TNF Single Nucleotide Polymorphisms Research Articles

Association between single nucleotide polymorphisms of tumor necrosis factor gene and grade II-IV acute GvHD: a systematic review and meta-analysis.

Acute GvHD (aGvHD) complicates up to 50% of allogeneic hematopoietic cell transplants and pre-transplant estimation of its risk can guide prophylaxis, monitoring and early intervention strategies. Inspired by the role of tumor necrosis factor alpha (TNFα) in the pathogenesis of aGvHD and the inconsistency of the association studies exploring single nucleotide polymorphisms (SNPs) of the TNF gene, we conducted a systematic review and meta-analysis of the available reports using PubMed and EMBASE. Original human studies reporting on the association between recipient TNF SNPs and grade II-IV aGvHD in a format convertible to effect size and confidence interval were included. One of the two most widely investigated SNPs (rs361525G>A) was marginally associated with increased risk of grade II-IV aGvHD in random-effects meta-analysis of six studies (627 patients in total, risk ratio=1.29, 95% confidence interval=0.99-1.69, P=0.06). If this result is validated in a large cohort with uniform conditioning and GvHD prophylaxis, TNF rs361525G>A may become a useful tool for aGvHD risk estimation before the transplant.

Association of combinations of interleukin-10 and pro-inflammatory cytokine gene polymorphisms with dengue hemorrhagic fever

Pro-inflammatory and anti-inflammatory cytokines have been shown to play an important role in dengue disease pathogenesis. In the present study, to find out whether single nucleotide polymorphisms (SNPs) in the pro-inflammatory and anti-inflammatory cytokine genes are associated with dengue disease severity, SNPs in TNF, IFNG, IL1B, IL8, IL0, IL17A and IL17F genes were investigated using polymerase chain reaction based methods in 132 dengue (DEN) cases [87 dengue fever (DF), 45 dengue hemorrhagic fever (DHF) cases] and 108 apparently healthy controls (HC) from Pune, Maharashtra, western India. Under recessive genetic model (C/C vs. T/T+T/C), the TNF rs1799964 C/C genotype was significantly associated with DEN [P=0.014, OR with 95% CI 3.07 (1.18–7.98)]. Frequency of T/C genotype of IL17F rs763780 was significantly lower in DEN group as compared to HC [P=0.033, OR with 95% CI 0.43 (0.19–0.95)]. Under overdominant genetic model (A/T vs. A/A+T/T), IL8 rs4973 A/T genotype was negatively associated with DHF compared to HCs [p=0.029, OR with 95% CI 0.43 (0.20–0.93)]. Under overdominant genetic model, A/G genotype of IL10 rs1800871 was significantly negatively associated with DHF compared to DF cases [p=0.014, OR with 95% CI 0.35 (0.15–0.84)]. Significantly higher frequency of the combined genotype IL10 A/A-IFNG A/T and lower frequency of the combined genotypes IL10 A/G-IL1B A/A, IL10 A/G-IL8 A/T and IL10 A/G-IL17F T/T were observed in DHF cases compared to DF. The results suggest that heterozygous genotypes of IL8 rs4973 and IL10 rs1800871 are associated with reduced risk of DHF. Combinations of IL10 rs1800871 and pro-inflammatory cytokine genotypes influence the risk of DHF.

Polymorphisms of Tumor Necrosis Factor Alpha in Moroccan Patients with Gastric Pathology: New Single-Nucleotide Polymorphisms in TNF-α(-193) (G/A).

Polymorphisms in tumor necrosis factor alpha (TNF-α) gene are emerging as key determinants of gastric diseases. The TNF-α −308 (G/A) and TNF-α −238 (G/A) single-nucleotide polymorphisms SNPs are the most extensively studied. However, all these studies are conducted in Caucasian and Asian populations. Thus, for the first time in Africa, we sought to investigate whether polymorphisms in TNF-α gene were associated with the development of gastric pathology in Morocco. Two SNPs located in the promoter region (positions −308 and −238) in TNF-α gene were genotyped in 244 individuals (170 patients and 74 healthy controls). Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression analysis. The TNF-α −238 (G/A) genotype was significantly associated with a high risk of gastritis and gastric cancer (GC) (P = 0.001 and P = 0.002, resp.). Furthermore, a new polymorphism located in the promoter region at position −193 in TNF-α gene was identified. The distribution of this SNP was markedly different in patients suffering from ulcers. The association between TNF-α −193 (G/A) genotype and high risk of ulcer was significant (P = 0.03). These results suggest that the TNF-α −193 (G/A) allele has a protective function against gastric cancer by developing ulcer.

