TNF-α Polymorphisms Research Articles

Quantile-Dependent Heritability of Glucose, Insulin, Proinsulin, Insulin Resistance, and Glycated Hemoglobin

Background: “Quantile-dependent expressivity” is a dependence of genetic effects on whether the phenotype (e.g., insulin resistance) is high or low relative to its distribution. Methods: Quantile-specific offspring-parent regression slopes (β_OP) were estimated by quantile regression for fasting glucose concentrations in 6,453 offspring-parent pairs from the Framingham Heart Study. Results: Quantile-specific heritability (h²), estimated by 2β_OP/(1 + r_spouse), increased 0.0045 ± 0.0007 (p = 8.8 × 10⁻¹⁴) for each 1% increment in the fasting glucose distribution, that is, h² ± SE were 0.057 ± 0.021, 0.095 ± 0.024, 0.146 ± 0.019, 0.293 ± 0.038, and 0.456 ± 0.061 at the 10th, 25th, 50th, 75th, and 90th percentiles of the fasting glucose distribution, respectively. Significant increases in quantile-specific heritability were also suggested for fasting insulin (p = 1.2 × 10⁻⁶), homeostatic model assessment of insulin resistance (HOMA-IR, p = 5.3 × 10⁻⁵), insulin/glucose ratio (p = 3.9 × 10⁻⁵), proinsulin (p = 1.4 × 10⁻⁶), proinsulin/insulin ratio (p = 2.7 × 10⁻⁵), and glucose concentrations during a glucose tolerance test (p = 0.001), and their logarithmically transformed values. Discussion/Conclusion: These findings suggest alternative interpretations to precision medicine and gene-environment interactions, including alternative interpretation of reported synergisms between ACE, ADRB3, PPAR-γ2, and TNF-α polymorphisms and being born small for gestational age on adult insulin resistance (fetal origin theory), and gene-adiposity (APOE, ENPP1, GCKR, IGF2BP2, IL-6, IRS-1, KIAA0280, LEPR, MFHAS1, RETN, TCF7L2), gene-exercise (INS), gene-diet (ACSL1, ELOVL6, IRS-1, PLIN, S100A9), and gene-socioeconomic interactions.

TNFA and IL10 Polymorphisms and IL-6 and IL-10 Levels Influence Disease Severity in Influenza A(H1N1)pdm09 Virus Infected Patients

Cytokines are key modulators of immune response, and dysregulated production of proinflammatory and anti-inflammatory cytokines contributes to the pathogenesis of influenza A(H1N1)pdm09 virus infection. Cytokine production is impacted by single nucleotide polymorphisms (SNPs) in the genes coding for them. In the present study, SNPs in the IL6, TNFA, IFNG, IL17A, IL10, and TGFB were investigated for their association with disease severity and fatality in influenza A(H1N1)pdm09-affected patients with mild disease (n = 293) and severe disease (n = 86). Among those with severe disease, 41 patients had fatal outcomes. In a subset of the patients, levels of IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, and IL-17 were assayed in the plasma for their association with severe disease. The frequency of TNFA rs1800629 G/A allele was significantly higher in severe cases and survived severe cases group compared to that of those with mild infection (OR with 95% for mild vs. severe cases 2.95 (1.52–5.73); mild vs. survived severe cases 4.02 (1.84–8.82)). IL10 rs1800896-rs1800872 G-C haplotype was significantly lower (OR with 95% 0.34 (0.12–0.95)), while IL10 rs1800896-rs1800872 G-A haplotype was significantly higher (OR with 95% 12.11 (2.23–76.96)) in fatal cases group compared to that of the mild group. IL-6 and IL-10 levels were significantly higher in fatal cases compared to that of survived severe cases. IL-6 levels had greater discriminatory power than IL-10 to predict progression to fatal outcome in influenza A(H1N1)pdm09 virus-infected patients. To conclude, the present study reports the association of TNFA and IL10 SNPs with severe disease in Influenza A(H1N1)pdm09 virus-infected subjects. Furthermore, IL-6 levels can be a potential biomarker for predicting fatal outcomes in Influenza A(H1N1)pdm09 virus infected subjects.

