Meta-analysis of TNF-α promoter − 238A/G polymorphism and SLE susceptibility

The tumor necrosis factor-α (TNF-α) promoter ? 238A/G polymorphism has been repeatedly associated with systemic lupus erythematosus (SLE), but findings are not consistent across studies. Our aim was to do a meta-analysis to assess the association between TNF-α promoter ? 238A/G polymorphism and SLE. Eleven published studies of this polymorphism with SLE in different ethnic groups were identified using a Medline search. Meta-analysis was performed for genotypes AA versus GG, GA versus GG, AA versus GG+GA, GA+AA versus GG, and A allele versus G allele in a fixed/random effect model. The overall odds ratio (OR) of the AA versus GG+GA genotypes was 3.46 (95% CI = 1.35–8.83, P = 0.01), and a similar result was found in Caucasian population (OR = 4.62, 95% CI = 1.20–17.80, P = 0.03); the overall OR of the AA versus GG genotypes was 3.36 (95% CI = 1.32–8.55, P = 0.01), and a similar result was found in Caucasian population (OR = 4.29, 95% CI = 1.11–16.53, P = 0.03); the OR of the GA versus GG genotypes was 0.48 (95% CI = 0.30–0.75, P = 0.001) in Caucasian population. In conclusion, this meta-analysis demonstrates the association between TNF-α promoter ? 238A/G polymorphism and SLE, especially in Caucasian population.     

Genetic polymorphisms in tumor necrosis factor (TNF)-alpha and TNF-beta in a population-based study of systemic lupus erythematosus: associations and interaction with the interleukin-1alpha-889 C/T polymorphism

Tumor necrosis factor (TNF) is involved in the pathogenesis of systemic lupus erythematosus (SLE), but the role of TNF polymorphisms in SLE susceptibility remains unclear. Previous studies in different populations report an inconsistent association of the TNF-alpha -308A allele with SLE, sometimes depending on the presence of HLA-DR3. We examined the association of polymorphisms in TNF-alpha (-308G/A, -238G/A) and TNFbeta (+252A/G) in a population-based study of SLE in the southeastern United States and considered TNF-SLE associations with respect to HLA-DR3 and DR2 and the interleukin (IL)-1alpha -889C/T polymorphism, previously linked to SLE in this population. Genotypes were analyzed for 230 recently diagnosed SLE patients who met American College of Rheumatology classification criteria and 276 age- and sex-matched controls, randomly selected from driver's license registries. Carriage of the TNF-alpha -308A allele was significantly associated with SLE in Caucasians (OR = 2.3; 95% CI 1.4, 3.9), but not African Americans. Analyses stratified by IL-1alpha -889 genotypes (C/C vs C/T or T/T) revealed independent associations of SLE with TNF-alpha -308A or HLA-DR2 and DR3. This reflected a significant interaction of TNF and IL-1 genotypes in Caucasians, and yielded a strong association (OR = 8.0, p < 0.00001) for the combined "HLA-DR3, TNF-alpha -308A, IL-1alpha -889C/C" genotype. These findings provide evidence of cytokine gene epistasis in SLE susceptibility.     

Genetic susceptibility to SLE is associated with TNF-alpha gene polymorphism -863, but not -308 and -238, in Thai population

The production of cytokine varies among individuals and correlates with the polymorphism of cytokine genes. Three functional single nucleotide polymorphisms (SNPs) at position -863, -308, and -238 in the tumour necrosis factor alpha (TNF-alpha) gene promoter were analysed for association with systemic lupus erythematosus (SLE) (n = 154), and clinical manifestations in a Thai population were compared with 154 ethnically matched controls. The genotyping was determined by polymerase chain reaction-restriction fragment length polymorphism method. The association between these SNPs and SLE was analysed using chi-squared test. The -863A allele and -863A, -308G, -238G haplotype were found to be significantly increased in SLE patients (25%) compared with healthy controls (15.3%) (Pc = 0.009, OR = 1.85, 95% CI = 1.21-2.83). In addition -863A allele was found to be significantly increased in the SLE group with Raynaud's phenomenon compared to SLE without Raynaud's phenomenon (35% vs. 19.4%) (Pc = 0.048, OR = 2.23, 95% CI = 1.21-4.10). The -863A allele of TNF-alpha gene and the extended haplotype of -863A, -308G, -238G can be used as a genetic marker for SLE susceptibility in Thai populations. In addition, the -863A genotype could produce high TNF levels and potentially induce the occurrence of Raynaud's phenomenon.     

