Tumor Necrosis Factor Polymorphisms Research Articles

Genetic variants in the TNF pathway impact TNFi response in a mixed population with rheumatoid arthritis

Rheumatoid arthritis (RA) is a multifactorial autoimmune inflammatory disease that mainly affects the joints, on reducing functional capacity and impacting quality of life. Cytokines such as tumor necrosis factor (TNF) and interleukin 6 (IL-6) are crucial in the pathogenesis and treatment of this disease. Some patients using TNF inhibitors (TNFi) do not respond or lose their response to these medications. Clinical, sociodemographic, and genetic data were used to evaluate the associations of single nucleotide polymorphisms (SNP) in TNF, TNFRSF1A, and TNFRSF1B genes with the diagnosis of RA, standardized score results, laboratory tests, and response to TNFi. In one subsample, TNF and IL-6 serum levels cytokines were performed. A total of 654 subjects (360 healthy controls and 294 diagnosed with RA) were included in the analysis. Higher levels of TNF have been found in individuals diagnosed with RA. IL-6 levels were higher in individuals who did not respond to TNFi treatment, while responders had levels comparable to those without the disease. No associations were found between the SNPs studied and the diagnosis of RA; however, rs767455-C seems to play a role in the response to golimumab treatment, being related to better therapeutic response and lower mean serum leukocyte levels. In addition, rs1061622-G was associated with poorer functional capacity and rs1800629-A was associated with higher leukocyte values and serum transaminase levels. The rs1061622-G and rs767455-C may play a role in the response to TNFi treatment, especially for patients using golimumab, although they do not seem to be associated with the diagnosis of RA. Polymosphisms in the TNF pathway may impact baseline levels of immune cells and markers of renal and hepatic function in RA patients. Our results highlight the importance of evaluating the impact of these polymorphisms on TNFi response and safety, particularly in larger-scale studies.

The rs11684747 and rs55790676 SNPs of ADAM17 influence tuberculosis susceptibility and plasma levels of TNF, TNFR1, and TNFR2.

The proteolytic activity of A Disintegrin and Metalloproteinase 17 (ADAM17) regulates the release of tumor necrosis factor (TNF) and TNF receptors (TNFRs) from cell surfaces. These molecules play important roles in tuberculosis (TB) shaping innate immune reactions and granuloma formation. Here, we investigated whether single nucleotide polymorphisms (SNPs) of ADAM17 influence TNF and TNFRs levels in 224 patients with active TB (ATB) and 118 healthy close contacts. Also, we looked for significant associations between SNPs of ADAM17 and ATB status. TNF, TNFR1, and TNFR2 levels were measured in plasma samples by ELISA. Four SNPs of ADAM17 (rs12692386, rs1524668, rs11684747, and rs55790676) were analyzed in DNA isolated from peripheral blood leucocytes. The association between ATB status, genotype, and cytokines was analyzed by multiple regression models. Our results showed a higher frequency of rs11684747 and rs55790676 in close contacts than ATB patients. Coincidentally, heterozygous to these SNPs of ADAM17 showed higher plasma levels of TNF compared to homozygous to their respective ancestral alleles. Strikingly, the levels of TNF and TNFRs distinguished participant groups, with ATB patients displaying lower TNF and higher TNFR1/TNFR2 levels compared to their close contacts. These findings suggest a role for SNPs of ADAM17 in genetic susceptibility to ATB.

Marcadores genéticos y séricos relacionados con una rápida progresión clínica de la arteriosclerosis coronaria

Introduction and objectivesPatients with clinically evident coronary artery disease differ in their rate of progression, which impacts prognosis. We aimed to characterize serum and genetic markers in patients with rapid clinical progression (RCP) of coronary artery disease vs those with long standing stable (LSS) disease. MethodsRetrospective study of cases (RCP) and controls (LSS) (1:2). Patients requiring ≥ 2 revascularizations due to atherosclerotic progression in the 10 years after a first angioplasty were considered to be RCP and those without events during the same period after the first angioplasty were considered to have LSS disease. After patient selection, we analyzed serum values, mRNA expression and genetic polymorphisms of inflammatory markers, including interleukin-6, C-reactive protein, and tumor necrosis factor (TNF)-a, and atherogenic markers consisted of proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor, sterol regulatory element binding transcription factor 2, and apolipoprotein-B. ResultsThe study included 180 patients (58 RCP and 122 LSS). Demographic characteristics, classic risk factors and the extent of coronary disease were similar in the 2 groups. Patients with RCP showed higher serum levels of interleukin-6 and PCSK9 and higher TNF mRNA expression. Interleukin-6 rs180075C, TNF rs3093664 non-G and PCSK9 rs2483205 T alleles conferred a risk of RCP (P<.05 in all cases). Among patients with RCP, 51.7% had all 3 risk alleles vs 18% of those with LSS (P<.001). ConclusionsWe suggest the existence of specific phenotypic and genotypic markers associated with RCP of coronary artery disease that could help to individualize the type and intensity of treatment.

