Linkage disequilibrium with predisposing DR3 haplotypes accounts for apparent effects of tumor necrosis factor and lymphotoxin-alpha polymorphisms on type 1 diabetes susceptibility

 Tumor necrosis factor (TNF) and lymphotoxin alpha (LT-α) are immunomodulators that have been hypothesized to contribute to susceptibility to type 1 diabetes (T1D). Several polymorphisms in the TNF and LT-α loci have been extensively studied for T1D association, with conflicting reports. In this study, we examined two TNF variants and one LT-α variant for T1D association in 283 Caucasian, multiplex T1D families for which complete human leukocyte antigen (HLA) genotyping data are available. Initially, association with T1D was seen for LT-α A1069G (intron A, p = 0.011, rs909253) and TNF G(−308)A (p < 1 × 10⁻⁵, rs1800629), but no association was observed for TNF G(−238)A (rs361525). After adjusting the data for linkage disequilibrium (LD) with DRB1-DQB1 haplotypes, however, only one polymorphism, TNF G(−238)A showed significant association with T1D (p < 0.006). When HLA-DR3 haplotypes were examined, the A allele of TNF G(−238)A was significantly overtransmitted to affected offspring (p < 0.009). Including HLA-B data in the analysis revealed that TNF (−238)A is present exclusively on DR3 haplotypes that also carry HLA-B18. Transmission proportion of B18-DR3 haplotypes did not differ between those with TNF (−238)A and those with TNF (−238)G. Thus, variation at TNF does not affect the T1D risk for B18-DR3 haplotypes, and the apparent association of TNF(−238)A with T1D may simply reflect its presence on a high-risk haplotype.     

Tumor necrosis factor-associated susceptibility to type 1 diabetes is caused by linkage disequilibrium with HLA-DR3 haplotypes

Tumor necrosis factor-α (TNF-α) is an important proinflammatory cytokine involved in the pathogenesis of autoimmune type 1 diabetes (T1D). The TNF gene locus is located in the major histocompatibility complex (MHC) class III region and its genetic polymorphisms have been reported to be associated with T1D. However, it is not clear whether these associations are primary or caused by their linkage disequilibrium with other predisposing genes within the MHC. We have tested 2 TNF-α single nucleotide polymorphisms at positions -308G/A and -238G/A in the 5' untranslated region and a (GT)n microsatellite TNFa in the North Indian healthy population and T1D patients with known HLA-A-B-DR-DQ haplotypes. The allele frequencies of TNFa5, -308A, and -238G were determined to be significantly increased among patients compared with controls. Although the observed positive association of -238G was caused by its presence on all 3 DR3(+) groups, namely, B8-DR3-DQ2, B50-DR3-DQ2, and B58-DR3-DQ2 haplotypes associated with T1D in this population, the increase of the -308A allele was caused by its association with the latter 2 haplotypes. On the other hand, TNF -308G occurred on B8-DR3 haplotypes along with -238G and TNFa5 alleles, particularly in T1D patients with late disease onset (at >20 years of age). These results indicate that TNF associations with T1D are caused by their linkage disequilibrium with specific HLA-DR3-DQ2 haplotypes in the Indian population. Because polymorphisms in the promoter region regulate TNF expression levels (e.g., -308A), they retain crucial immunological significance in the development of T1D and its management.     

肿瘤坏死因子α308G/A基因多态性与食管鳞状细胞癌预后的相关性

食管癌是常见的恶性肿瘤之一,影响食管癌预后的因素很多,除肿瘤分级、临床分期、淋巴结转移等,机体的免疫状况和遗传易感性日益受到重视.肿瘤坏死因子(TNF)α是一种具有多种生物活性的致炎细胞因子,由激活的单核巨噬细胞产生.该基因启动子区域转录起始位点上游第308位点存在的G/A等位基因的多态性备受关注.该位点为G时,定义为TNF1,为A时定义为TNF2.     