Association between TNF-alpha promoter polymorphism and Helicobacter pylori cagA subtype infection

AIMS: To assess the importance of tumour necrosis factor alpha (TNF-alpha) promoter polymorphism in relation to infection with the cytotoxin associated gene A (cagA) subtype of Helicobacter pylori within a dyspeptic Korean population. METHODS: Eighty three patients with gastric disease and 113 healthy controls were studied. The DNA from gastric biopsy specimens was analysed by H pylori specific and cagA specific polymerase chain reaction (PCR). To characterise TNF-alpha polymorphism at positions -308 and -238, PCR based restriction fragment length polymorphism analysis was performed. RESULTS: Helicobacter pylori infection was closely correlated with G to A transition at position -308 of the TNF-alpha promoter when compared with healthy controls (odds ratio (OR), 2.912; 95% confidence interval (CI), 1.082 to 7.836; p = 0.034). Although TNF-alpha -308 polymorphism in patients with H pylori was not significantly different from that in patients without H pylori, the -308A polymorphism was strongly associated with H pylori cagA subtype infection when compared with the polymorphism in cagA negative H pylori infection (OR, 8.757; 95% CI, 1.413 to 54.262; p = 0.019) and healthy controls (OR, 3.683; 95% CI, 1.343 to 10.101; p = 0.011). G to A genetic change at position -238 of the TNF-alpha gene was not significantly associated with H pylori cagA subtype infection. In addition, genetic polymorphisms at both sites of the TNF-alpha promoter in patients with H pylori infection did not correlate with the severity of disease. CONCLUSION: TNF-alpha -308A polymorphism was significantly related to infection with the H pylori cagA subtype in Korean patients with gastric disease.     

TNF-α-308 promoter G/A and PTPN22 (1858 C/T) genes polymorphisms in Egyptian patients with systemic lupus erythematosus

Tumor necrosis factor alpha (TNF-α) promoter gene polymorphism at position 308 and that of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) at position 1858 C/T have been inconsistently implicated as genetic risk factors for systemic lupus erythematosus (SLE) in some populations. We investigated the possible association of these polymorphisms with SLE susceptibility, and whether serum TNF-α level is related to different genotypes and disease activity in Egyptian SLE patients. TNF-α-308 G/A and PTPN22 C1858T polymorphisms were determined by PCR-restriction fragment length polymorphism analysis in 40 SLE patients and 40 unrelated healthy controls. Serum TNF-α level was measured by ELISA method. The median serum TNF-α was significantly higher in SLE patients than in controls (P?<?0.001). A significant positive correlation was detected between serum TNF-α and SLE activity index (r?=?0.723, P?<?0.001). There was no significant difference in TNF-α-308 G/A genotypes or allele frequency between SLE cases and controls (P?=?0.108 and P?=?0.133, respectively). Diabetes was the only clinical feature in SLE patients that showed significant higher frequency with GA genotype than with GG genotype (P?=?0.001). Risk estimation for the TNF-α-308 genotypes was of no significant (odds ratio?=?2.429; 95 % CI?=?0.8–7.2; P?=?0.108). Concerning PTPN22 1858 C/T, there was no significant difference in PTPN22 C/T genotypes or allele frequency between SLE cases and controls (P?=?0.152 and P?=?0.155, respectively). TNF-α-308 G/A and PTPN22 (1858 C/T) polymorphisms do not exhibit a significant influence on the susceptibility of SLE in Egyptian patients. However, serum TNF-α level could be a sensitive marker of SLE disease activity.     