Single nucleotide polymorphisms in candidate genes and dengue severity in children: A case–control, functional and meta-analysis study

Dengue is an arthropod-borne emerging viral disease with high morbidity and mortality risk in tropical countries like Brazil. Clinical manifestations are vast, ranging from asymptomatic to most severe forms of dengue such as shock. Previous data have shown that host genetics play a role in disease susceptibility and severity. Herein, we have tested the association of single nucleotide polymorphisms (SNPs) at TNF, IL10, MIF, DCSIGN, CLEC5A, NOD2, CCR5 and MRC1 as candidate genes using a matched case–control study design including 88 severe children cases of dengue patients and 335 healthy unrelated subjects that was also separated in IgG+ and IgG− controls. We demonstrated that the TT genotype of CLEC5A SNP (rs1285933 C>T) is associated with dengue severity (OR=2.25; p=0.03) and that GG genotype of −336G>A DCSIGN (CD209) SNP is associated with protection to severe dengue (OR=0.12; p=0.04). Both comparisons were borderline significant when cases were compared with IgG+ controls subgroup. Nevertheless, genotype–phenotype correlation was also assessed using serum levels of TNF from infected patients at the onset of dengue fever, and CT/TT carriers in CLEC5A secreted higher levels of TNF than CC individuals in 5–7days of infection. No significant difference was observed in TNF levels between genotypes GG versus AG/AA at DCSIGN promoter. Next, we performed a meta-analysis retrieving results from the literature for −336G>A DCSIGN and −308G>A TNF SNPs demonstrating that the consensus estimates of these SNPs indicated no association with dengue severity (when compared to Dengue fever) in the overall analysis. But, a subgroup analysis in the −336G>A DCSIGN, the G allele was associated with severe dengue susceptibility in Asians (ORallele=2.77; p=0.0001; ORcarriers=2.99; p=0.0001) and protection in Brazilians (ORallele=0.66; p=0.013). In summary, our results suggest that genetic variations at CLEC5A increase the risk and regulate TNF secretion in dengue severity among Brazilians. Also, combined data of the literature suggest population-specific effect of the −336 DCSIGN SNP more prominent in Asians and in a different direction than Brazilians.

Interaction of HLA-DRB1*1501 and TNF-Alpha in a Population-based Case-control Study of Multiple Sclerosis.

This study was conducted to determine whether single nucleotide polymorphisms (SNPs) in nine genes (human leukocyte antigen (HLA), T cell receptor beta (TCA receptor β), tumor necrosis factor α (TNF α), tumor necrosis factor β (TNF β), apolipoprotein E (APOE), interleukin 7 receptor alpha chain (IL7RA) interleukin 2 receptor alpha chain (IL2RA) myelin basic protein (MBP) and vitamin D receptor (VDR)) associated with multiple sclerosis (MS) could be replicated in a population-based sample, and to determine if these associations are modified by presence of HLA DRB1*1501. DNA was available from 722 individuals (223 with MS and 499 controls) who participated in a population-based case-control study. Cases and controls were matched on ancestry, age, gender and geographic area. HLA DRB1*1501 risk allele (T) was confirmed in this population using a genotypic test, controlling for multiple comparisons. Examining the effect of each SNP in the presence or absence of the HLA DRB1*1501 risk allele identified significant associations with TNF α -1031 (rs1799964) among those without the HLA risk allele. No additional interactions were significant in a cases-only analysis. Our results indicate that an interaction between SNPs in TNF α and HLA DRB1*1501 may influence the risk of developing MS.