Serum and genetic markers related to rapid clinical progression of coronary artery disease

Introduction and objectivesPatients with clinically evident coronary artery disease differ in their rate of progression, which impacts prognosis. We aimed to characterize serum and genetic markers in patients with rapid clinical progression (RCP) of coronary artery disease vs those with long standing stable (LSS) disease. MethodsRetrospective study of cases (RCP) and controls (LSS) (1:2). Patients requiring ≥ 2 revascularizations due to atherosclerotic progression in the 10 years after a first angioplasty were considered to be RCP and those without events during the same period after the first angioplasty were considered to have LSS disease. After patient selection, we analyzed serum values, mRNA expression and genetic polymorphisms of inflammatory markers, including interleukin-6, C-reactive protein, and tumor necrosis factor (TNF)-a, and atherogenic markers consisted of proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor, sterol regulatory element binding transcription factor 2, and apolipoprotein-B. ResultsThe study included 180 patients (58 RCP and 122 LSS). Demographic characteristics, classic risk factors and the extent of coronary disease were similar in the 2 groups. Patients with RCP showed higher serum levels of interleukin-6 and PCSK9 and higher TNF mRNA expression. Interleukin-6 rs180075C, TNF rs3093664 non-G and PCSK9 rs2483205 T alleles conferred a risk of RCP (P<.05 in all cases). Among patients with RCP, 51.7% had all 3 risk alleles vs 18% of those with LSS (P<.001). ConclusionsWe suggest the existence of specific phenotypic and genotypic markers associated with RCP of coronary artery disease that could help to individualize the type and intensity of treatment.

Rol polimorfizmiv heniv HTRA serynovoi peptydazy 1, faktora rostu endoteliiu sudyn, faktora nekrozu pukhlyn u likuvanni «volohoi» formy vikovoi makuliarnoi deheneratsii

Introduction. Age-related macular degeneration (AMD) of the retina is still considered the leading cause of vision loss in the elderly. The multifactoriality of the disease impairs the clinical effectiveness of modern AMD treatment methods. however, the study of single-nucleotide polymorphisms, in particular, of the HtrA serine peptidase 1 (HTRA1), vascular endothelial growth factor A (VEGF A) and tumor necrosis factor (TNF) genesis a promising link on the way to improve and develope more effective treatment strategies of the disease. The Aim of the Study. To investigate role of HTRA 1, VEGF A and TNF gene polymorphisms in the treatment of wet age-related macular degeneration. Materials and Methods. 162 people with diagnosed wet AMD took part in the investigation. They received anti-VEGF A therapy in the form of injections of aflibercept monthly for half a year. Structural changes of the eyes were studied using optical coherence tomography (OCT); polymerase chain reaction (PCR) studies were performed using a Bio-Rad CFX 96 apparatus (BioRad, USA) using a reagent package (Lytech, Russia). Statistical analysis of the obtained results was performed using a set of software packages Statistica 10 (StatSoft, Inc., USA) and SPSS 23.0. Results. It was revealed best prognostic significance in patients with the TC rs2010963 genotype of the VEGFA gene was registered during the analysis of OCT 2 (RR=2.7; 95% CI 1.556 – 4.8), OCT 4 (RR=2.9 ; 95% CI 1.7 – 5.03) and OCT 8 (RR=2.6; 95% CI 1.6 – 4.12) sections, while in patients with the CC genotype these indicators in the OCT 2 section were: RR= 6.1; 95% CI 3.66 – 10.27; in OCT zone 4 RR=4.9; 95% CI 2.9 – 8.29, and in the OCT section 8: RR=4.23; 95% CI 2.7 – 6.556, which indicates a more pronounced influence of the CC genotype. When analyzing rs1800629 of the TNF gene, the best prognostic significance of the GA genotype was established in the OCT 4 (RR=1.77; 95% CI 1.218 – 2.56) and OCT 8 (RR=1.9; 95% CI 1.17 – 3.175) areas (p-value less than 0.05), with the AA genotype in OCT 4 (RR=3.77; 95% CI 2.17 – 6.58), OCT 8 (RR=3.1; 95% CI 1 .7 – 5.59) zones and when evaluating changes in visual acuity of patients with wet AMD (RR=4.2; 95% CI 2 – 8.98). No statistically significant results were found in the evaluation of the HTRA1 gene rs11200638 (p-value more than 0.05). Conclusions. The data obtained in our study indicate a direct influence of the vascular endothelial growth factor A (rs2010963) and tumor necrosis factor (rs1800629) polymorphisms on the emergence of resistance to aflibercept. However, the study of this influence in the presence of the HtrA serine peptidase 1 gene rs11200638 requires further research.