Interaction of HLA-DRB1*1501 allele and TNF-alpha -308 G/A single nucleotide polymorphism in the susceptibility to multiple sclerosis

Multiple sclerosis is a multifactorial disorder with complex genetic basis. It is believed that genes encoding HLA molecule and cytokines are involved in the pathogenesis of MS. In this study, we have evaluated the impact of HLA-DRB1*1501 allele and TNF-alpha -308 G/A single nucleotide polymorphism, and their interaction, in the susceptibility to MS in Iranian population. Genomic DNA samples were prepared from whole blood of 366 MS Patients and 414 control subjects. The genotypes were determined by SSP-PCR method. Frequency of alleles and genotypes were compared between the two groups by using Fisher's exact test. HLA-DRB1*1501 allele was more frequent among patients (OR=1.57, P=0.0026). TNF-α -308 G allele and G/G genotype had higher frequency among MS patients than control subjects (G vs. A: OR=1.26, P<0.05); G/G vs. A/A: OR=4.59, P=0.0003). The odds ratio was higher among HLA-DRB1*1501 positive individuals. Co-existence of TNF G and HLA-DRB1*1501 alleles showed higher prevalence among MS patients (OR=7.07, P=0.0007). Our results have shown that HLA-DRB1*1501 allele and TNF-α -308 G/A polymorphism are associated with the risk of multiple sclerosis in Iranian population. We also observed an interaction between these two loci that support the role of HLA alleles and cytokine genes and gene-gene interaction in the development and pathogenesis of MS.     

Tumor necrosis factor-alpha promoter polymorphisms in Mexican patients with rheumatic heart disease

The major histocompatibility genes (MHC) have been associated with the genetic susceptibility to rheumatic heart disease (RHD). Results have been inconsistent and new genes located on the MHC region such as tumor necrosis factor (TNF-alpha) need to be analyzed. TNF-alpha polymorphisms (positions -238 and -308) were determined in 87 RHD Mexican Mestizo patients and 101 healthy controls. Patients were classified into mitral valve damage (MVD) and multivalvular lesion (MVL) categories. TNF-238 G allele and GG genotype were increased in patients when compared to healthy controls (pC=0.001, OR=14.1 and pC=0.003, OR=14.1, respectively). Also, decreased frequencies of TNF-238 A allele (pC=0.001) and AG genotype (pC=0.003) were found. TNF-308 polymorphism analysis showed increased frequencies of T2 (A) allele (pC<10(-3), OR=10.8) and T1T2 (AG) genotype (pC<10(-3), OR=9.85) and decreased frequencies of T1 (G) allele and T1T1 (GG) genotype (pC<10(-3)). When comparing valvular damage to healthy controls, patients with MVD showed increased frequencies of -238 GG (pC=0.03, OR=ND), -308 T1T2 (AG) (pC<10(-3), OR=14) and -308 T2 (A) (pC<10(-3), OR=11.7). Also, this group showed decreased frequencies of T1 (G) allele and T1T1 (GG) genotype (pC<10(-3)). Patients with MVL presented increased frequency of -308 T2 (A) allele (pC=0.0003, OR=8.65) and decreased frequencies of -308 T1 (G) allele and -308 T1T1 (GG) genotype (pC=0.0003 and pC=0.006, respectively). Distribution of -238 and -308 polymorphisms were similar between MVD and MVL. The data demonstrate that RHD is associated with TNF-alpha polymorphisms in the Mexican population; however, these polymorphisms do not have relation with the valve damage.     

Meta-Analysis of the Relationship between TNF-α (−308G/A) and IL-10 (−819C/T) Gene Polymorphisms and Susceptibility to Dengue

Objective: This study determined whether tumor necrosis factor alpha (TNF-α) and Interleukin-10 (IL-10) polymorphisms are associated with susceptibility to dengue.

Methods: a systematic review with meta-analysis was conducted of the associations between the TNF-α (?308G/A) and IL-10 (?819C/T) polymorphisms and dengue.

Results: A total of eight case-controls studies involving 384 individuals with symptomatic dengue, 571 individuals with dengue hemorrhagic fever, and 995 healthy controls were considered in the meta-analysis. There was no significant association between TNF-α (?308G/A) and IL-10 (?819C/T) polymorphism and dengue in overall population. However, stratifying meta-analysis by groups, the meta-analysis revealed association between the TNF-α ?308 G/G (OR: 1.62, CI: 1.02–2.57, p = 0.04) genotype and allele G (OR: 1.62, CI: 1.04–2.55, p = 0.03) that confers susceptibility to symptomatic dengue, while the TNF-α ?308 G/A genotype (OR: 0.69, CI = 0.39–0.99, p = 0.04) and allele A (OR: 0.64, CI: 0.41–1.00, p = 0.05) confers protection to symptomatic dengue. No difference was observed for the TNF-α (?308) and IL-10 (?819C/T) polymorphisms in the comparisons of hemorrhagic dengue versus control and hemorrhagic dengue versus symptomatic dengue.