Replication of Identified Inflammatory Bowel Diseases Genetic Associations: A Case–Control Study in the Tunisian Population

Inflammatory bowel diseases (IBD) — Crohn’s disease (CD) and ulcerative colitis (UC) — are chronic gastrointestinal inflammatory disorders with a complex genetic background. A genome wide association scan by the Welcome Trust Case Control Consortium (WTCCC) recently identified several novel susceptibility loci. We performed a replication study in 107 IBD patients (39 CD and 68 UC) and 162 controls. In total, 19 single nucleotide polymorphisms (SNPs) from previously identified susceptibility genes PTPN11, TNF α, IL23R, PTPN2, PTPN22, IL2 and IL10 were studied. In UC, we confirmed the association with PTPN2 (rs254215, GG, P=0.013, Pcorr=0.039; OR= 6.23 (1.18; 32.95)). In CD, we confirmed a marginal association with ((rs11066320, GG, P=0.018, Pcorr=0.054, OR= 0.4 (0.19; 0.82)). No significant association was found at the allele and genotype levels of SNPs in TNF α, IL23R, PTPN22, IL2, and IL10. However, on the haplotype analysis the AG haplotype of TNFα was more frequent in CD patients compared to controls (23.1% vs. 13.7%; P = 0.039; OR= 1.89 (1.02; 3.5)). The PTPN11ATG haplotype was also more frequent in CD patients compared to controls (32.1% vs 21.3%; P = 0.04; OR= 1.75 (1.01; 3.01). These results reveal limited replication in Tunisian population and indicate differences in genetic architecture between populations.

Interaction between early maternal smoking and variants in TNF and GSTP1 in childhood wheezing

Children exposed to tobacco smoke early in life have a higher risk of wheeze. Individual susceptibility may depend on genetic factors. We studied whether variations in single nucleotide polymorphisms (SNPs) in the TNF, glutathione S transferase P1 (GSTP1) and beta2-adrenoreceptor (ADRB2) genes modify the effect of early maternal smoking on the development of childhood asthma, wheeze and allergic sensitization. In the Swedish prospective birth cohort BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey) (n=4089), data collection included questionnaires to measure tobacco smoke exposure and clinical outcomes up to age 4 and medical examinations with blood sampling for specific IgE measurements and genotyping. We defined early maternal smoking as daily smoking by the mother during pregnancy and/or postnatally. We investigated five TNF, six GSTP1 and three ADRB2 SNPs in 982 selected wheezers and non-wheezers. An interaction with early maternal smoking was found for three TNF SNPs (-857C/T, Intron 1, Intron 3) with respect to early wheeze (up to 2 years of age). For example, the odds ratio (OR) for developing early wheeze related to early maternal smoking was 2.4 [95% confidence interval (CI) 1.6-3.7] in children with a wild-type CC homozygote genotype of the TNF-857 SNP, while no tobacco-related risk was seen in children carrying the rare T allele. A clear dose response was observed in children with the CC genotype, with an OR of 1.3 (95% CI 1.1-1.5) per each additional pack per week smoked by the mother during pregnancy. A suggestive interaction with early maternal smoking was also seen for three GSTP1 SNPs (Intron 5, Intron 6 and Ile105Val) with respect to transient wheeze, but not for ADRB2 and wheeze phenotypes. No effect modifications were observed for allergic sensitization. Our results suggest that the risk of early childhood wheeze associated with early maternal smoking may be modified by TNF and GSTP1 polymorphisms.

IL6 genotype and creatine kinase response to exercise

Dear Editor, Yamin and colleagues recently reported an association of a common single nucleotide polymorphisms (SNP) in the promoter region of interleukin-6 (IL6) gene creating a change from a G to C at position -174, and that of tumor necrosis alpha (TNF) gene creating a change from a G to A at position -308 with systemic creatine kinase response to eccentric exercise (Yamin et al. 2008). Previously, Olomolaiye et al. (1998) described that the presence of allele C of the IL6 SNP -174 creates a restriction site for NlaIII, and Fishman et al. (1998) further investigated the eVect of this SNP on IL6 promoter activity and also genotyped healthy Caucasian subjects and patients with juvenile chronic arthritis. However, in the paper Yamin et al. (2008) erroneously refer to this polymorphism with a NCBI reference SNP ID rs13447445, which is in fact located at position -61 of the IL6 gene, and not at position -174 with an ID rs1800795. Similarly, the TNF SNP -308 investigated by the authors should be referred with rs1800629, and not with rs361525 which is located at position -238. Furthermore, the authors describe that they ampliWed a region for genotyping with NlaIII digestion although this genomic region contains the two IL6 SNPs (rs1800795 and rs13447445) that share a G to C transition, thus creating multiple sites for NlaIII, in addition to an internal site at location -293 to -296. Hence this raises a concern and argues whether the relatively low frequency for genotype CC reported (0.03) (Yamin et al. 2008) can rather be explained by technical limitations of the assay or data interpretation than true characteristics of the population investigated. Fortunately, genotyping assays are available that can better overcome such potential pitfalls (Marras et al. 1999; Sylvain et al. 2004). Nevertheless, it is imperative that the authors address this for their data interpretation as it may otherwise leave the reported association of IL6 -174 SNP on eccentric exercise-associated creatine kinase response unrevealed.

