analysis. The strongest effect was at rs17301249, mapping to the EYA4 gene on chromosome 6: the minor allele conferred improved response to treatment (coefficient −0.27, P = 5.67⁻⁰⁵). The minor allele of rs1532269, mapping to the PDZD2 gene, was associated with a reduced treatment response (coefficient 0.20, P = 7.37⁻⁰⁴). The remaining associated SNPs mapped to intergenic regions on chromosomes 1, 4, 11, and 12.

Conclusion

Using a genome‐wide strategy, we have identified and validated the association of 7 genetic loci with response to anti‐TNF treatment in RA. Additional confirmation of these findings in further cohorts will be required.

     

Vascular endothelial growth factor and tumor necrosis factor genes polymorphisms in Turkish patients with sarcoidosis

Polymorphism at -857 locus of tumor necrosis factor (TNF)-alpha gene is considered to be a predisposition factor in sarcoidosis and held responsible for pathogenesis of the disease and polymorphism at +813 locus of vascular endothelial growth factor (VEGF) gene is thought to decrease predisposition to sarcoidosis. In our study, we examined and compared these polymorphisms in healthy Turkish control subjects and Turkish patients with sarcoidosis. We examined gene polymorphisms in 70 cases which were histopathologically diagnosed as sarcoidosis and 80 healthy subjects without any history of a chronic disease. 5 cc of blood were collected in tubes with EDTA from all of the cases. TNF-alpha-857 gene polymorphism and VEGF+813 gene polymorphism were determined using PCR + RFLP method after DNA isolation. TNF-alpha promoter polymorphism, at position -857, revealed no differences in genotype and allele frequency between patients and control subjects but more relapses were found in sarcoidosis patients who have this polymorphism. Considering the VEGF polymorphism at position +813, we observed a significant increase in the frequency of rarer T allele at this position in healthy subjects compared with sarcoidosis patients. VEGF gene polymorphism at +813 locus may diminish susceptibility to sarcoidosis. TNF-alpha-857 gene polymorphism influence severity of the disease.     

Cord blood leptin and insulin-like growth factor levels are independent predictors of fetal growth

The insulin-like growth factor (IGF) system is the dominant endocrine regulator of fetal growth, whereas insulin has a permissive role. Although a role for leptin in fetal growth has been suggested recently, the mechanism by which leptin may be related to fetal growth is not known; but leptin may interact with the IGF system in utero as it does in the extrauterine life. In the context of a hospital-based case control study, we collected anthropometric and demographic data and measured serum leptin, IGF-I, IGF-II, insulin, cortisol, and IGF binding protein 3 concentrations in 142 cord blood samples from full-term deliveries. Cord leptin, IGF-I, and insulin levels correlated positively with birth weight (r = 0.46, r = 0.41, and r = 0.21, respectively, P < 0.01) by univariate analysis and were significantly higher in large-for-gestational-age (LGA) infants, compared with appropriate-for-gestational-age (AGA) infants. Cord leptin concentrations correlated with insulin levels (r = 0.36, P < 0.01) but not with IGF-I levels (r = 0.20). Multiple linear and logistic regression analysis demonstrated an independent positive relationship of both leptin and IGF-I with birth weight and AGA/LGA status. The positive association of leptin levels with birth weight and AGA/LGA status cannot be attributed to IGF-I. This suggests the existence of alternative mechanisms underlying leptin's associations with fetal growth that should be further explored.     

Recombinant tumor necrosis factor increases pulmonary vascular permeability independent of neutrophils.

We studied the effects of intravenous infusion of recombinant human tumor necrosis factor type alpha (rTNF-alpha; 12 micrograms/kg) on lung fluid balance in sheep prepared with chronic lung lymph fistulas. The role of neutrophils was examined in sheep made neutropenic with hydroxyurea (200 mg/kg for 4 or 5 days) before receiving rTNF-alpha. Infusion of rTNF-alpha resulted in respiratory distress and 3-fold increases in pulmonary arterial pressure and pulmonary vascular resistance within 15 min, indicating intense pulmonary vasoconstriction. Pulmonary lymph flow (i.e., net transvascular fluid filtration rate) and transvascular protein clearance rate (a measure of vascular permeability to protein) increased 2-fold within 30 min. The increased permeability was associated with leukopenia and neutropenia. The pulmonary hypertension and vasoconstriction subsided but fluid filtration and vascular permeability continued to increase. Sheep made neutropenic had similar increases in pulmonary transvascular fluid filtration and vascular permeability. rTNF-alpha also produced concentration-dependent increases in permeability of 125I-labeled albumin across ovine endothelial cell monolayers in the absence of neutrophils or other inflammatory mediators. The results indicate that rTNF-alpha increases pulmonary vascular permeability to protein by an effect on the endothelium.     