Conclusion: This meta-analysis showed that TNF-α (?308) polymorphism is associated with dengue symptomatic susceptibility.     

The relationship between tumour necrosis factor-α gene polymorphism and susceptibility and clearance of the persistent hepatitis B virus infection in a Chinese population: a meta-analysis

To date, many studies conducted in the Chinese population have determined the correlation between the tumour necrosis factor-α (TNF-α)-238G/A, -308G/A, -857C/T and -863C/A polymorphisms and persistent hepatitis B virus (HBV) infection. However, their results remain inconclusive. With the aim of confirming this correlation, we performed a meta-analysis of 19 studies. The dichotomous data are presented as the OR with a 95% CI. The results of our study indicate that carriers of the TNF-a-857T allele among the pooled Chinese population were more likely to show spontaneous clearance of HBV (T vs C: OR = 0.824, 95% CI = 0.713–0.953, p 0.009; TT vs CC: OR = 0.701, 95% CI = 0.507–0.970, p 0.032; TC vs CC: OR = 0.804, 95% CI = 0.683–0.947, p 0.009; TT + TC vs CC: OR = 0.835, 95% CI = 0.716–0.974, p 0.021). The TNF-a-308A allele was associated with significantly reduced persistent HBV infection risk in the Chinese (A vs G: OR = 0.585, 95% CI = 0.456–0.751, p 0.002; AG vs GG: OR = 0.519, 95% CI = 0.341–0.789, p <0.000; AA + AG vs GG: OR = 0.512, 95% CI = 0.339–0.772, p 0.001). Persistent HBV infection susceptibility is associated with the TNF-α-308G/A gene polymorphism in the Chinese population, whereas HBV clearance is associated with the TNF-α-857C/T gene polymorphism.     

Association of tumour necrosis factor-alpha -308 G/A promoter polymorphism with susceptibility and disease profile of rheumatoid arthritis

The objective was to analyze the possible involvement of tumour necrosis factor-alpha (TNF-α) -308 G/A promoter polymorphism in the susceptibility and/or the disease profile of rheumatoid arthritis (RA) in Egyptian patients. TNF-α-308 G/promoter polymorphism detection by amplification refractory mutation system (ARMS) technique was carried out for 122 RA patients and 120 healthy controls. TNF-α-308 G allele/GG homozygous genotype were higher in patients with rheumatoid arthritis than those in control group (P < 0.001, respectively). A statistically significant association was found between the frequency of the A allele and presence of erosion (OR = 3.42, P = 0.015). No associations were found between the distribution of TNF-α-308 G/A alleles/genotypes and age of patients, disease duration, absence of remission, presence of deformity, clinical manifestations of the disease and presence or absence of rheumatoid factor. The positivity of rheumatoid factor was associated with occurrence of erosion (OR = 25.0, P < 0.001). The results of this study demonstrate the association of the TNF-α-308 G allele and GG homozygous genotype with susceptibility to RA and the A allele with the presence of erosion in the Egyptian patients.     

Parkin基因多态性与四川地区散发性帕金森病的相关性研究

目的了解四川地区散发性帕金森病parkin基因多态性与帕金森病(Parkinson’s disease,PD)的相关性。方法采用病例-对照研究,应用聚合酶链反应、限制性片段长度多态性、变性高效液相色谱及DNA测序等技术,对四川地区汉族人群198例帕金森病患者和187名正常对照parkin基因-258T/G及IVS3-20T/C多态性位点进行研究,并通过比较各多态性在PD患者和正常对照人群中的频率分布,探讨基因多态性与PD的可能关系。结果parkin基因-258T/G多态性PD组G等位基因频率明显高于对照组(52.5%vs43.3%),两组差异有统计学意义(χ2=6.17,P<0.025,OR=1.45,95%CI:1.04~1.86);进一步将PD组按发病年龄分层发现,只有50岁以上发病患者与对照组相比G等位基因频率差异具有统计学意义(χ2=9.048,P<0.01,OR=1.57,95%CI:1.08~2.06);同样,与对照组(69.51%)相比,PD组TG GG基因型频率(78.79%)亦增加,两者间差异具有统计学意义(χ2=3.854,P<0.05,OR=1.63,95%CI0.88~2.38);PD组不同基因型组间发病年龄差异具有统计学意义(P<0.05),GG基因型组的平均发病年龄比TT或TG基因型的发病晚近5年左右。parkin基因IVS3-20T/C多态性以CC基因型多见,TC型杂合子的频率较低,该实验未发现TT基因型。结论核心启动子区-258T/G多态G等位基因可能增加了四川地区汉族人群散发性PD发生的风险,尤其是50岁以后的发病风险;四川地区汉族人群IVS3-20T/C位点,以CC基因型多见,TC型杂合子的频率较低,无TT基因型。     