The rs17713054 and rs1800629 polymorphisms of genes LZTFL1 and TNF are associated with COVID-19 severity

Both genetic and non-genetic factors are responsible for high interindividual variability in response to SARS-CoV-2. Despite the fact that multiple genetic polymorphisms have been identified as risk factors of severe COVID-19, such polymorphisms are still insufficiently studied in the Russian population. The study was aimed to identify genetic determinants associated with severe COVID-19 in the sample of patients from the Russian Federation. The correlation of the rs17713054 polymorphism in gene LZTFL1 and rs1800629 polymorphism in gene TNF (tumor necrosis factor) with the COVID-19 severity was assessed. DNA samples obtained from 713 patients (324 males and 389 females) aged 18‒95 with COVID-19 of varying severity were analyzed. The rs1800629 polymorphism of gene TNF (OR = 1.5; p = 0.02) and rs17713054 polymorphism of gene LZTFL1 (OR = 1.60; p = 0.0043) were identified as risk factors of severe disease. The TNF polymorphism rs1800629 and LZTFL1 polymorphism rs17713054 could be considered as potential predictive biomarkers. The rs17713054 G &gt; A polymorphism was strongly associated with severe disease. In the future the findings may provide the basis for the development of test-systems for prediction of the risk of severe viral respiratory diseases.

Genetic polymorphism in the tumour necrosis factor alpha gene (G-308A) is associated with persistent apical periodontitis in Brazilians.

To investigate if there was an association between genetic polymorphisms in tumour necrosis factor (TNF)-⍺ and its receptors TNFRSF1A and TNFRSF1B with persistent apical periodontitis (PAP) in Brazilian subjects. Patients who had pulpal necrosis and apical periodontitis at the time of treatment, with at least 1-year of follow-up after non-surgical root canal treatment were recalled. Three hundred and seventy eight subjects were included, 150 subjects with signs/symptoms of PAP and 228 subjects with root canal-treated teeth exhibiting healthy perirradicular tissues (healed). Genomic DNA was extracted from saliva and used for TNF-⍺ (rs1800629), TNFRSF1A (rs1800693) and TNFRSF1B (rs1061622) genotyping by real-time PCR. Genotypes and alleles frequencies were evaluated by c2 or Fisher's exact tests and odds ratios were implemented (α=5%). The genetic polymorphism in TNF-α (rs1800629) was associated as a protective factor for the development of PAP (p < .05), once subjects who presented at least one allele A (AA+AG X GG), had a higher chance to lesion repair (p < .05). The polymorphisms rs1800693 and rs1061622 in TNF receptors (TNFRSF1A and TNFRSF1B, respectively) were not associated with the development of PAP (p > .05). The observed results demonstrate that polymorphism in TNF-α but not in its receptors is associated with PAP.

Effects of gene polymorphisms in tumor necrosis factor-α on the susceptibility of type I diabetes mellitus in an Iraqi population

Background: Type 1 diabetes mellitus (T1DM) is a chronic, immune-mediated disease characterized by the destruction of insulin-producing β cells in the pancreas. This study investigated the influence of single nucleotide polymorphisms (SNP) in tumor necrosis factor (TNF-α) –308 G/A (rs1800629,) on T1DM patients. Method: The study was included 75 T1DM patients and 25 healthy subjects. The SNP–308 G/A TNF-α gene was detected by using polymerase chain reaction restriction fragment length polymorphism (RFLP-PCR) technique in T1DM patients and controls. Results: The genotype distribution results of the -308G/A SNP of Tumor Necrosis Factor - α (TNF- α)-308 G/A gene showed significant difference (p&lt;0.05) between controls (GG: n= 24, 96%; GA: n=1, 4%; AA: n=0, 0%) and T1DM patients (GG: n= 44, 58.67%; GA: n=21, 28%; AA: n=10, 13.33%).These results showed an increased in GA, AA genotype and G allele of the TNF- α(-308) G/A in T1DM patients than controls, and they were significantly more likely than controls to have the mutant allele (OR=18.431, 95%CI= 2.464-137.855, p=0.00001). These results indicate a possible role for the G genotype in T1DM disease.

Polymorphisms of Pro-Inflammatory IL-6 and IL-1β Cytokines in Ascending Aortic Aneurysms as Genetic Modifiers and Predictive and Prognostic Biomarkers.