肿瘤坏死因子-α-308G/A与川崎病遗传易感性的荟萃分析

目的 用荟萃(Meta)分析的方法研究肿瘤坏死因子α(TNF-α)基因启动子区多态位点(-308 G/A)与川崎病(KD)遗传易感性的关系.方法 收集Medline和EMBASE数据库中关于TNF-α-308 G/A与KD遗传易感性的相关文献,对其进行Meta分析.结果 经数据库检索,有4篇文献纳入本研究.对等位基因和基因型频率进行分析,结果显示TNF-α-308 G/A等位基因A的频率与川崎病遗传易感性无显著相关( OR =0.836,95％CI =0.347-2.012).基因型频率与川崎病遗传易感性无显著相关(Aavs.GG,OR=0.817,95％ CI=0.292-2.284;Aavs.GA,OR=0.980,95％ CI=0.300-3.206;AA +GA vs.GG,OR=0.840,95％CI =0.356-1.981;AA+GG vs.AA,OR =0.884,95％CI=0.636-1.227).结论 TNF-α-308 G/A位点基因多态性与川崎病遗传易感性无显著相关,仍需扩大研究样本量进行分析.     

Association of the tumour necrosis factor alpha -308G/A polymorphism with the risk of diabetes in an elderly population-based cohort

Ample evidence supports a role for tumour necrosis factor alpha (TNFalpha) in the development of type 2 diabetes and cardiovascular disease. TNFalpha expression was found to be influenced by a -308G/A polymorphism in the promoter of the gene encoding TNFalpha (TNF). We investigated the contribution of this polymorphism to diabetes and cardiovascular mortality in a population-based cohort of 664 subjects aged 85 years and over (Leiden 85-plus Study). The -308G/A TNF promoter polymorphism was associated with the prevalence of diabetes in old age (P = 0.006). The risk of diabetes among subjects homozygous for the A-allele was estimated to be 4.6-fold (95% CI, 1.6-13.3) higher than among subjects homozygous for the common G-allele. The promoter polymorphism did not, however, predict mortality from all causes, cardiovascular diseases, cancer or infectious diseases during a 10-year follow-up period. In addition to the promoter polymorphism, TNFa and TNFc microsatellite genotypes were determined but these polymorphisms were not associated with morbidity or mortality. In conclusion, the -308G/A polymorphism in the TNF promoter is strongly associated with the risk of diabetes but not cardiovascular mortality in old age.     

Tumor necrosis factor-alpha gene promoter -308G/A and -238G/A polymorphisms in Mexican patients with type 2 diabetes mellitus

The association between some Tumor necrosis factor-alpha (TNF-α) promoter polymorphisms and Type 2 diabetes mellitus (T2DM) remains controversial. Ethnic differences may play a role in these conflicting results. The aim of this study was to investigate the association between -308G/A and -238G/A polymorphisms located in the promoter region of the TNF-α gene and T2DM in Mexican mestizo patients. Nine hundred four individuals (259 patients with T2DM and 645~controls) were genotyped for the -308G/A and -238G/A polymorphisms by PCR--RFLP. We found that the -238A allele increased the risk of developing T2DM in Mexican patients (OR=1.57, 95% CI: 1.07-2.29; p=0.018). Moreover, we found that the frequency of the GA haplotype (created by the -308G and -238A alleles) was significantly increased in patients with T2DM when compared with controls (OR =1.56, 95% CI: 1.05-2.31; p=0.026). Our results suggest that the -238G/A polymorphism and a specific haplotype (GA) are genetic risk factors for the development of T2DM in Mexican population.     

Tumour necrosis factor alpha -308G/A polymorphism and risk of the four most frequent cancers: a meta-analysis