Cytokine gene polymorphisms in Colombian patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) patients exhibit alterations in cytokine production that may be relevant to SLE pathogenesis. There is evidence that cytokine gene polymorphisms control cytokine production; thus, these polymorphisms may be associated with SLE or its clinical manifestations. To establish the association of tumor necrosis factor alpha (TNF-alpha), transforming growth factor (TGF) beta1, interleukin (IL)-10, and IL-6 gene polymorphisms in Colombian SLE patients and their clinical manifestations, 120 SLE patients and 102 healthy controls were studied. Single nucleotide polymorphisms were studied by sequence-specific primers polymerase chain reaction (SSP-PCR) at: TNFalpha-308 (G/A), TGFbeta1 codon 10 (C/T) and codon 25 (G/C), IL-10 -1082 (G/A), -819 (C/T) and -592 (C/A), and IL-6 + 174 (G/C). Human leukocyte antigen (HLA)-DRbeta1 was typed by SSP-PCR. SLE patients had increased frequency of allele C at TGFbeta1 codon 25 (P = 0.0001, odds ratio (OR): 4.25, 95% confidence interval (CI): 2.17-8.35) and allele A at TNFalpha-308 (P = 0.0004 OR: 3.9, 95% CI: 1.65-5.80) compared with healthy controls. There was higher frequency of GC genotype at TGFbeta1 codon 25 in SLE patients (P < 0.0001). Extended genotypic analysis showed that SLE patients have decreased frequency of TNFalphaLow/TGFbeta1High (0.50) compared with healthy controls (0.80) (P < 0.0001). No association was found between these polymorphisms and SLE clinical manifestations except for Sm and Ro autoantibodies that were associated with TNFalpha allele A. There is an association between TNFalpha-308A/TGFbeta1 codon 25C with SLE susceptibility in Colombian population. This association may result in a highly inflammatory response with a decrease regulatory function mediated by TNFalpha and TGFbeta1, respectively. The TNFalpha-308A/TGFbeta1 25C genotype may be one component of genetic susceptibility to SLE in Colombian population.     

Tumor necrosis factor gene polymorphisms in Tunisian patients with Behcet's disease

Behcet's disease (BD) is an inflammatory disorder that is mainly characterized by recurrent oral and genital ulcers, skin lesions, and uveitis. Recent reports focused on the genetic factors of susceptibility to this disease and especially the TNF in view of the major role played by this proinflammatory cytokine in the lesional process of Behcet's disease. In this report, we investigated the possible association between Behcet's disease and the TNF-alpha gene promoter polymorphisms -1031T/C, -308A/G, and the TNF-beta polymorphism +252A/G in Tunisian population. We compared the distribution of these polymorphisms between 89 BD patients and 157 healthy controls using polymerase chain reaction restriction fragment length-polymorphism (PCR-RFLP) analysis. The frequency of the TNF-alpha -1031C allele was significantly higher in Behcet's patients than in healthy controls (p = 0.015; chi(2) = 5.84; OR = 1.65; 95% CI = 1.08-2.54), whereas the frequencies of the TNF-alpha -308G and the TNF-beta +252G alleles were similar in the two compared groups. These results suggest that the variability of the TNF-alpha -1031T/C polymorphism can be associated with the susceptibility to Behcet's disease in our study group. Therefore, the TNF molecule may have an important genetically and/or functionally implication in the pathogenesis of BD in the Tunisian population.     