M12. Network Meta-Analysis about Cytokine Gene Functional Polymorphisms Towards the Susceptibility and Severity of Acute Rheumatic Fever and Rheumatic Heart Disease among Asian and Non-Asian People

Abstract Background Great diversity among public hereditary variants may play a role in the susceptibility and severity of acute rheumatic fever (ARF)/rheumatic heart disease (RHD). Cytokine gene polymorphisms may contribute to the disease-associated cytokine imbalance. However, to the best of our knowledge, there is no existing meta-analysis concerning an association of the cytokine gene functional polymorphisms with the susceptibility / severity of ARF/RHD. Aims To investigate the potential association between cytokine gene functional polymorphisms of TNF-α, TGF-β, IL-10, IL-6 and IL-1β and the susceptibility and severity of ARF/RHD. Methods Comprehensive and structured search on Pubmed/Medline, Embase, EBSCO, and Cochrane Central Register of Controlled Trials was performed. Statistical analyses were performed using STATA. First, we performed direct pairwise meta-analysis. Then, a network meta-analysis was performed with the consistency model to compare the genetic models of different cytokine gene polymorphisms. Results Evidence derived from the meta-analysis of 24 retrospective cohort and case-control studies identified that elevated serum levels of TNF-α have been observed in ARF cases, occurring as a result of a SNP (-308G>A) in the promoter site of the TNF-α gene. Our results also suggest that IL-1β (-511) C/T polymorphism, TGF-β1 [rs1800469], and IL-1β [rs2853550] single nucleotide polymorphisms (SNPs) contributed to the susceptibility of ARF/RHD. Egger’s test did not demonstrate significant asymmetry in the dominant. Conclusion In summary, the polymorphism model increased the risk of RHD in the dominant genetic model, recessive genetic model, homozygote model and allelic genetic model among non-Asians while, recessive genetic model and homozygote model among Asians.

Genetics and Cognitive Vulnerability to Sleep Deprivation in Healthy Subjects: Interaction of ADORA2A, TNF-α and COMT Polymorphisms.

Several genetic polymorphisms differentiate between healthy individuals who are more cognitively vulnerable or resistant during total sleep deprivation (TSD). Common metrics of cognitive functioning for classifying vulnerable and resilient individuals include the Psychomotor Vigilance Test (PVT), Go/noGo executive inhibition task, and subjective daytime sleepiness. We evaluated the influence of 14 single-nucleotide polymorphisms (SNPs) on cognitive responses during total sleep deprivation (continuous wakefulness for 38 h) in 47 healthy subjects (age 37.0 ± 1.1 years). SNPs selected after a literature review included SNPs of the adenosine-A2A receptor gene (including the most studied rs5751876), pro-inflammatory cytokines (TNF-α, IL1-β, IL-6), catechol-O-methyl-transferase (COMT), and PER3. Subjects performed a psychomotor vigilance test (PVT) and a Go/noGo-inhibition task, and completed the Karolinska Sleepiness Scale (KSS) every 6 h during TSD. For PVT lapses (reaction time >500 ms), an interaction between SNP and SDT (p < 0.05) was observed for ADORA2A (rs5751862 and rs2236624) and TNF-α (rs1800629). During TSD, carriers of the A allele for ADORA2A (rs5751862) and TNF-α were significantly more impaired for cognitive responses than their respective ancestral G/G genotypes. Carriers of the ancestral G/G genotype of ADORA2A rs5751862 were found to be very similar to the most resilient subjects for PVT lapses and Go/noGo commission errors. Carriers of the ancestral G/G genotype of COMT were close to the most vulnerable subjects. ADORA2A (rs5751862) was significantly associated with COMT (rs4680) (p = 0.001). In conclusion, we show that genetic polymorphisms in ADORA2A (rs5751862), TNF-α (rs1800629), and COMT (rs4680) are involved in creating profiles of high vulnerability or high resilience to sleep deprivation. (NCT03859882).

Polymorphisms of androgens-related genes and idiopathic male infertility in Turkish men.

Androgens, testosterone and dihydrotestosterone (DHT) are endocrine regulators of spermatogenesis and act via androgen receptor (AR). The aim of this study was to investigate the association(s) of AR (CAG repeat length), SRD5A2 (rs523349, V89L) and TNF-α (rs1800629, -308G/A) polymorphisms with idiopathic male infertility in Turkish men. This case-control study consisted of 312 men with idiopathic infertility and 113 fertile men. Polyacrylamide gel electrophoresis (PAGE) or PCR-restriction fragment length polymorphism methods were used for genotyping. The mean AR CAG repeat length was significantly longer in infertile men than in fertile men (p=0.015). However, there was no significant association between the SRD5A2 genotypes (VV, VL and LL) and the risk of infertility (p=0.516). The genotype frequency and allele distribution of TNF-α -308G/A polymorphism (GG, GA, AA genotypes and G, A alleles) were not associated with male infertility (p=0.779 and p=0.743 respectively). AR CAG repeat expansion might be one of the risk factors for idiopathic male infertility in Turkish men. Further studies investigating the association of male infertility with AR CAG, V89L and -308G/A polymorphisms are warranted to understand the possible associations among them.

