Influence of Promoter Polymorphisms of the TNF-? (-308G/A) and IL-6 (-174G/C) Genes on Therapeutic Response to Etanercept in Rheumatoid Arthritis.
ABSTRACT: The study was undertaken to assess the influence of functional -308G/A TNF-? (rs 1800629) and -174G/C IL-6 (rs1800795) promoter polymorphisms on the therapeutic response to etanercept, a TNF-? blocker, in patients with rheumatoid arthritis (RA).Seventy-three patients suffering from active RA were studied, at baseline and 6 and 12 months after therapy. The therapeutic response was estimated according to the European League Against Rheumatism response criteria. Patients were genotyped for -308G/A TNF-? and -174G/C IL-6 polymorphisms by the PCR-RFLP method, and the influence of genotype on etanercept response was assessed.No difference in the percentage of responders (patients who had DAS28 improvement > 1.2) between patients with the TNF-?-308GG and GA and AA genotype was detected after 6 and 12 months of treatment. After 12 months of treatment the percentage of responders was significantly increased in patients with the IL-6 -174GG genotype compared with those with the GC or CC genotype (p=0.006 by Chi-square test). Evaluation of the patients according to their combined IL-6/TNF-? genotypes showed that patients with the IL-6 -174GG / TNF-?-308GG genotype were more frequent among the responders compared to those with other combined genotypes (p=0.022 by Chi-square test). More precisely, all patients with the combined IL-6 -174GG / TNF-?-308GG genotype were responders after 12 months of etanercept treatment.The study suggests that patients who are genetically low TNF-? and IL-6 producers are the best responders to etanercept therapy.
Project description:Cutaneous malignant melanoma (CMM) is one of the most immunogenic types of cancer, with a 6-fold higher rate of spontaneous regression than any other malignancy. In addition to responsiveness to different immunotherapies, the immunogenicity of CMM highlights the important role of the host immune system in the response to CMM. The present study aimed to explore the role of two functional promoter polymorphisms [IL6 -174G>C (rs1800785) and TNFA -308G>A (rs1800629)] in the regulation of the genes encoding the pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-?, specifically in patients with CMM. A total of 76 patients with CMM and 200 control subjects were genotyped using PCR-restriction fragment length polymorphism. The genotype frequencies for both single nucleotide polymorphisms (SNPs) did not differ significantly between the patients and controls (P=0.358 and P=0.810 for IL6 and TNFA, respectively). However, compared with carriers of C-allele genotypes (CG+CC), patients with the IL6 -174GG genotype exhibited more advanced melanoma (Clark scale ?3; P=0.037) and shorter survival times, particularly those who worked outdoors (in conditions with increased sunlight exposure; P=0.016). Furthermore, the serum IL-6 levels of patients with CMM were significantly higher than those of the control subjects, which were associated with unfavorable blood and serum characteristics and tumor progression (development of new distant metastases; P=0.004), and with a shorter overall survival time (P=0.042). Using a Cox proportional hazard model, the IL6 -174GG genotype was found to be an independent prognostic factor for reduced survival time (P=0.030), together with sex (being male; P=0.004) and occupations with higher exposure to sunlight (P=0.047). In conclusion, the results of the present study indicated that the promoter polymorphisms IL6 -174G>C and TNFA -308G>A are not predisposing factors for CMM. However, the IL6 -174G>C SNP and IL-6 serum concentrations are likely to influence the progression of the disease, and the GG genotype and higher IL-6 serum levels may indicate shorter survival.
Project description:Associations between inflammatory gene polymorphisms (TNF-? 308G/A, TNF-? 238G/A, TNF-? 252A/G, TGF-?1 29T/C, IL-6 174G/C and IL-10 1082A/G) and osteosarcoma (OS) risk remain unclear. We conducted a systematic search to retrieve studies that investigated associations between inflammatory gene polymorphisms and OS risk. Nine studies that met the inclusion criteria were finally recruited in this meta-analysis. Overall, there was a significant association between TNF-? 308G/A, IL-10 1082A/G and OS risk, while there was no significant association between TNF-? 238G/A, TNF-? 252A/G and IL-6 174G/C and OS risk. Our subgroup analysis showed a significant association between IL-6 174G/C and IL-10 1082A/G and OS risk in Asians, while no such significant correlation was observed with TNF-? 308G/A, TNF-? 238G/A, TNF-? 252A/G and TGF-?1 29T/C polymorphisms. In Caucasians, there was a significant association between TNF-? 238G/A and the decreased incidence of OS. In conclusion, inflammatory gene polymorphisms play a key role in the occurrence and progression of OS. IL-6 174G/C polymorphism was obviously associated with OS risk in Asians, while TNF-? 238G/A polymorphism seemed to be associated with the decreased susceptibility to OS in Caucasians as Altman and Bland test indicated. Although controversial results were observed between IL-10 1082A/G and OS risk in Asians and Caucasians, it is difficult to make a definite conclusion about the role of IL-10 1082A/G polymorphism in the etiology of OS because our Altman and Bland test showed no good evidence to support a different effect in Asians and Caucasians.