Background: Previous studies have demonstrated that polymorphisms involved in immune genes can affect the risk, pathogenesis, and outcome of thoracic ascending aortic aneurysms (TAAA). Here, we explored the potential associations of five functional promoter polymorphisms in interleukin-6 (IL-6), IL-1B, IL-1A, IL-18, and Tumor necrosis factor (TNF)A genes with TAAA. Methods: 144 TAAA patients and 150 age/gender matched controls were typed using KASPar assays. Effects on telomere length and levels of TAAA related histopathological and serological markers were analyzed. Results: Significant associations with TAAA risk were obtained for IL-6 rs1800795G>C and IL-1B rs16944C>T SNPs. In addition, the combined rs1800795C/rs16944T genotype showed a synergic effect on TAAA pathogenesis and outcome. The combined rs1800795C/rs16944T genotype was significantly associated with: (a) higher serum levels of both cytokines and MMP-9 and -2; (b) a significant CD3+CD4+CD8+ CD68+CD20+ cell infiltration in aorta aneurysm tissues; (c) a significant shorter telomere length and alterations in telomerase activity. Finally, it significantly correlated with TAAA aorta tissue alterations, including elastic fragmentation, medial cell apoptosis, cystic medial changes, and MMP-9 levels. Conclusions: the combined rs1800795C/rs16944T genotype appears to modulate TAAA risk, pathogenesis, and outcome, and consequently can represent a potential predictive and prognostic TAAA biomarker for individual management, implementation of innovative treatments, and selection of the more proper surgical timing and approaches.

Prevalence of TNFa (G308A and G238A) and LTa (A252G) polymorphisms in women with pregnancy loss ? study carried out in a private clinic of Mexico City

Background: Tumor necrosis factor (TNF) is a cytokine that includes different types of molecules that participate in cellular and organic responses, and Single Nucleotide Polymorphisms (SNPs) in TNF are associated to the pathogenesis of chronic inflammatory diseases and local or systemic autoimmune diseases. Objective: To know the prevalence of TNFα (G238A and G308A) and LTα (A252G) polymorphisms in a population of Mexican women with pregnancy loss. Materials and methods: This is a retrospective, observational and cross-sectional study of 184 Mexican women, with the aim of evaluating the presence of TNFa (G238A and G308A) and LTa A252G polymorphism; 3 groups were formed: 1) TNFa G238A, 2) TNFa G308A and 3) LTa A252G and each group was separated by homozygous and heterozygous mutation. Results: It was found an increase in prevalence in TNFa, G238A compared with TNFa G308A and LTa A252G (31.9 vs 25.4 and 26.5%). The heterozygous form was higher in prevalence compared with the homozygous. In 50.3% no mutations of TNFa G238A, TNFa G308A and LTa A252G were found; the number of patients that only presented one polymorphism was 23.2%, with 2 polymorphisms represent 21%, and presented 3 polymorphisms (5.3%). Conclusion: The prevalence of TNFa G238A, TNFa G308A and LTa A252G polymorphisms in Mexican population could be high. Said polymorphisms are associated to almost 50% of cases of women with pregnancy loss in this study; and patients with more than one polymorphism are susceptible to complications such as pregnancy loss.

Association of single-nucleotide polymorphisms in tumour necrosis factor and human leukocyte antigens genes with type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive destruction of insulin-producing pancreatic beta cells. This multifactorial disease has a strong genetic component associated with the human leukocyte antigens (HLA) and non-HLA regions. In this study, we compared frequencies of HLA-DRB1 alleles and single-nucleotide polymorphisms (SNPs) associated the genes coding for: toll-like receptors (TLRs), tumour necrosis factor (TNF), interleukin-1 (IL-1), interleukin-1 receptor type 1 (IL-1R1), interleukin-1 receptor antagonist (IL-1RN), interleukin-2 (IL-2) and interleukin-12B (IL-12B), between T1D patients and healthy controls. The aim was to identify frequency differences and linkage between these genetic markers in T1D patients and healthy controls. Twelve SNPs were investigated as follows: rs16944 (IL-1B), rs1143634 (IL-1B), rs1800587 (IL-1A), rs2069762 (IL-2), rs3212227 (IL-12B), rs2234650 (IL-1R1), rs315952 (IL-1RN), rs3804099 (TLR2), rs4986790 (TLR4), rs4986791 (TLR4), rs1800629 (TNF) and rs361525 (TNF). TaqMan genotype assay method was used for SNPs genotyping. HLA-DRB1* genes were typed by Sequence Specific Oligonucleotide Probe (SSOP). SPSS and SNPStats programs were used for the statistical analysis. Significant differences between T1D and control groups were found for the dominant model of rs361525 and rs1800629A:rs361525G genotypes for TNF. Increased frequencies of DRB1*03 and DRB1*04 and decreased frequencies of DRB1*07, DRB1*11 and DRB1*13 and DRB1*15 were observed in T1D patients compared with controls. However, the genotype, DRB1*07 with rs1800629A/G was associated with T1D. We have confirmed that DRB1*03 and DRB1*04 are associated with increased risk and DRB1*07, DRB1*11 and DRB1*13 and DRB1*15 with decreased risk of T1D. Also, the dominant model of rs361525A, and the rs1800629G:361525A genotype were associated with increased risk. The simultaneous presence of DRB1*07 and rs1800629A/G genotypes in 23 out of 27 DRB1*07 positive T1D patients implied that islet cell peptide processing may have been biased towards autoimmunity by upregulation of TNF associated intronic SNPs.