Distinct TNF-alpha and HLA polymorphisms associate with fibrotic and non-fibrotic subtypes of hypersensitivity pneumonitis

IntroductionSince Hypersensitivity Pneumonitis (HP) categorization in fibrotic and nonfibrotic/inflammatory types seems to be more consistent with the distinctive clinical course and outcomes, recent international guidelines recommended the use of this classification. Moreover, fibrotic subtype may share immunogenetic and pathophysiological mechanisms with other fibrotic lung diseases. AimTo investigate HLA -A, -B, -DRB1 and TNF-α –308 gene polymorphisms among fibrotic and nonfibrotic HP patients due to avian exposure, also in comparison with asymptomatic exposed controls. MethodsWe prospectively enrolled 40 HP patients, classified as fibrotic or nonfibrotic/inflammatory, and 70 exposed controls. HLA and TNF-α polymorphisms were determined by polymerase chain reaction–sequence specific primer amplification. ResultsWhile HLA alleles were not associated to HP susceptibility, fibrotic HP patients showed increased frequencies of HLA A*02 (46.7% vs 25.7%; OR=2.53, p = 0.02) and HLA DRB1*14 (10.0% vs 0.7%; OR=15.44, p=0.02) alleles when compared with exposed controls, although not statistically significant after correction for multiple comparisons. TNF-α G/G genotype (associated with low TNF-α production) frequencies were significantly increased among the non-fibrotic/inflammatory HP patients comparatively to fibrotic presentations (88% vs 60%; RR=0.44; p=0.04) and controls (88% vs 63%, OR 4.33, p=0.037). Also, these patients had a significantly increased frequency of the G allele (94.0% vs 73.3%, RR=0.44, p=0.01), while fibrotic HP patients predominantly presented the A allele (26.7% vs 6.0%, RR=2.28, p=0.01). ConclusionsOur results support the hypothesis that fibrotic and non-fibrotic HP subtypes exhibit a distinct profile of TNF-α and HLA polymorphisms, which may be relevant to predict disease course and better define treatment strategies.

Potential Value of TNF-α (-376G/A) Polymorphism and Cystatin C (CysC) in the Diagnosis of Sepsis Associated Acute Kidney Injury (S-AK I) and Prediction of Mortality in Critically Ill patients.

Sepsis Associated Kidney Injury represents a major health concern as it is frequently associated with increased risk of mortality and morbidity. We aimed to evaluate the potential value of TNF-α (−376 G/A) and cystatin C in the diagnosis of S-AKI and prediction of mortality in critically ill patients. This study included 200 critically ill patients and 200 healthy controls. Patients were categorized into 116 with acute septic shock and 84 with sepsis, from which 142 (71%) developed S-AKI. Genotyping of TNF-α (−376 G/A) was performed by RT-PCR and serum CysC was assessed by Enzyme Linked Immunosorbent Assay. Our results showed a highly significant difference in the genotype frequencies of TNF-α (−376 G/A) SNP between S-AKI and non-AKI patients (p < 0.001). Additionally, sCysC levels were significantly higher in the S-AKI group (p = 0.011). The combination of both sCysC and TNF-α (−376 G/A) together had a better diagnostic ability for S-AKI than sCysC alone (AUC = 0.610, 0.838, respectively). Both GA and AA genotypes were independent predictors of S-AKI (p= < 0.001, p = 0.002 respectively). Additionally, sCysC was significantly associated with the risk of S-AKI development (Odds Ratio = 1.111). Both genotypes and sCysC were significant predictors of non-survival (p < 0.001), suggesting their potential role in the diagnosis of S-AKI and prediction of mortality.

Association between common polymorphisms in IL-1 and TNFα and risk of peri-implant disease: A meta-analysis.