TNF-alpha G-308A polymorphism is associated with rheumatic fever and correlates with increased TNF-alpha production

Previous studies suggested that abnormal regulation of TNF-alpha production may have a role in the pathogenesis of rheumatic fever (RF). Polymorphism at the promoter region of TNF-alpha gene (-308 A) has recently been shown to be associated with rheumatic heart disease (RHD) in Mexican patients. Although this polymorphism has long been shown to affect TNF-alpha gene expression in cell lines, its role in production of the cytokine in RF patients has not been studied. We therefore investigated TNF-alpha G-308A single nucleotide polymorphism and its effect on TNF-alpha production in 71 Turkish RF patients and 89 ethnically matched healthy controls. The TNF-alpha-308A allele frequency was found to be significantly higher in RF patients (RHD+arthritis) than in healthy controls [p<0.0032 Odds ratio (OR)=3.4, 95% confidence interval (CI) (1.5-7.7)]. When RHD patients were analyzed as a separate group, significant difference persisted [p<0.0055, OR=3.3, 95% CI (1.5-7.6)]. More importantly, ELISPOT analysis demonstrated that existence of A allele was associated with higher TNF-alpha production compared with G allele. Our data suggest that carrying a high responder TNF-alpha-308A allele may be a genetic factor in increasing the susceptibility to develop RF disease.     

Association between tumor necrosis factor-α gene polymorphisms and diffuse large B-cell lymphoma in Chinese Han population: evidence from two center case-control study and a meta-analysis

Objectives: The tumor necrosis factor-α (TNF-α) gene, which plays crucial roles in tumorigenesis, is reported to be an independent marker for cancer. This study aims to examine the association between the TNF-α G308A polymorphism and DLBCL risk based on the two center case-control studies and meta-analysis. Methods: In the current study, we performed a two centers case-control study to investigate the effect of the TNF-α G308A polymorphism on DLBCL risk in Chinese Han population. A meta-analysis including 10 published datasets along with current dataset, including 111 comparisons containing 34,041 cases and 42,730 controls were enrolled, was next performed to further confirm the association after literature search was conducted and relevant studies were identified from PubMed, Embase, and Web of Science. Results: The TNF-α -308A allele was associated with a significantly increased DLBCL risk in the two independent patient case-control studies and additionally for pooled analysis from the two sets (P<0.05 for both). The result of meta-analysis further demonstrated that the A allele of -308A was significantly correlated with DLBCL risk under the allelic model (OR=1.35, 95% CI=1.27-1.44) without heterogeneity by fixed-effects model analysis (Q=17.30, P=0.139). Moreover, sensitivity analysis supported the robustness of this meta-analysis. Conclusion: This study suggested that -308A polymorphism may be associated with the susceptibility of DLBCL in a Chinese population. The further meta-analysis provides additional evidence supporting the above result that the risk allele of the -308A polymorphism may increase DLBCL risk.     

TNF-alpha (-308 G/A) and CD14 (-159T/C) polymorphisms in the bronchial responsiveness of Korean children with asthma

BACKGROUND: TNF-alpha is a pivotal proinflammatory cytokine increased in asthmatic airways. The TNF-alpha gene family might be linked to asthma or bronchial hyperresponsiveness (BHR), and TNF-alpha production might be modulated by CD14(+) cells. OBJECTIVE: We investigated the association between asthma susceptibility or asthma-related phenotypes and TNF-alpha (-308G/A) polymorphism and examined the combined effect with CD14 (-159T/C) polymorphism in Korean children. METHODS: Asthmatic (n = 788) and control (n = 153) children were evaluated for asthma phenotypes. Genotypes were determined by using the single-base extension method and PCR-restriction fragment length polymorphism. RESULTS: There was no difference between asthmatic children and control subjects in terms of the allele frequencies of TNF-alpha (-308G/A) and CD14 (-159T/C). Significantly lower PC(20) values were seen in asthmatic (P = .016) children with the TNF-alpha risk allele (-308A). Higher frequencies of 1 or 2 copies of the risk allele were found in asthmatic children with moderate-to-severe BHR to methacholine and exercise compared with control children (adjusted odds ratio of 2.57 [95% CI, 1.30-5.08] and adjusted odds ratio of 2.04 [95% CI 0.99-4.20], respectively). In addition, asthmatic children with risk alleles at both loci had significantly greater BHR than those homozygous for the common alleles (P = .018). CONCLUSION: The TNF-alpha promoter polymorphism (-308G/A) might be associated with severe BHR in Korean children with asthma. In addition, these children show a synergistic effect between the TNF-alpha promoter (-308A) and CD14 promoter (-159C) polymorphisms in terms of BHR. CLINICAL IMPLICATIONS: The TNF-alpha polymorphism might be a disease-modifying gene in asthma and modulated by the CD14 gene.     