Project description:BACKGROUND:Polymorphisms in genes encoding adiponectin (ADIPOQ) and interleukin-6 (IL6) have been associated with adiposity and obese-related phenotypes. This study investigated the relationship of ADIPOQ and IL6 gene polymorphisms with pro-inflammatory and cardiometabolic markers in obese patients. METHODS:Anthropometric and body composition parameters were measured in 249 Brazilian subjects (30 to 68 yr). Metabolic and inflammatory markers and adipokines were analyzed in blood samples. ADIPOQ rs2241766 (45 T?>?G) and IL6 rs1800795 (-174G?>?C) polymorphisms were analyzed by real-time PCR and PCR-RFLP, respectively. RESULTS:Type 2 diabetes, hypertension, dyslipidemia and increased values of waist circumference, body fat, leptin, fibrinogen, IL-1?, hsCRP and TNF? were related to obesity (p?<?0.05). Multiple linear regression analysis showed a positive correlation between BMI and waist circumference, body fat, leptin, fibrinogen, PAI-1, IL-1?, hsCRP and TNF? values (p?<?0.001) but not with adiponectin. Obese group had altered metabolic status, resistance to leptin and insulin, and atherogenic and pro-inflammatory profiles. ADIPOQ and IL6 variants were not directely related to obesity, leptin resistance or alterations in cardiometabolic markers. Individuals carrying ADIPOQ 45G allele (TG?+?GG genotype) had higher IL-6, IL-1? and TNF? levels than TT genotype carriers (p?<?0.05). IL6 -174GG genotype was associated with increased IL-1? levels (p?=?0.033). CONCLUSION:Obesity is associated with leptin resistance, cardiometabolic alterations and a pro-inflammatory status. Our results are suggestive that ADIPOQ and IL6 polymorphisms contribute to cardiometabolic risk in obese individuals.
Project description:Interleukin-6 (IL-6) plays a contributory role in the progression and severity of many forms of cancer; it however remains unclear whether the relevance between circulating IL-6 and cancer is causal. We therefore meta-analyzed published articles in this regard using IL-6 gene -174G/C variant as an instrument. Seventy-eight and six articles were eligible for the association of -174G/C variant with cancer and circulating IL-6, respectively. Overall analyses failed to identify any significance between -174G/C and cancer risk. In Asians, carriers of the -174CC genotype had an 1.95-fold increased cancer risk compared with the -174GG genotype carriers (P = 0.009). By cancer type, significance was only attained for liver cancer with the -174C allele conferring a reduced risk under allelic (odds ratio or OR = 0.74; P = 0.001), homozygous genotypic (OR = 0.59; P = 0.029) and dominant (OR = 0.67; P = 0.004) models. Carriers of the -174CC genotype (weighted mean difference or WMD = -4.23 pg/mL; P < 0.001) and -174C allele (WMD = -3.43 pg/mL; P < 0.001) had circulating IL-6 reduced significantly compared with the non-carriers. In further Mendelian randomization analysis, a reduction of 1 pg/mL in circulating IL-6 was significantly associated with an 12% reduced risk of liver cancer. Long-term genetically-reduced circulating IL-6 might be causally associated with a lower risk of liver cancer.