BackgroundPro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) play important roles in host immune response and bone metabolism during dental implant osseointegration. Whether the functional polymorphisms in IL-1α, IL-1β and TNFα were associated with peri-implant disease was unclear, and we performed the present meta-analysis for this purpose.MethodsEligible studies investigating IL-1α C-889T, IL-1β C+3954T and C-511T, TNFα G-308A, composite genotype of IL-1α C-889T and IL-1β C+3954T for association with peri-implant disease, including peri-implantitis (PI), marginal bone loss (MBL) and implant failure/loss (IF/IL), were searched on several literature databases prior to April 30, 2021. Odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated for each polymorphism in different genetic models and for composite genotype comparing carriers to non-carriers.ResultsTwenty-seven studies (1324 cases with peri-implant disease and 1808 controls with healthy implants) were included. There was significant correlation between IL-1α C-889T and peri-implant disease in all genetic models. IL-1β C+3954T was associated with peri-implant disease risk in allelic (OR = 1.66, 95%CI 1.17–2.35, p = 0.004) and dominant model (OR = 1.74, 95%CI 1.19–2.53, p = 0.004), and in subgroups of Asians, Caucasians, non-smokers, IF/IL and PI. TT genotype of IL-1β C-511T increased the risk of peri-implant disease (OR = 1.68, 95%CI 1.15–2.43, p = 0.007) and MBL (OR = 4.33, 95%CI 1.72–10.9, p = 0.002) compared to CC+CT genotypes. We did not observed a significant association between TNFα G-308A and peri-implant diseases in overall or subgroups analysis. Carriers of positive composite genotype of IL-1α C-889T and IL-1β C+3954T had 1.95-fold (95%CI 1.35–2.80, p<0.001) risk of peri-implant disease and 1.76-fold (95%CI 1.05–2.95, p = 0.032) risk of IF/IL than non-carriers.ConclusionFunctional polymorphisms of IL-1α (C-889T), IL-1β (C+3954T, C-511T) and composite genotype of IL-1 can be used as predictive markers for peri-implant disease, whereas TNFα G-308A polymorphism was not associated with peri-implant disease.

Time-Specific Associations of Tumor Necrosis Factor-α Levels and Polymorphisms (-850 C/T or -308 G/A) With Suicidal Ideation in Acute Coronary Syndrome Patients.

Background: Considering the association of inflammation with suicide and acute coronary syndrome (ACS), we investigated the individual and interactive effects of serum tumor necrosis factor-alpha (sTNFα) levels and two polymorphisms (−850 C/T and −308 G/A) on suicidal ideation (SI) after ACS.Methods: The SI status using items on the Montgomery–Åsberg Depression Rating Scale (MADRS), related covariates including sociodemographic and clinical characteristics, sTNFα levels, and tumor necrosis factor-alpha (TNF-α) polymorphisms were evaluated in 969 patients within 2 weeks after ACS. Of the patients, 711 were evaluated 1 year later for SI. Multivariate logistic regression models were used to calculate individual and interactive associations after adjusting for the covariates.Results: Higher (vs. lower) sTNFα levels and the −850 C/T or T/T (vs. C/C) polymorphism were significantly associated with SI 2 weeks after ACS, while only higher sTNFα levels were significantly associated with SI after 1 year. Significant interactive effects were detected between sTNFα (higher) levels and the −850 C/T (C/C or C/T) polymorphism on SI 2 weeks after ACS and between the two (−850 CC or CT and −308 G/A or AA) polymorphisms on SI 1 year after ACS.Conclusions: The sTNFα level and two polymorphisms (−850C/T and −308 G/A), separately or in combination, could be time-specific biomarkers for SI in ACS. Focused interventions for ACS patients at risk of SI might reduce the suicidal burden in patients with ACS.

Association of tumor necrosis factor-α (−308 G/A) and interleukin-10 (−1082 A/G) gene polymorphisms with polycystic ovary syndrome in Iraqi women