Association and interaction of the TNF-alpha gene with other pro- and anti-inflammatory cytokine genes and HLA genes in patients with type 1 diabetes from North India

Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where major histocompatibility complex (MHC) genes and the insulin-linked polymorphic region have been shown to play major roles. We report here an integrated effect of tumor necrosis factor (TNF) alpha with other cytokine genes. The TNF-alpha-308 GA and AA (high secretor) polymorphisms were significantly increased in the patients with T1D (n = 235) [P < 7 x 10(-6), odds ratio (OR) = 3.04, 95% confidence interval (CI) = 1.8-5.3] compared with the controls (n= 128). The variants of interferon-gamma (IFN-gamma) (A(+874)T), interleukin (IL)-6 (G(-174)C), IL-10 (A(-1082)G, T(-819)C, C(-592)A) and transforming growth factor (TGF) beta1 (T(cdn10)C, G(cdn25)C) did not show a significant difference between patients and controls. However, simultaneous presence of TNF-alpha-308 GA+AA along with both high and low secretor genotypes of IFN-gamma (P < 0.003) was significantly increased in patients. Simultaneous presence of TNF-alpha-308 GA + AA along with high secretor genotypes of IL-6 (P < 0.0001, OR = 2.61, 95% CI = 1.5-4.56), IL-10 (P < 0.0001, OR = 4.26, 95% CI = 1.9-10.1) and TGF-beta1 (P < 0.00004, OR = 2.8, 95% CI = 1.6-4.86) was also significantly increased in patients with T1D. Low secretor genotype of TNF-alpha-308 GG along with low secretor genotypes of IFN-gamma (P < 0.001, OR = 0.465, 95% CI = 0.28-0.77), high secretor genotypes of IL-6 (P < 0.000004, OR = 0.76, 95% CI = 0.227-0.621) and TGF-beta1 (P < 0.000006, OR = 0.336, 95% CI = 0.198-0.568) was protective. The TNF-alpha-308 G allele was in linkage disequilibrium (LD) with the human leukocyte antigen (HLA)-B*0801-DRB1*0301 haplotype, while TNF-alpha-308 A allele was in LD with the HLA-B*5001-DRB1*0301 and B*5801-DRB1*0301 haplotypes, suggesting that the effect of TNF-alpha -308 A allele is not because of its being in LD with any HLA alleles, but because of its functional role and its integrated effect with other cytokines.     

Independent effects of the -219 G>T and epsilon 2/ epsilon 3/ epsilon 4 polymorphisms in the apolipoprotein E gene on coronary artery disease: the Southampton Atherosclerosis Study

A number of studies have shown that coronary artery disease severity is associated with the epsilon 2/ epsilon 3/ epsilon 4 polymorphism in the coding region of the apolipoprotein E gene. In this study, we investigated whether the severity of the disease was also influenced by a functional polymorphism (-219 G>T) in the promoter of the gene, and if so, whether the effects of the two polymorphisms were independent. A cohort of 1170 patients with angiographically documented coronary artery disease were genotyped for the two polymorphisms. The frequency of the epsilon 4 allele of the epsilon 2/ epsilon 3/ epsilon 4 polymorphism increased linearly with increasing number of diseased vessels, so did the -219T allele of the -219 G>T polymorphism. In the sample as a whole, logistic regression analyses indicated that compared with the G/G genotype, the T/T genotype conferred an odds ratio of 1.598 (95% CI=1.161-2.201, P=0.004) in favor of increased disease severity, and the relationship remained significant after adjustment for epsilon 2/ epsilon 3/ epsilon 4 polymorphism genotypes, plasma cholesterol and triglyceride levels, and other risk factors. The effect of the T/T genotype on disease severity was more significant in patients who did not carry the epsilon 4 allele (OR=1.510, 95% CI=1.028-2.221) than in epsilon 4 allele carriers (OR=1.303, 95% CI=0.619-2.742). There was considerable linkage disequilibrium between the two polymorphisms (rho=0.9, P<0.001). Logistic regression analysis showed that the -219T- epsilon 4 haplotype conferred an odds ratio of 1.488 (95% CI=1.133-1.954). These findings suggest that the -219 G>T and epsilon 2/ epsilon 3/ epsilon 4 polymorphisms, which may affect respectively the quantity and quality of apoE, have independent and possibly additive effects on coronary artery disease severity.     