Tumour necrosis factor-alpha single nucleotide polymorphisms are not independent of HLA class I in UK Caucasians with adult onset idiopathic inflammatory myopathies

OBJECTIVE: To investigate haplotype tagging single nucleotide polymorphisms (SNPs) in the tumour necrosis factor alpha (TNF-alpha) gene, in UK Caucasian idiopathic inflammatory myopathy (IIM) patients. METHODS: A cross-sectional, case-control study of four TNF-alpha SNPs was undertaken, comparing cases of polymyositis (PM) (n = 121), dermatomyositis (DM) (n = 109) and myositis overlapping with other connective tissue diseases (CTD-overlap) (n = 73) with normal subjects (n = 177). Subgroup analyses were undertaken after stratifying for myositis specific/associated antibodies. RESULTS: The TNF-308A allele demonstrated a strong association with each myositis disease subgroup vs controls [PM, odds ratio (OR) 2.8, 95% confidence interval 1.9-4.3; DM, OR 2.5, 1.6-3.8; CTD-overlap, OR 3.3, 2.1-5.1]. The TNF-308GA/AA genotype frequency was significantly increased vs controls (PM, OR 3.7, 2.1-6.3; DM, OR 3.2, 1.8-5.5; CTD-overlap, OR 5.0, 2.6-9.6) suggesting a dominant model. The association was strongest in patients possessing anti-aminoacyl transfer RNA synthetase (anti-synthetase) (OR 5.1, 3.3-8.0) or -PM-Scl (OR 5.0, 2.7-8.9) antibodies. The -1031T allele was also a significant risk factor in DM (OR 2.2, 1.4-3.6), anti-synthetase (OR 2.9, 1.6-5.3) and -PM-Scl (OR 5.6, 1.9-6.4) antibody positive patients. The TNF-308A association was lost after adjusting for HLA-B*08, but remained independent of HLA-DQB1*02 (both are alleles forming part of the common ancestral haplotype). The HLA-B*08/TNF-308A/DRB1*03/DQA1*05/DQB1*02 haplotype was a risk factor in all myositis subgroups vs controls (OR 3.0, 1.8-5.3). CONCLUSIONS: TNF-308A and -1031T alleles are significant risk factors in the IIMs. In the IIMs, the TNF-308A allele is part of the common ancestral haplotype, but is not independent of HLA-B*08.     

Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1.

Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that mediates endothelial leukocyte interactions by inducing expression of adhesion molecules. In this report, we demonstrate that human dermal mast cells contain sizeable stores of immunoreactive and biologically active TNF-alpha within granules, which can be released rapidly into the extracellular space upon degranulation. Among normal human dermal cells, mast cells are the predominant cell type that expresses both TNF-alpha protein and TNF-alpha mRNA. Moreover, induction of endothelial leukocyte adhesion molecule 1 expression is a direct consequence of release of mast cell-derived TNF-alpha. These findings establish a role for human mast cells as "gatekeepers" of the dermal microvasculature and indicate that mast cell products other than vasoactive amines influence endothelium in a proinflammatory fashion.     

炎症性肠病与肿瘤坏死因子基因多态性的研究进展

炎症性肠病包括溃疡性结肠炎与克罗恩病,病因至今未明,可能与肿瘤坏死因子相关,后者受其基因多态性影响.肿瘤坏死因子的等位基因频率,基因型频率和基因携带率影响炎症性肠病的疾病易感性与临床表现,存在种族与区域差异,对疾病的发展和预后产生重要作用.     