BackgroundThe etiologic factors of polycystic ovary syndrome (PCOS) are not well understood, however, several studies reported that genetics and environmental factors might be involved in the appearance of PCOS. Therefore understanding some molecular pathways can provide more information about PCOS. The imbalance of pro-inflammatory and anti-inflammatory cytokines could be associated with its pathophysiology. There are huge numbers of polymorphisms within cytokine genes that may affect their production and bring in the women more susceptible for PCOS. The aim of the present study was for evaluation the correlation of single nucleotide polymorphism (−308 G/A) in tumor necrosis factor-alpha (TNF-α) gene and (−1082 A/G) in interleukin-10 (IL-10) gene with PCOS. MethodsPatients group included 80 women who had a history of PCOS diagnosed using transvaginal or transabdominal ultrasound and don't have any of the inherited disorders such as androgen-secreting neoplasms, congenital adrenal hyperplasia, thyroid dysfunction, and hyperprolactinemia with a mean age (27.23 year). The control group included 70 women with a mean age (26.89 year). Levels of serum IL-10 and TNF-α in woman with PCOS and healthy control have been measured by Enzyme linked immunosorbent assay (ELISA). Single nucleotide polymorphism (SNP) in TNF-α (−308 G/A) and IL-10 (−1082 A/G) genes and the frequency of mutations in patient and control group were evaluated using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). ResultsShowed that serum IL-10 concentration was significantly decreased (p < 0.01) while TNF-α level was significantly increased (p < 0.01) in patients compared to control group. While the genotype prevalence of TNF-α (−308 G/A) and IL-10 (−1082 A/G) and the allele frequency show non-significant difference (p > 0.05) between women with PCOS and healthy controls. ConclusionIt is concluded that the level of TNF–α and IL-10 could be considered as possible biomarkers for PCOS while polymorphisms in IL-10 gene and TNF-α gene are not considered as risk factors of PCOS in Iraqi women, this suggests that further studies on other loci or other cytokines are required.

The Role of Tumor Necrosis Factor-α (TNF-α) Polymorphisms in Gastric Cancer: a Meta-Analysis.

Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine which may play a role in the development of gastric cancer (GC). This study aimed to investigate the association of five TNF-α polymorphisms including TNF-α-857, TNF-α-1031, TNF-α-863, TNF-α-308, and TNF-α-238 polymorphisms with GC risk. All eligible case-control studies were collected by searching PubMed, Scopus, and Web of Science. The association of the risk of GC with TNF-α polymorphisms was estimated using odds ratio (OR) and 95% confidence interval (CI). Heterogeneity was assessed via Cochrane's Q and I2 analyses. A total of 46 publications involving 16, 715 cases with GC and 27, 998 controls were recruited. The study revealed a significant association for TNF-α 308 (recessive model: OR = 0.646, P = 0.035), TNF-α-1031 (homozygote model: OR = 1.584, P = 0.027), and TNF-α-857 (homozygote model: OR = 1.760, P = 0.001) polymorphisms with the GC risk. The results of subgroup analysisbased ethnicity found a significant association between GC risk and TNF-α-857 polymorphism in Caucasian subgroup (P = 0.005) and TNF-α-1031 polymorphism and GC risk in Asians (P = 0.018). This study suggested that TNF-α-857 and TNF-α-1031 polymorphisms may be associated with the increased gastric cancer risk.

Association Of -308G/A, -238G/A TNF-α Polymorphisms with Multiple Myeloma Risk and Survival: A Systematic Review and Meta-Analysis

IntroductionTumor necrosis factor alpha (TNF-α) is a cytokine with a key role in proinflammation and multiple diseases, including cancer. The gene encoding TNF-α is located within a highly polymorphic region on chromosome 6p21.3; two polymorphisms -308G/A (rs1800629) and -238G/A (rs361525) have been associated with occurrence of human diseases. There is a debate in recent meta-analyses that reached discrepant conclusions regarding the potential role of TNF-α polymorphisms in multiple myeloma (MM) risk. The aim of this systematic review and meta-analysis is to investigate the association between the aforementioned two polymorphisms with the risk and survival of MM. Materials and methodsEligible articles were identified through an extensive search in PubMed database (end of search: June 18, 2020). The pooled effect estimates were calculated following the random-effects models by Der Simonian and Laird. Separate analyses were conducted by ethnicity. Between-study heterogeneity was quantified, and the deviation of genotype frequencies in controls from the Hardy-Weinberg equilibrium was evaluated. ResultsEighteen studies (2934 cases, 4291 controls) have been included in the quantitative synthesis examining risk and 5 studies for survival (557 cases). No association was found between -308G/A and -238G/A TNF-α polymorphisms and MM susceptibility in all genetic models for both Caucasian and East Asian populations. There was no association between -308G/A and -238G/A TNF-α polymorphisms and survival (overall or progression-free) of MM. ConclusionThis systematic review and meta-analysis did not reveal a significant effect of -308G/A and -238G/A TNF-α polymorphisms upon risk or survival of MM.

Association of IL-10 and TNF-α Polymorphisms with Dental Peri-Implant Disease Risk: A Meta-Analysis, Meta-Regression, and Trial Sequential Analysis.