TNF-α-308G/A polymorphism associated with TNF-α protein expression in patients with diabetic nephropathy

Aims: This study was to clarify the regulated effects of TNF-α -308G/A polymorphism on TNF-α and investigate the relationship of -308G/A polymorphisms with diabetic nephropathy (DN) susceptibility. Methods: 86 DN patients and 94 healthy individuals were enrolled in our study. Polymerase chain reaction-sequence specific primer (PCR-SSP) detection technology was used to testify single nucleotide polymorphism (SNP) of TNF-α gene. Enzyme-linked immunosorbent assay (ELISA) was used to measure the content of TNF-α protein. Odds ratio (OR) with 95% CI were used to evaluate the association of TNF-α -308G/A polymorphism and DN susceptibility. Results: The level of TNF-α protein was much higher in DN patients compared to that of controls (P < 0.05). For TNF-α -308G/A, G/A genotype could increase the risk for DN (OR = 2.15, 95% CI = 1.08-4.30). Moreover, a allele frequency was found higher in cases compared with controls, which suggested that A allele served as an genetic-susceptibility factor for DN (OR = 1.89, 95% CI = 1.10-3.26). Further analysis indicated that level of TNF-α for individuals with mutant genotype (GA and AA) were higher than that of individuals with wild genotype (P < 0.05). However, AA genotype showed no effects on DN susceptibility (OR = 2.08, 95% CI = 0.56-7.33). Conclusion: TNF-α-308G/A polymorphism was associated with expression level of TNF-α and served as an genetic-susceptibility factor for DN.     

The −675 4G/5G PAI-1 polymorphism confers genetic susceptibility to systemic lupus erythematosus,its clinical manifestations,and comorbidities in Mexican-Mestizo population

Abstract

Systemic lupus erythematosus (SLE) involves a broad range of factors that contribute to the development of the disease and its comorbidities. Genetic predisposition influences the development of SLE, and the ?675 4G/5G PAI-1 polymorphism has been associated with several pathologies with a chronic inflammatory component. Our objective was to investigate the genetic association between the ?675 4G/5G PAI-1 polymorphism with SLE, its clinical manifestations, and comorbidities in a Mexican-Mestizo population. The ?675 PAI-1 polymorphism was determined by PCR-RFLP in 716 subjects: 293 SLE patients and 423 control subjects. Significant associations for SLE genetic susceptibility were found in carriers of 4G/5G (OR = 2.63; CI 1.81–3.87; p?<?.001) and 4G/4G (OR = 2.70; CI 1.62–4.51; p?<?.001) genotype in comparison with the 5G/5G genotype; 4G allele carriers also presented genetic risk for SLE (OR = 1.63; CI 1.31–2.03; p?<?.001) compared to the 5G allele. Following a dominant genetic model, a similar association was found with the 4G allele to SLE (OR = 2.66; CI1.84–3.84; p?<?.001). The 4G/5G genotype was associated with shorter disease duration (p?=?.039), as well as lower levels of haemoglobin (p?=?.001) and haematocrit (p?=?.009); the need for prednisone treatment (p?=?.001), higher BMI (p?=?.03), presence of type 2?DM (p?=?.015), clinical activity (Mex-SLEDAI = 57%; p?=?.047), Chronicity (SLICC-ACR = 0; p?=?.015) and CRP levels (p?=?.015) were associated with 5G/5G genotypes. In conclusion, the ?675 4G/5G and 4G/4G PAI-1genotypes were found as genetic risk markers of susceptibility for SLE in the Mexican-Mestizo population, and each genotype could influence the clinical manifestations and comorbidities differently in SLE.