IL10 Polymorphisms Are Associated with Airflow Obstruction in Severe α1-Antitrypsin Deficiency

Severe alpha(1)-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV(1)) and the ratio of FEV(1)/forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV(1) </= 50 percent predicted. Six of 11 single-nucleotide polymorphisms (SNPs) in IL10 (P = 0.0005-0.05) and 3 of 5 SNPs in TNF (P = 0.01-0.05) were associated with FEV(1) and/or FEV(1)/FVC. IL10 SNPs also demonstrated association with the qualitative COPD phenotype. When phenotypes of individuals with a physician's diagnosis of asthma were excluded, IL10 SNPs remained significantly associated, suggesting that the association with airflow obstruction was independent of an association with asthma. Haplotype analysis of IL10 SNPs suggested the strongest association with IL10 promoter SNPs. IL10 is likely an important modifier gene for the development of COPD in individuals with severe AAT deficiency.

An analysis of tumor necrosis factor alpha gene polymorphisms and haplotypes with natural clearance of hepatitis C virus infection.

The cytokine tumor necrosis factor alpha (TNF-alpha) is important in generating an immune response against a hepatitis C virus (HCV) infection. The functions of TNF-alpha may be altered by single-nucleotide polymorphisms (SNPs) in its gene, TNF. We hypothesized that SNPs in TNF may be important in determining the outcome of an HCV infection. To test this hypothesis, we typed nine TNF SNPs in a cohort of individuals with well-defined HCV outcomes. Three of these SNPs were typed in a second cohort. Data were analyzed using logistic regression stratifying by ethnicity, since rates of HCV clearance differ in black subjects versus white subjects. The SNP -863A was associated with viral clearance in black subjects (odds ratios (OR) 0.52, 95% confidence interval (CI) 0.29-0.93). Furthermore, the common wild-type haplotype -863C/-308G was associated with viral persistence in black subjects (OR 1.91, 95% CI 1.24-2.95). These findings were independent of linkage with human leukocyte antigen (HLA) alleles. Further study of this polymorphism and haplotype is needed to understand these associations and the role of TNF-alpha in determining outcomes of HCV infection.

Polymorphisms within the tumor necrosis factor and lymphotoxin-alpha genes and endemic pemphigus foliaceus--are there any associations?

The purpose of this study was to analyze the possible influence of the TNF and LTA loci polymorphisms on the susceptibility/resistance to endemic pemphigus foliaceus, also named fogo selvagem (FS), an autoimmune disease characterized by blisters due to acantholysis of the superficial-most epidermal cells. Autoantibodies, mainly of the IgG4 subclass, are directed against a desmosomal glycoprotein known as desmoglein 1. FS shares clinical, histological and immunological features with nonendemic pemphigus foliaceus. Most residents of the endemic regions do not develop the disease, and familial clustering has been documented, suggesting that host factors play a role in susceptibility. In fact, strong positive and negative associations with HLA class II genes have been reported. The TNF and LTA genes are located in the class III region of the Human Major Histocompatibility Complex. Their location, the function of their products, which are cytokines and pluripotent immunomodulators, as well as their genetic variability make them candidate genes for complex diseases with an altered immune response. A total of 162 patients and 191 controls were enrolled in this study. No significant associations were found with any one of the three LTA single nucleotide polymorphisms (SNP) analyzed (at nucleotides 249, 365, 720), nor with the TNF SNP located at positions -863 and -308. The frequency of allele TNF*238A was slightly decreased in patients (OR = 0.45). In conclusion, the results of this study indicate that genetic variability of the TNF and LTA genes does not play a major role in susceptibility/resistance to pemphigus foliaceus.

Haplotypic analysis of the TNF locus by association efficiency and entropy.

To understand the causal basis of TNF associations with disease, it is necessary to understand the haplotypic structure of this locus. The TNF locus in Gambian and Malawi human samples is haplotypically diverse and has a rich history of intragenic recombination. As a consequence, a large proportion of TNF single nucleotide polymorphisms (SNPs) must be typed to detect a disease-modifying SNP at this locus. The most informative subset of SNPs to genotype differs between the two populations.