Genetic susceptibility has been reported to be an important risk factor for peri-implant disease (PID). The aim of this meta-analysis was to assess the association between TNF-α and IL-10 polymorphisms and PID susceptibility. The Web of Science, Cochrane Library, Scopus, and PubMed/Medline databases were searched for studies published until 12 April 2021. RevMan 5.3, CMA 2.0, SPSS 22.0, and trial sequential analysis software were used. Twelve studies were included in our analysis. The pooled ORs for the association of TNF-α (−308 G > A), IL-10 (−1082 A > G), IL-10 (−819 C > T), and IL-10 (−592 A > C) polymorphisms were 1.12, 0.93, 1.35, and 0.77 for allelic; 1.42, 0.95, 3.41, and 0.34 for homozygous; 1.19, 1.88, 1.23, and 0.49 for heterozygous, 1.53, 1.12, 1.41, and 0.39 for recessive; and 1.16, 1.87, 2.65, and 0.75 for dominant models, respectively, with all the estimates being insignificant. The results showed an association between TNF-α (−308 G > A) polymorphism and the risk of PID in patients of Asian ethnicity (OR = 1.59; p = 0.03). The present meta-analysis illustrated that TNF-α (−308 G > A), IL-10 (−1082 A > G), IL-10 (−819 C > T), and IL-10 (−592 A > C) polymorphisms were not associated with the risk of PID, whereas TNF-α (−308 G > A) polymorphism was associated with an elevated risk of PID in Asian patients.

Association of TNF-α polymorphisms (-857, -863 and -1031), TNF-α serum level and lipid profile with acne vulgaris.

BackgroundAcne is an inflammatory condition principally affected by genetic and dietary factors. Investigation into functional polymorphisms of TNF-α gene and their association with acne vulgaris will be helpful in exploring genetic influence on skin immune mediated inflammatory events. In the present study, we analyzed association of TNF-α gene polymorphisms, its expression levels and lipid profiles in a large cohort of acne patients and controls.MethodsWe used PCR-RFLP to study association of TNF-α polymorphisms at −857C/T, −863C/A and −1031 T/C sites with acne vulgaris. Lipid profiles were measured using enzymatic end-point method. The serum levels of TNF-α and apolipoprotein a were measured using ELISA. NIH, LDlink was used to investigate patterns of linkage disequilibrium across south Asian reference genome (Punjabi from Lahore Pakistan).ResultsWe found that TNF-α −863 polymorphism is strongly associated with acne in overall population as well as in gender and severity based groups of acne patients. Polymorphisms at −863 and −1031 position were in linkage disequilibrium. Importantly, TNF-α serum level was significantly increased in acne patients with severe disease symptoms. Furthermore, levels of total cholesterol (TC) and triglycerides (TG) were significantly increased, whereas high density lipoprotein cholesterol (HDL-C) level was significantly decreased in acne patients. The levels of apolipoprotein a varied widely in studied populations and no significant difference was found in the analyzed groups.ConclusionIn conclusion, we found that TNF-α expression increases in acne patients affected by TNF-α polymorphisms, and that the lipid profile is specifically disrupted in acne patients.

The TNF-α (-238 G/A) polymorphism could protect against development of severe sepsis.

Primary responses in sepsis-mediated inflammation are regulated by pro-inflammatory cytokines. Variations in the cytokine genes might modify their transcription or expression, plasma cytokines levels and response to sepsis. Activation protein-1 (AP-1) and NF-κB regulate cytokines gene expression in sepsis. A total of 90 severely septic and 91 non-infected patients were prospectively studied. IL-1α (–889 C/T), IL-1β (+3954 C/T), IL-6 (–174 G/C), TNF-α (–238 G/A), TNF-α (–308G/A), IL-8 (–251A/T) and IL-10 (–1082 G/A) SNPs, plasma IL-1β, IL-4, IL-6, IL-8, IL-10, IL-13, IFN-γ, TNF-α and monocyte chemoattractant protein 1 (MCP-1) levels, and AP-1 and NF-κB gene expression by neutrophils were assessed. A allele carriers of TNF-α (–238 G/A) SNP were less frequent among septic patients. IL-6, IL-8, IL-10, TNF-α and MCP-1 levels were higher, and AP-1 and NF-κB gene expressions lower in septic patients. Sepsis was independently associated with higher fibrinogen, neutrophils counts and IL-8 levels, lower prothrombin, absence of the variant A allele of the TNF-α (–238 G/A) SNP, and haemodynamic failure. Death was independently associated with a higher APACHE II score, higher IL-8 levels, and the diagnosis of sepsis. TNF-a (–238 G/A) SNP could protect against sepsis development. Higher IL-8 levels are predictive of sepsis and mortality.