Project description:Opisthorchis viverrini infection induces chronic inflammation, and a minor proportion of infected individuals develop advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA). Inflammatory cytokines and/or their gene polymorphisms may link to these biliary pathologies. We therefore investigated associations among cytokine gene polymorphisms and cytokine production in 510 Thai cases infected with O. viverrini who presented with APF+ or APF-, as established by abdominal ultrasonography as well as in patients diagnosed with CCA. Levels of pro-inflammatory and anti-inflammatory cytokines were determined in culture supernatants after stimulation of peripheral blood mononuclear cells (PBMCs) with O. viverrini excretory-secretory (ES) products. Pro-inflammatory cytokines, IL-1?, IL-6, IFN-?, LT-?, and TNF-? were significantly increased in CCA patients compared with non-CCA (APF- and APF+) cases. Polymorphisms in genes encoding IL-1?-511C/T, IL-6-174G/C, IFN-? +874T/A, LT-? +252A/G, and TNF-? -308G/A were then investigated by using PCR-RFLP or allele specific-PCR (AS-PCR) analyses. In the CCA cases, LT-? +252A/G and TNF-? -308G/A heterozygous and homozygous variants showed significantly higher levels of these cytokines than the wild type. By contrast, levels of cytokines in wild type of IFN-? +874T/A were significantly higher than the variants in CCA cases. IFN-? +874T/A polymorphisms were associated with advanced periductal fibrosis, whereas IL-6 -174G/C polymorphisms were associated with CCA. To our knowledge, these findings provide the first demonstration that O. viverrini infected individuals carrying several specific cytokine gene polymorphisms are susceptible to develop fibrosis and CCA.
Project description:Stem cell transplantation affects patient׳s vulnerability to infections due to immunological changes related to chemotherapy. Multiple myeloma is characterized by susceptibility to infections, and IL-6 and TNF-α increased levels affect immune response (IR). Polymorphisms in promoter region of cytokine genes may alter expression levels and affect IR. We performed interaction analysis of IL-6 (-174G/C) and TNF-α (-308G/A) polymorphisms with infection susceptibility in 148 patients classified accordingly to infection status and found an interaction when compared groups with and without bacteremia (p=0.0380). The interaction may be more important than single effects for the IR associated with the infection susceptibility in ASCT.
Project description:The associations between TNF-? and Interleukin gene polymorphisms and polycystic ovary syndrome (PCOS) risk have been studied in numerous epidemiological studies, but the results remain controversial. To investigate whether these polymorphisms facilitate susceptibility to PCOS, we conducted a comprehensive systematic review and meta-analysis.PubMed, Embase, Web of Science, Medline, CNKI, and Google Scholar were searched to obtain the genetic association studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Odds ratios (OR) with corresponding 95 % confidence intervals (CI) were used to assess the strengths of the associations. Funnel plots and Egger's tests were performed to test for possible publication bias. All statistical analyses were performed using Review Manager 5.2 and STATA11.0.Eighteen articles were included in the final meta-analysis. The studies involved the following polymorphisms: TNF-? -308G?>?A, TNF-? -805C>T, TNF-? -1031 T>C, IL-1A -889C>T, IL-1B -511C>T, IL-1B +3953 T>C, IL-6 -174G>C, IL-10 -819C>T, IL-10 -1082A>G, IL-18 -607C>A, and IL-18 -137G>C. Our results show a significant association between PCOS risk and the TNF-? -1031 T>C polymorphism (For TC+CC vs. TT: OR=2.09, 95 % CI=1.58-2.76, p<0.0001. For C allele vs. T allele: OR=1.67, 95 % CI=1.33-2.09, p<0.0001) and between PCOS risk and the IL-6 -174>C polymorphism (For CC+GC vs. GG: OR=0.49, 95 % CI=0.25-0.95, p=0.03. For CC vs. GG: OR=0.48, 95 % CI=0.28-0.80, p=0.005. For C vs. G: OR=0.60, 95 % CI=0.42-0.87, p=0.007). No associations were found with the other genetic models.The results of the meta-analysis suggest positive associations between the TNF-? -1031 T>C and IL-6 -174G>C polymorphisms and the risk of PCOS. No associations are found between PCOS risk and the TNF-? -308G>A, TNF-? -805C>T, IL-1A -889C>T, IL-1B -511C>T, IL-1B +3953C>T, IL-10 -819C>T, IL-10 -1082 A>G, IL-18 -607C>A, and IL-18 -137G>C polymorphisms. However, due to the heterogeneity and low quality of the studies related to PCOS polymorphisms in the meta-analysis, the results should be interpreted with caution. Future multi-ethnicity studies of homogeneous populations of PCOS patients with larger sample sizes and well-matched controls are needed.