Admission glycemia and markers of inflammation are independent outcome predictors in primary PCI in non-diabetic patients

AIM: To assess the prognostic value of admission plasma glucose (APG) respect to clinical variables and inflammatory markers in a selected population of non-diabetic patients with ST elevation myocardial infarction (STEMI) treated with primary angioplasty (primary coronary intervention, PCI). METHODS: A total of 188 consecutive non-diabetic STEMI patients undergoing primary PCI were divided into four quartiles based on APG (<117, 117-140, 141-170, >170 mg/dL). Combined end-point of major adverse cardiac events (MACE) was defined as death, acute heart failure, re-infarction, unstable angina or inducible ischemia. RESULTS: Event-free survival from MACE was significantly (P<0.001) correlated with APG quartiles and decrease from the lowest to the highest: 6 months event-free survival was 89.3%, 77.4%, 59.1%, 42.5%. Patients with higher APG were characterized by a significantly higher Killip class (P<0.001), higher serum creatinine (P<0.05) on admission, and a lower rate of thrombolysis in myocardial infarction (TIMI) 3 flow after PCI (P<0.05). Multivariate analysis showed APG>170 mg/dL (hazard ratio [HR] 2.39, 95% confidence interval [CI] 1.24 to 4.65, P<0.01), admission high-sensitivity C-reactive protein level (HR 1.19, 95% CI 1.07 to 1.31, P<0.001), white blood cells count (HR 1.07, 95% CI 1.00 to 1.14, P<0.04) and heart rate (HR 1.02, 95% CI 1.00 to 1.04, P<0.02) to be independent predictors of MACE. CONCLUSION: Admission glycemia and inflammatory markers are independent predictors of MACE in the mid-term follow-up in non-diabetic STEMI treated with primary PCI. Further investigations are needed to study the pathogenesis of stress hyperglycaemia, interactions with mechanisms of inflammation and whether early and aggressive treatment with insulin may influence outcome of primary PCI.     

Association between hepatocellular carcinoma and tumor necrosis factor alpha polymorphisms in South Korea

AIM: To investigate associations between the tumor necrosis factor alpha(TNF-α)-1031 TC,-863 CA,-857 CT,-308 GA,and-238 GA polymorphisms and HCC in Korea.METHODS: Hepatocellular carcinoma(HCC) cases were diagnosed at CHA Bundang Medical Center from June 1996 to August 2008. The association between TNF-α polymorphisms and HCC was analyzed in 157HCC patients and 201 controls using a polymerase chain reaction-restriction fragment length polymorphism assay. We investigated five TNF-α polymorphisms,which are TNF-α-1031 TC,-863 CA,-857 CT,-308 GA,and-238 GA. The TNF-α genotype frequencies,genotype combinations and haplotypes were analyzed to disclose the association with HCC.RESULTS: None of the TNF-α polymorphisms was significantly associated with HCC. However,nine genotype combinations had associations with increased likelihood of HCC. Among them,TNF-α-1031/-857/-238 TT/CC/GA(AOR = 18.849,95%CI: 2.203-161.246,P = 0.007),TNF-α-1031/-308/-238 TT/GG/GA(AOR = 26.956,95%CI: 3.071-236.584,P = 0.003),and TNF-α-1031/-238 TT/GA(AOR = 21.576,95%CI: 2.581-180.394,P = 0.005) showed marked association with HCC. There were five haplotypes of TNF-α polymorphisms which were significantly associated with HCC. They are TNF-α-1031/-863/-857/-308/-238 T-C-C-G-A(OR = 25.824,95%CI: 1.491-447.223,P = 0.0005),TNF-α-1031/-857/-308/-238 T-C-G-A(OR = 12.059,95%CI: 2.747-52.950,P 0.0001),TNF-α-1031/-857/-238 T-C-A(OR = 10.696,95%CI: 2.428-47.110,P = 0.0001),TNF-α-1031/-308/-238 T-G-A(OR = 7.556,95%CI: 2.173-26.280,P = 0.0002) and TNF-α-1031/-238 T-A(OR = 10.865,95%CI: 2.473-47.740,P = 0.0001). Moreover,HCC Okuda stage Ⅲ cases with the TNF-α-1031 CC genotype had better survival than those with the TT genotype(AOR = 5.795,95%CI: 1.145-29.323). CONCLUSION: Although no single TNF-α polymorphism is associated with HCC in this study,some TNF-α genotype combinations and haplotypes are associated with HCC. In addition,HCC Okuda stage Ⅲ cases with the TNF-α-1031 TT genotype may have a better prognosis than those with the CC genotype.