The latest data show that breast, prostate, lung and colorectal cancer are the four most frequent cancers in both sexes worldwide. A number of molecular epidemiological studies have been conducted to examine the association between TNF alpha -308G/A and the risk of those cancers. However the results have been inconclusive or inconsistent. We then performed a meta-analysis to derive a precise estimation of this association. We carried out a comprehensive search in Medline, EMBASE, OVID and Chinese Biomedical Literature Database for studies using related keywords. The inclusion criteria were (i) in English or Chinese; (ii) case-control study on this association; (iii) provide usable genotype frequencies; and (iv) sufficient published data for estimating an odds ratio (OR) with 95% confidence interval (CI). ORs and 95% CIs were calculated to assess the strength of this association under homozygote comparison (AA vs GG), heterozygote comparison (GA vs GG), dominant (AA/GA vs GG) and recessive (AA vs GA/GG) genetic model comparison. Thirty case-control studies with a total number of 16,507 cases and 19,749 controls were selected for analysis. Overall, no significant association was found between this polymorphism and the risk of total four cancers (GA vs GG: OR=1.02, 95% CI=0.91-1.14, P=0.78). However, there was a significant association between this polymorphism and breast cancer risk in western populations (GA vs GG: OR=0.91, 95% CI=0.85-0.96, P=0.002). This meta-analysis also revealed that this polymorphism was not associated with susceptibility to the other three cancers.     

Association of the tumor necrosis factor ‐308 A/G promoter polymorphism with Tourette syndrome

Several lines of evidence suggest that certain subtypes of obsessive‐compulsive and tic disorders might be paediatric manifestations of post‐streptococcal autoimmunity caused by cross‐reactive autoantibodies. As tumor necrosis factor (TNF) is known to play a seminal role in coordinating the humoral immune response, TNF gene polymorphisms have been proposed as genetic risk factors both in obsessive‐compulsive disorder (OCD) and Tourette syndrome (TS). The aim of this study was to investigate two TNF promoter polymorphisms (‐238 A/G: rs361525 and ‐308 A/G: rs1800629) on the genetic susceptibility to OCD and TS in a child psychiatric sample (102 patients with OCD and 117 patients with TS). In the case–control set‐up, the genotype and allele frequencies were compared to a control group from the general population (n = 405). As a control child psychiatric sample, 194 children with attention‐deficit hyperactivity disorder were also genotyped. Our results revealed that the TNF ‐308 G‐allele was more frequent in children with TS compared to controls (90.2% vs 84.8%, P = 0.037). For confirmation of this genetic association, a family‐based analysis, the transmission disequilibrium test was used, which showed preferential transmission of the G‐allele to patients with TS (nominal P‐value 0.011). Moreover, this allele was also transmitted more frequently to children with tic symptoms (nominal P‐value 0.039). No association was found between OCD or obsessive‐compulsive symptoms and the studied TNF polymorphisms. Based on these findings, the TNF ‐308 G‐allele can be associated with Tourette syndrome, highlighting the potential pathophysiological role of TNF dysregulation.     

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.     

Interleukin-18 promoter -607 C/A and -137 G/C polymorphisms and susceptibility to type 1 diabetes: A meta-analysis

ObjectiveThe aim of this study was to determine whether the functional interleukin-18 (IL-18) promoter -607 C/A (rs1946518) and -137 G/C (rs187238) polymorphisms are associated with susceptibility to type 1 diabetes (TID).MethodsA meta-analysis was conducted to assess the associations between the IL-18 -607 C/A and -137 G/C polymorphisms and T1D in overall and by ethnic group.ResultsA total of 6075 cases and 5744 controls from ten studies were considered in this meta-analysis. In all study subjects, the meta-analysis showed no association between T1D and the IL-18 -607 C allele (OR = 1.083, 95% CI = 0.930–1.260, p = 0.307). However, stratification by ethnicity indicated an association between the IL-18 -607 C allele and T1D in Asians (OR = 1.506, 95% CI = 1.172–1.936, p = 0.001), but not in Europeans (OR = 0.988, 95% CI = 0.808–1.209, p = 0.907). Analysis using recessive and dominant models and homozygote contrast showed the same -607 C allele pattern in Asians and Europeans. Meta-analysis of the IL-18 -137 G/C polymorphism showed no association between T1D and the IL-18 -137 G allele in all study subjects (OR = 1.066, 95% CI = 0.926–1.2289, p = 0.375). Stratification by ethnicity indicated no association between the IL-18 -137 G allele and T1D in Europeans and Asians (OR = 1.021, 95% CI = 0.961–1.085, p = 0.504; OR = 0.851, 95% CI = 0.5821–1.245, p = 0.406).ConclusionsOur meta-analysis demonstrates that the IL-18 -607 C/A polymorphism may be associated with susceptibility to T1D in Asians, but not in Europeans.     