Polymorphism of Interleukins and Tumor Necrosis Factor a Genes in Multiple Myeloma Patients with Autologous Hematopoietic Stem Cell Transplantation

Aim. To assess polymorphism value of interleukins (IL6, IL1B, IL10) and tumor necrosis factor α (TNF) genes in multiple myeloma (MM) patients who received autologous hematopoietic stem cell transplantation (auto-HSCT). Materials &amp; Methods. The study enrolled 37 MM patients (15 men and 22 women) aged 38-66 years (mean age 54.5 ± 6.4 years), who received auto-HSCT. After transplantation, partial (PR), very good partial (VGPR), and complete (CR) responses were reported in 11, 7, and 19 patients, respectively. In 23 (62.2 %) patients CD34+ cell collection on the day of the first leukocytapheresis session exceeded the suboptimal level of 2.5 &lt;sup&gt;x&lt;/sup&gt; 10&lt;sup&gt;6&lt;/sup&gt;/kg. The control group included 236 healthy subjects. Genotyping by PCR with subsequent analysis of restriction fragment length polymorphism of amplified products was performed. To identify between-group differences in genotype distribution, Fisher's exact test with measurements of odds ratio (OR) and р-value was used. Results. The study group of patients was distinguished from the control group by more than twofold increased proportion of homozygous IL1B -31C (OR 2.7; p = 0.029). The proportion of heterozygous -174G/C allelic variant of IL6 gene in the subgroup of patients with CR after auto-HSCT was considerably higher than in patients with VGPR and PR (OR 5.6; p = 0.022). In the subgroup of patients with CD34+ cell collection &gt; 2.5 x 10&lt;sup&gt;6&lt;/sup&gt;/kg the proportion of those with IL10 -592C/C genotype was twice as high as in patients with lower CD34+ cell collection (OR 3.9; p = 0.091). Conclusion. The present study confirms the relationship of -31C/T polymorphism in IL1B gene in homozygous state with higher MM risk. It proved the association of -174G/C polymorphism in IL6 gene and -592C/A polymorphism in IL10 gene with the chosen criteria for auto-HSCT efficacy. To precisely clarify the value of variants in the above genes for predicting chemotherapy effect in MM, further studies involving more patients are required.

Whether the risk of gestational diabetes mellitus is affected by TNF-\u03b1, IL-6, IL-10 or ADIPOQ polymorphisms: a meta-analysis

BackgroundWhether polymorphisms in tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10) or adiponectin (ADIPOQ) influence the risk of gestational diabetes mellitus (GDM) or not remain inconclusive. Therefore, the authors conducted a meta-analysis to robustly assess relationships between polymorphisms in TNF-α, IL-6, IL-10 or ADIPOQ and the risk of GDM by merging the results of eligible publications.MethodsA through literature searching in Medline, Embase, Wanfang, VIP and CNKI was conducted by the authors to identify eligible publications, and twenty-two publications were finally found to be eligible for merged quantitative analyses.ResultsThe merged quantitative analyses revealed that ADIPOQ + 45T/G (rs2241766) polymorphism was significantly associated with the risk of GDM in overall population (dominant comparison: OR = 0.70, p < 0.001; recessive comparison: OR = 1.95, p < 0.001; over-dominant comparison: OR = 1.18, p = 0.03; allele comparison: OR = 0.71, p < 0.001) and Asians (dominant comparison: OR = 0.70, p < 0.001; recessive comparison: OR = 1.94, p < 0.001; allele comparison: OR = 0.72, p < 0.001). Nevertheless, we did not observe any positive results for TNF-α − 238G/A (rs361525), TNF-α − 308G/A (rs1800629), IL6 − 174G/C (rs1800795), IL-10 − 819C/T (rs1800871), IL-10 − 592C/A (rs1800872), IL-10 − 1082A/G (rs1800896) and ADIPOQ + 276G/T (rs1501299) polymorphisms.ConclusionsThe present meta-analysis shows that among investigated TNF-α, IL-6, IL-10 or ADIPOQ polymorphisms, only ADIPOQ + 45T/G (rs2241766) polymorphism may affect the risk of GDM.