Polymorphisms of Monocyte-Activating Cytokine/Chemokine Genes Affect the Susceptibility to, and Severity of Chronic ITP

Introduction: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by the production of platelet antibodies, resulting in the destruction of platelets and inhibition of their production. A shift toward Th1 and Th17 cells together with impaired Tregs has been reported using quantitative RT-PCR and flow cytometry method. Further, recent reports have shown that CD16 (+) monocytes in ITP patients are polarized to secrete the Th1 cytokine IL-12, promoting Th1 responses. Enhanced phagocytosis of splenic macrophages was also observed in ITP patients. Thus, monocytes/macrophages are also involved in the pathogenesis of ITP. However, it remains unclear whether genetic factors of cytokines/chemokines activating monocytes increase the risk of chronic ITP. We investigated the impact of monocyte-related gene polymorphisms: TNF-α -857C/T, IFN-γ +874T/A, and MCP1+2518G/A on the susceptibility and clinical feature of chronic ITP (cITP) and Th1/Th2 ratio in peripheral blood of cITP patients,Patients and methods: In this study, 126 Japanese cITP patients (92 females and 34 males with a median age of 47.7 [range: 2.4-82.3] years), as well as 202 race-matched healthy subjects were examined. The diagnosis of cITP was defined according to International Working Group criteria. Genotyping of the polymorphisms was determined by PCR based technique and direct sequencing. We evaluated Th1/Th2 ratio in peripheral blood of 15 normal donors and 25 ITP patients. Intracellular IL-4 (Th2 cytokine) and IFN-γ (Th1 cytokine) production was assessed in CD4+ T lymphocytes activated by phorbol 12-myristate 13-acetate and ionomycin by flow cytometry.This study was approved by the Institutional Review Board of Gunma University Hospital.Results: The platelet count ranged from 1×109/L to 98×109/L with a mean count of 32×109/L at the initial diagnosis. Steroid treatment was given to 86 patients (58.1%), and splenectomy was performed in only 18 patients (12.2%). The genotype distributions of these three polymorphisms in healthy subjects were similar to those observed in previous studies of Japanese populations. Patients with cITP had a significantly higher frequency of the TNF-α -857 TT genotype (high producer type) and MCP1+2518 G allele (high-producer type) compared to healthy controls (14.0% vs 5.4%, p < 0.01; 67.6% vs. 60.6%, P < 0.01). However, no significant difference in the genotype frequencies of IFN-γ was observed between cITP patients and healthy controls. Thus, it was suggested that the TNF-α and MCP-1 polymorphisms shifted toward monocyte activation in cITP patients. We examined the association between these polymorphisms and the clinical characteristics of cITP patients. cITP patients with IFN-γ +874 non-AA genotype (high expression type) showed a lower minimum platelet count than those with an AA genotype (12.9 × 109/L ± 10.7 ×109/L vs 19.4×109/L ± 18.9 ×109/L, P < 0.05). We also examined the association between these polymorphisms and Th1/Th2 ratio in both normal donors and cITP patients. The median Th1/Th2 ratio in patients with cITP was significantly higher than that of healthy controls (31.4, range 0.6-98.8 vs. 17.8, range, 2.2-52.5, P < 0.001). Patients with the IFN-γ +874 non-AA genotype (high expression type) had a significantly higher Th1/Th2 ratio compared to those with the IFN-γ +874 AA genotype (low expression type) (71.5, range 29.4-92.8 vs. 27.5, range 0.6-98.8, P < 0.05). However, there was no significant association between the Th1/Th2 ratio and other polymorphism in cITP patients.Conclusion: These findings suggested that the high expression type of monocyte-activating cytokine/chemokine genes increased the susceptibility to, and severity of chronic ITP DisclosuresMurakami:Ono: Honoraria; BMS: Honoraria; Fujimoto: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

Effect of Cytokine Gene Polymorphisms on Eltrombopag Reactivity in Japanese Patients with Immune Thrombocytopenia.