Associations between the tumor necrosis factor alpha gene (-308G→A) and event-related potential indices of attention and mental rotation

The tumor necrosis factor alpha (TNF-α) is a cytokine that exerts neuroprotective and neurodegenerative effects. While some research suggests enhancing effects of the TNF-α gene (TNF-α -308G→A) on cognitive function, further research is needed to clarify the association between the TNF-α gene and specific areas of cognitive performance including their neurophysiological correlates. In this study we examine association of the TNF-α -308G→A single nucleotide polymorphism (rs1800629) with attention and mental rotation performance in an event-related potential (ERP) study in healthy participants (n=67). The results show that carriers of the -308 A allele display elevated attentional processes (i.e. a stronger N1) as compared to the GG genotype group. Mental rotation performance varied across genotypes when demands on mental rotation were high. Here, carriers of the -308 A allele performed better than the GG genotype group. This is paralleled by the neurophysiological data showing genotype-dependent variations in parietal positivities only under the condition of high demands on mental rotation. The finding of enhanced attentional and mental rotation performance in A allele carriers supports recent findings that the A allele of this single nucleotide polymorphism (SNP) enhances cognitive performance on a general measure of cognitive processing speed.     

Modulation of cellular susceptibility to the cytotoxic/cytostatic action of tumor necrosis factor by adenovirus E1 gene expression is cell type-dependent

Primary baby rat kidney cells, primary human embryonic retinoblast cells, established NIH3T3 and established normal rat kidney (NRK) cells, expressing E1A and/or E1B gene regions of adenovirus 5 (Ad5) or Ad12, were investigated for susceptibility to the cytotoxic/cytostatic action of Tumor Necrosis Factor (TNF). In the primary cells and in the NRK cells, there was no correlation between TNF sensitivity and E1 gene expression; neither did sensitivity to TNF correlate with the oncogenicity of the Ad serotype. In contrast, the expression of Ad E1 gene regions in NIH3T3 cells was found to enhance TNF sensitivity of this cell line. Differences in E1A expression levels between cell types cannot explain this discrepancy regarding modulation of TNF sensitivity by E1A.     

The CTLA4 +49 A/G polymorphism is not associated with susceptibility to type 1 diabetes mellitus in the Portuguese population

CTLA4 genetic polymorphisms have been associated with type 1 diabetes. We genotyped 207 patients and 249 controls for the most frequently investigated polymorphism of the CTLA4 gene (+49A/G (rs231775)). No significant differences were observed, suggesting that this polymorphism is not strongly associated with type 1 diabetes in the Portuguese population.     

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.     

The CTLA4 +49 A/G dimorphism is not associated with type 1 diabetes in Czech children

We investigated the association of the CTLA4 +49 A/G dimorphism with type 1 diabetes in Czech children. Genotyping of 305 diabetic children and 289 controls by a novel PCR‐ARMS assay revealed no significant differences in the genotypic or allelic frequencies. This may be another piece of evidence against the +49 A/G transition as the aetiological polymorphism within the CTLA4 gene.     

Insulin gene VNTR, CTLA-4 +49A/G and HLA-DQB1 alleles distinguish latent autoimmune diabetes in adults from type 1 diabetes and from type 2 diabetes group

Recent research has underlined the need to explore pathogenic, genetic and clinical spectrum of adult onset autoimmune diabetes, also known as latent autoimmune diabetes in adults (LADA). We aimed to investigate whether genetic factors that are associated with type 1 diabetes (T1D) susceptibility, namely HLA-DQB1 alleles, cytotoxic T-lymphocyte antigen 4 gene (CTLA-4) and insulin gene (INS) polymorphisms, are also associated with an atypical subset of patients diagnosed with type 2 diabetes (T2D). The case-control study included 70 T1D, 305 T2D and 252 nondiabetic controls. The T2D group was divided into atypical T2D (LADA, n = 61) or typical T2D (n = 244) subgroups based on the presence of at least one pancreas-specific antibody. Our data suggested that HLA-DQB1 alleles of all three risk classes, INS variable number of tandem repeat (VNTR) I/I and CTLA-4 +49 GG or AG genotypes, were independent risk factors for developing LADA and could be used as a diagnostic tool to discriminate between LADA and T2D. Additionally, there was an increased association between LADA and CTLA-4 diabetes-susceptibility genotypes and decreased association with INS VNTR and high-risk HLA-DQB1 alleles, compared with T1D. Our study suggested the need for further investigation into the genetic background and functional genomics of LADA in comparison with T1D and T2D.     