Association of IL-10 and TNF-\u03b1 polymorphisms with risk and aggressiveness of hepatocellular carcinoma in patients with HCV-related cirrhosis

BackgroundHepatitis C virus (HCV) infection is a significant risk factor for cirrhosis and hepatocellular carcinoma (HCC) that carry a high mortality. The study aims to investigate the effect of tumour necrosis factor (TNF)-α and interleukin (IL)-10 polymorphisms on risk and pattern of HCC in patients with HCV-related cirrhosis.ResultsThe mean age of the HCC group was 56.21 ± 4.62 years and 54.27 ± 7.63 years for the cirrhotic group. The GG genotype of TNF-ɑ and TT genotype of IL-10 showed a higher incidence of HCC in comparison to the cirrhotic group with P = 0.01 and 0.004. On the calculation of the aggressiveness index (AgI), the TT haplotype was significantly associated with more aggressive tumours in contrast to the other haplotypes with P < 0.001. There is a significant association of portal vein thrombosis, ascites and high AgI with the GG haplotype in contrast to the other haplotypes with P = 0.002, 0.029 and < 0.001, respectively, as regards TNF-α. High AgI (C) was associated with the TT haplotype of IL-10 and GG haplotype of TNF-ɑ.ConclusionOur data bring an essential association of IL-10 and TNF polymorphism with the occurrence of HCC in patients with HCV-related liver cirrhosis. The GG haplotype of TNF-ɑ and TT/AT haplotype of IL-10 are associated with the more aggressive pattern of HCC, so those patients must be treated as early as possible.

Exposure to biomass smoke, cigarettes, and alcohol modifies the association between tumour necrosis factor (-308G/A, -238G/A) polymorphisms and tuberculosis in Mexican carriers.

IntroductionExposure to biomass smoke, cigarettes, alcohol, and the impairment of immunoregulation are considered to be risk factors for tuberculosis. Tumour necrosis factor (TNF) –308G/A and –238G/A gene polymorphisms have been associated with tuberculosis. However, the results remain inconsistent. The aim of this study was to determine the association between TNF polymorphisms and tuberculosis in the presence of biomass smoke, cigarettes, and alcohol in a Mexican population.Material and methodsTNF polymorphisms were determined in 118 tuberculosis patients and 223 controls. We performed a univariate, bivariate, stratified analysis. Odds ratios, confidence intervals, and p-values were calculated.ResultsOccupational biomass smoke exposure was associated with tuberculosis between the patients and controls (OR = 1.70, 95% CI: 1.08–2.70, p = 0.02). We also found an association of the –308A allele carriers between the patients and controls without exposure to occupational (p = 0.04, OR = 0.16, 95% CI: 0.01–0.92) and in-home (p = 0.02, OR = 0.14, 95% CI: 0.01–0.81) biomass smoke, as well as an association with alcohol (p = 0.01, OR = 0.24, 95% CI: 0.05–0.75). The haplotype analysis revealed an association of the –308A/–238G haplotype between patients and nonconsanguineous controls without exposure to occupational (p = 0.02, OR = 0.12, 95% CI: 0.01–0.99) and in-home (p = 0.01, OR = 0.1, 95% CI: 0.01–0.9) biomass smoke, cigarette use (p = 0.04, OR = 0.28, 95% CI: 0.08–0.98), and alcohol (p = 0.02, OR = 0.22, 95% CI: 0.05–0.88) intake.ConclusionsThe TNF –308A allele and the –308A/–238G haplotype are associated with tuberculosis, as are exposure to biomass smoke, cigarettes, and alcohol. No association for the –238G/A polymorphism was found. Our results provide insight into a possible protective role of TNF polymorphisms in tuberculosis in our population.

The Relationship Between Tumor Necrosis Factor-Alpha (-308G/A, +488G/A, -857C/T, and -1031T/C) Gene Polymorphisms and Risk of Intracerebral Hemorrhage in the North Indian Population: A Hospital-Based Case-Control Study.