BackgroundImmune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by low platelet counts resulting from antiplatelet autoantibodies. Analysis of polymorphisms in cytokine-encoding genes is important for understanding the pathophysiology of ITP and selecting appropriate treatments. We investigated associations between polymorphisms in cytokine-encoding genes and responses to therapy in Japanese patients with ITP.MethodsThe participants in this study comprised 153 patients with ITP and 70 healthy controls. We extracted data on sex, age, platelet counts, bleeding symptoms, and therapeutic responses, including those to prednisolone (PSL) and eltrombopag. Genomic DNA was isolated from peripheral blood and polymorphisms in TNF-α, IL-10, TGF-β1, and IFN-γ genes were analyzed using the PCR-SSP method.ResultsOur results showed that the TGF-β1 +869 C/C genotype might be related to ITP in Japanese patients. The IL-10 −592 C/C and A/A, −819 C/C and T/T, and −1082, −819, −592 ATA/ATA genotypes might be associated with reactivity to PSL. Furthermore, the IL-10 −592 C/A −819 C/T genotypes, IL-10 ACC/ATA genotype, and TGF-β1 +869 T/T and T/C genotypes might be linked to the response to eltrombopag.ConclusionOur results indicate that analysis of polymorphisms in cytokine-encoding genes could aid in understanding PSL and eltrombopag responsiveness in Japanese patients with ITP.

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.

IL-1β, IL-10 and TNF-α polymorphisms may affect systemic lupus erythematosus risk and phenotype.

Systemic lupus erythematosus (SLE) is an autoimmune disease, and IL-1β, IL-10, and TNF-α genes are important in the pathogenesis of this disease. We studied the impact of IL-1β-511, IL-1β +3953, IL-10 -592, IL-10 -1082, TNF-α -308, TNF-α -238, and TNF-α +489 polymorphisms on SLE risk and phenotype in SLE patients and healthy controls. We genotyped SLE patients and healthy controls by real-time PCR on QuantStudio 5 (Applied Biosystems) and measured levels of cytokines by enzyme-linked immunosorbent assay (ELISA). We indicated that TNF-α -308, IL-10 -592, IL-10 -1082, IL-1β-511 and IL-1β +3953 polymorphisms affect SLE risk. Furthermore, we exposed that some of the TNF-α +489, TNF-α -238, IL-10 -1082 and IL-1β +3953 genotypes are connected with the SLE phenotype. Moreover, we discovered the linking between specific genotypes and the serum concentrations of TNF-α, IL-1β, and IL-10. In conclusion, our study revealed that IL-1β-511, IL-1β +3953, IL-10 -592, IL-10 -1082, and TNF-α -308 polymorphisms may affect SLE risk and phenotype.

Association of NOS3 and TNF Genetic Polymorphisms With the Predisposition to Elevated Cholesterol, Retrospective Study

Background: Endothelial nitric oxide synthetase (eNOS) encoded by NOS3 gene has an important role in modulating vascular endothelial function. TNFα gene is responsible for coding TNFα protein that plays a significant role in regulating body inflammation and lipid metabolism. Many studies reported an association between NOS3 and TNFα genetic polymorphisms and elevated total cholesterol (TC) level, low-density lipoprotein (LDL), triglyceride (TG). In this study, we investigated the association of NOS3 (G>T) rs1799983 and TNFα -308G>A rs1800629 genetic polymorphisms with TC level. Methods: A random sample of 250 subjects with an elevated TC level (defined by TC level ≥ 200mg/dL) compared with 500 healthy subjects. Sample obtained from Palestinian adults who consented to genetic and biochemical testing. Subjects genotyped for NOS3 SNP (G > T) rs1799983 and TNFα -308G>A rs1800629 using ARMS PCR. TC level was obtained for all subjects. Logistic regression analysis adjusted for age and body mass index (BMI) was performed to test for association between NOS3 and TNFα genetic polymorphisms and TC level. Results: NOS3 T allele was significantly more frequent in the elevated TC group, (odds ratio = 1.8, 95% CI =1.02–3.18) with likelihood ratio statistically significant (P = 0.004). Homozygous TNFα variant was more frequent in the elevated cholesterol group without a statistically significant association (P = 0.54). Discussion: Many studies reported an association between NOS3 and TNFα genetic polymorphisms and elevated TC levels. Homozygous NOS3 variant was associated with a 1.8-fold increase in the risk of high TC after adjustment for age and BMI. TNFα polymorphism didn’t show a statisticallysignificant association with having elevated TC levels. With the increasing popularity and availability of genetic testing, NOS3 can serve as a screening tool to identify people with high risk for elevated TC. Further studies are required to understand the exact role of NOS3 genetic polymorphism in cholesterol metabolism. Conclusion: NOS3 genetic polymorphism had a statistically significant relationship with TC levels. These results support the association between NOS3 polymorphism and elevated TC.