The CTLA4 +49 A/G dimorphism is not associated with type 1 diabetes in Czech children.

We investigated the association of the CTLA4 +49 A/G dimorphism with type 1 diabetes in Czech children. Genotyping of 305 diabetic children and 289 controls by a novel PCR-ARMS assay revealed no significant differences in the genotypic or allelic frequencies. This may be another piece of evidence against the +49 A/G transition as the aetiological polymorphism within the CTLA4 gene.     

Promoter region -318 C/ T and -1661 A/G CTLA-4 single nucleotide polymorphisms and type 1 diabetes in North Indians

Single nucleotide polymorphisms (SNPs) of the CTLA-4 gene have been associated with manifestation of type 1 diabetes in several populations. We assessed the association of five SNPs present in the CTLA-4 gene [-318C/T, -1661A/G and -1722C/T in the promoter region, +49A/G in exon 1 and CT60 in the 3' untranslated region (UTR) region] with type 1 diabetes in North Indian subjects. Genotyping was performed in the patients (n = 130) and the healthy control (n = 180) subjects by polymerase chain reaction-fragment length polymorphism analysis using MseI, BbvI, BstEII and NcoI restriction endonucleases for the -318, -1661, -1722, +49 and CT60 SNPs, respectively. The frequency of G alleles at -1661 locus was significantly higher in the patient group compared with the control subjects. Although the frequency of T alleles at -318 SNP was significantly higher in patients with type 1 diabetes compared with the controls, it did not remain significant after Bonferroni correction for the number of alleles tested. The frequencies of C/T alleles and genotypes at -1722C/T and G allele at +49A/G and CT60 SNPs were not significantly different between the patient and the control groups. Of the various possible haplotypes constructed using the five genetic loci tested (-318, -1661, -1722, +49, CT60), the frequency of 'TGTAG' haplotype was significantly higher in the patients when compared with the controls. The results of the present study indicate that the presence of G allele at -1661 locus at the CTLA-4 gene (IDDM12 locus) is associated with increased susceptibility to type 1 diabetes in North Indians, whereas A allele is protective.     

IL-18 gene promoter -137C/G and -607C/A polymorphisms in Chinese Han children with type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM) is a heterogeneous autoimmune disease, and both environmental and genetic factors play a role in its pathogenesis. Interleukin (IL)-18 is a potent pro-inflammatory cytokine capable of inducing interferon-gamma production that is associated with the development of T1DM. The gene for IL-18 is located on chromosome 11q22.2-q22.3 and has been reported to be associated with a susceptibility to T1DM. To test the putative involvement between IL-18 gene polymorphism and predisposition to T1DM, we conducted a case-control study in Chinese Han children. The single nucleotide polymorphisms at position -607(C/A) and -137(C/G) in the promoter region of the IL-18 gene were analysed by sequence-specific primers-polymerase chain reaction in 118 patients with T1DM and 150 healthy controls. (1) The allele frequency of -607A was 41.2% and 53.0%, respectively, in patients and in control subjects (P = 0.01), but the allele frequency of -137C/G was not statistically significant (P = 0.37). (2) The distribution of CC genotype at position -607 was significantly different between patients and normal controls (P = 0.03), while the distribution of AA genotype in patients was significantly lower than that in the controls (P = 0.03). (3) Furthermore, there was a significant increase in haplotype (-137C/-607G) and genotype combination (-137GG/ -607CC) in patients compared with controls (P = 0.03 and P = 0.04, respectively). The results of this study show that IL-18 gene promoter polymorphisms confer susceptibility to T1DM in Chinese Han children. Moreover, subjects carrying AA genotype at position -607 of the promoter of IL-18 gene may be a low risk of T1DM development.