Genetic factors may play a role in the susceptibility of intracerebral hemorrhage (ICH). The present case-control study hypothesized that genetic polymorphisms in tumor necrosis factor- α (TNF-α) gene may affect the risk of ICH. In this study, we investigated the association of four single nucleotide polymorphisms (-308G/A, +488G/A, -857C/T, and -1031T/C) within TNF-α gene promoter and their haplotypes with the risk of ICH in a North Indian population. Genotyping was determined by using the SNaPshot method for 100 ICH patients and 100 age and sex-matched ICH-free controls. Conditional logistic regression analysis with adjusting multiple demographic and risk factor variables was used to calculate the strength of association between TNF-α gene polymorphisms and risk of ICH. Haplotypes were reconstructed using PHASE 2.0, and patterns of linkage disequilibrium (LD) analysis were performed using Haploview version 4.2 software. TNF-α +488G/A gene polymorphism was found to be independently associated with the risk of ICH under dominant [GG + GA vs. AA] (OR = 3.1; 95% CI = 1.2-8.2; P = 0.001) and allelic [G vs. A] (OR = 2.2; 95% CI = 1.2-4.2; P = 0.007) models. However, no significant association between -308G/A, -857C/T, and -1031T/C gene polymorphisms and risk of ICH was observed. Haplotype analysis showed that 308A-488G-857C-1031T and 308G-488A-857T-1031T haplotypes were significantly associated with an increased risk of ICH. Strong LD was observed for + 488G/A and -857C/T TNF-α polymorphisms (D' = 0.72, r2= 0.01). Our findings suggest that the TNF-α +488G/A polymorphism may be an important risk factor for ICH, whereas -308G/A, -857C/T, and -1031T/C gene polymorphisms may not be associated with risk of ICH in North Indian population.

The Overall Survival of Breast Cancer Patients Depends on a Combination of Polymorphisms of Tumor Necrosis Factor Gene and HLA Haplotypes

Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of a number of diseases, including oncological and autoimmune diseases. The –308(g/a)TNF and –238(G/A)TNF polymorphisms are included in the extended ancestral haplotypes covering the whole complex of HLA genes. We assumed that the previously found effect of these polymorphisms on the overall survival (OS) of breast cancer (BC) patients may be a consequence of cooperation with the genomic environment, namely, with the AH8.1 and B57 haplotypes associated with autoimmune conditions. The archival collection of DNA from 442 primary BC patients and 327 women from the control group with known –308(g/a)TNF and –238(G/A)TNF genotypes was used in the work. Four hundred and twelve BC patients were tested for AH8.1 and B57 markers. During the study, the association of –308a and –238A alleles of the TNF gene with haplotypes AH8.1 and B57, respectively, was confirmed. Analysis of the results of the study demonstrated that TNF gene polymorphisms do not affect the predisposition to BC disease, but significantly decrease the OS of BC patients; moreover, the final effect of the TNF gene polymorphisms on the disease prognosis depends on genomic context. At stage II of the disease, the carriers of the –308ag/–238GG genotype in the presence of marker AH8.1 alleles and the –308gg/–238GG carriers, regardless of AH8.1 markers, had a 10-year OS above 80%, while a 10-year OS was lower than 50% in the –308ag/–238GG carriers in the absence of AH8.1 markers and in the –308gg/–238AG genotype carriers (p = 0.0076). The mechanisms of action of –308(g/a)TNF and ‒238(G/A)TNF differ, and a decrease in OS in the carriers of minor –238A allele is mediated by its association with HLA-B*57, while a decrease in OS in the carriers of –308a, on the contrary, is not associated with the ancestral AH8.1 haplotype. Thus, two genetically determined BC patient groups that have an unfavorable prognosis in conditions of standard BC therapy were detected.

P1748TNF and ANXA2 gene polymorphism associated with outcome and coronary angiography features in patients with early acute coronary syndrome

Abstract Background Genetic predisposition makes a considerable contribution to premature acute coronary syndrome (ACS) development. Tumour necrosis factor (TNF) is an important proinflammatory cytokine influencing intravascular inflammation. Annexin A2 (ANXA2) is an endogenous PCSK9 inhibitor. Higher LDL level is associated with AA genotype of ANXA2 gene SNP rs17845226. Aim The aim of the study was to elucidate the association of TNF and ANXA2 gene polymorphism with coronary angiography features and outcome in patients (pts) with early ACS. Methods We analyzed data from two prospective observational trials (2004–2007; 2014–2016) - 672 pts (498 men and 174 women) with premature ACS (men≤55, women≤60 years of age). Coronary angiography (CAG) data were analyzed in 225 pts. Genotyping of SNP rs1800629 of TNF (502 pts) and rs17845226 of ANXA2 gene (235 pts) was performed by RT-PCR with allele-specific primers. The primary endpoint was calculated as a combination of all-cause mortality, recurrent ACS, stroke, and peripheral vascular disease. We also analyzed recurrent coronary events (CE) (coronary deaths &amp; recurrent ACS). The mean follow-up time: 414±347.6 days. Results Mean age was 48.6±5.8 (M), 52.7±6.3 (F) years. 298 (44.3%) pts had STEMI, 362 (53.9%) pts – history of CAD, 500 (74.4%) – arterial hypertension, 32 (4.8%) – history of stroke, 81 (12.1%) – diabetes mellitus, 241 (37.1%) – heart failure (HF). The genotype distribution did not differ from the expected Hardy–Weinberg equilibrium: GG/AG/AA=0.557/0.191/0.006 (χ2=3.34, p=0.07) for TNF and CC/AC/AA=0.86/0.136/0.004 (χ2=0.05, p=0.82) for ANXA2. Carriers of allele A of TNF gene SNP had higher frequency of no significant coronary lesion (17.6% vs 5.9%; p=0.021) and NSTEMI (69.5% vs 50.8%, p&lt;0.001). Carriers of allele A of ANXA2 gene SNP had higher frequency of coronary calcinosis (39.3% vs 19.6%; p=0.019) and HF (39.4% vs 22.3%, p=0.034). Carriers of A allele of TNF had higher frequency of CE (30.5% vs 19.5%, p=0.01, log-rank χ2=7.29, p=0.007). HF (OR, 2.686; 95% CI, 1.769–4.077; p&lt;0.001), creatinine level (OR, 1.009; 95% CI, 1.001–1.017; p=0.025) and carrying of A allele of TNF gene SNP (OR, 1.836; 95% CI, 1.163–2.898; p=0.007) and STEMI at admission (OR, 1.009; 95% CI, 1.001–1.017; p=0.025) were independent predictors of any unfavorable outcome and CE in a multivariable Cox regression model. LAD and left main coronary artery involvement (OR, 1.836; 95% CI, 1.163–2.898; p=0.007) was an independent predictor of any unfavorable outcome. Identified relationship was independent of invasive treatment of ACS. Conclusion Thus, in patients with early ACS TNF mediated inflammation is associated with NSTEMI, no significant coronary lesion and could play a significant role in the development of unfavourable outcome. Carrying of A allele of ANXA2 gene may accelerate coronary atherosclerosis in these patients and is associated with HF.

TNF-\u03b1 G-308A genetic variants, serum CRP-hs concentration and DNA damage in obese women

Obesity is associated with inflammation, which can disturb genome stability. Tumor necrosis factor (TNF-α) polymorphism was found to affect TNF-α protein production and inflammation. Therefore, the present study illustrates the relationship between TNF-α polymorphism, the degree of inflammation assessed by serum high sensitivity C-reactive protein concentration (CRP-hs) and basal DNA damage in patients with obesity (BMI 30–34.9 kg/m2) and control subjects with proper body mass (BMI < 25 kg/m2). A total of 115 participants (75 obese premenopausal women; and 40 age-, and gender-matched controls) were included. Biochemical parameters (serum concentrations of total-cholesterol, HDL-cholesterol, LDL- cholesterol, triglycerides, glucose, apolipoprotein AI, CRP-hs) and endogenous DNA damage (determined by comet assay) were measured. TNF-α G-308A polymorphism (rs1800629) was analyzed by PCR-RFLP (PCR-restriction fragments length polymorphism). An effect of TNF-α genotype on serum CRP-hs concentration was noted (p = 0.031). In general, carriers of the rare A allele of the TNF-α G-308A polymorphism had significantly lower endogenous DNA damage and serum CRP-hs concentrations than GG homozygotes, however, the protective effect of the A allele was especially visible in non-obese women. Serum CRP-hs concentrations and levels of DNA damage (% DNA in tail) were significantly higher in obese than in controls (p = 0.001 and p < 0.0001, respectively). The adjusted multiple linear regression analyses revealed a significant, independent impact of obesity on DNA damage (p = 0.00000) and no effect of other covariates i.e. age, TNF-α genotype and serum CRP-hs concentration. Our study showed that obesity has a significant impact on the levels of endogenous DNA damage. Obesity abolished the protective effect of A allele of the TNF-α G-308A polymorphism on DNA damage and on inflammation development observed in non-obese A allele carriers.

Genetic Factors and Psoriatic Arthritis

Psoriatic arthritis (PsA) is a complex immune-mediated disease and its pathogenesis depends both on genetic factors and environment. PsA patients may present a wide range of clinical manifestations including skin and nail abnormalities. Indeed, articular involvement is variable too. Disease development relies on a heterogeneous net made of multiple cytokines pathways which are regulated by several factors including human leucocyte antigen (HLA) expression, miRNAs, microbiome. Among genetic polymorphisms which can lead to abnormal cytokine expression, tumor necrosis factor (TNF) polymorphisms have been studied. Thus, leading to the development of new therapeutic agents. Finally, further studies on genetic factors and epigenetics will give new insights into this complex disorder. The aim of this mini-review is to provide the reader with a summary of the fundamental and most innovative aspects of genetic and epigenetic factors involved in the PsA, thus including human leucocyte antigen (HLA) expression, tumor necrosis factor (TNF) polymorphisms, micro RNAs and microbiome.