Project description:Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disease. Cytokines play an important role in the pathogenesis and disease progression of OLP. Various reports have implicated cytokine gene polymorphisms in susceptibility to develop some immune mediated conditions including OLP. The purpose of this study was to investigate the association of tumor necrosis factor (TNF)-?, TNF-? and interleukin (IL)-10 gene polymorphisms with the OLP risk.Forty two unrelated patients with OLP and 211 healthy volunteers were genotyped for TNF-? (-308 G/A), TNF-? (+252A/G), IL-10 (-1082G/A), IL-10 (-819C/T), and IL-10 (-592C/A) polymorphisms.The frequencies of allele A and genotype GA of TNF-? (-308G/A) were significantly higher while allele G and GG genotypes were lower in OLP patients as compared to the controls (P<0.001). The frequency of GA genotype of TNF-? (+252A/G) was significantly higher in patients than in controls while the AA genotype was completely absent in OLP patients. These results indicated that allele A and genotype GA of TNF-? (-308G/A) as well as the GA genotype of TNF-? (+252A/G) polymorphisms are associated with OLP risk. The frequencies of alleles and genotypes of -1082G/A, -819C/T and -592C/A polymorphisms in IL-10 gene did not differ significantly between OLP patients and controls (P>0.05). However, haplotype ATA extracted from 1082G/A, -819C/T, -592C/A polymorphisms of IL-10 were more prevalent in OLP patients when compared to controls indicating its possible association with OLP susceptibility.It is concluded that TNF-? (-308G/A), TNF-? (+252A/G) and IL-10 (-1082G/A, -819C/T and -592C/A) polymorphisms are associated with the susceptibility of OLP, thus giving additional support for the genetic basis of this disease.
Project description:PURPOSE: To evaluate the role of interleukin-6 (IL-6) in the inflammatory and proliferative stages of Eales' disease (ED) and to determine the influence of IL-6-174G/C polymorphism in the IL-6 and IL-6-regulated protein expression, as well as the development of ED. METHODS: One hundred and twenty-one patients diagnosed with ED, 223 matched healthy controls, and 16 control patients with macular holes were recruited from the eastern Indian population. Serum and vitreous levels of IL-6 and vascular endothelial growth factors (VEGF) were measured by enzyme-linked immunosorbent assay. Serum levels of high-sensitivity C-reactive protein (hsCRP) were measured by enzyme immunoassay. Subjects were genotyped for the IL-6-174G/C polymorphism (rs1800795) by a custom TaqMan single-nucleotide polymorphism (SNP) Genotyping Assays system. RESULTS: Serum IL-6 (p<0.0001), hsCRP (p<0.0001), and VEGF (p=0.0031) levels were significantly higher in the inflammatory stage of ED than in healthy controls. Serum IL-6 also significantly correlated with hsCRP (Spearman's correlation coefficient; r=0.4992, p=0.0009), but not with VEGF in this stage in ED patients. At the proliferative stage of ED, significantly higher levels of vitreous IL-6 (p=<0.0001) and VEGF (p=<0.0001) were found compared with the vitreous of patients with macular holes. A significant correlation was observed between vitreous IL-6 and VEGF in ED patients (Spearman's correlation coefficient; r=0.5834, p=0.0087). A statistically significant association was found between the -174GG genotype (p=0.006) and occurrence of ED. Mean serum and vitreous concentrations of IL-6 were also higher in the subjects with the GG genotype than in those with the GC or CC genotype in this population. CONCLUSIONS: IL-6 expression, regulated by the allelic distribution of -174 loci and the enhanced level of IL-6, modulates CRP and VEGF concentration depending respectively on the acute inflammatory stimulation at the initial stage and angiogenic stimulation at the advanced stage of ED.
Project description:Behçet's disease (BD) is a complex, multisystemic inflammatory disorder of unclear etiology. Single nucleotide polymorphisms in tumor necrosis factor (TNF) and interleukin (IL)-10 genes have been implicated in susceptibility to BD with inconsistent results in several ethnic populations. The aim of this case-control study was to evaluate the association of TNF-? (-308G/A), TNF-? (+252A/G), and IL-10 (-1082G/A, -819C/T, and -592 C/A) polymorphisms with susceptibility of BD in Saudi patients. Molecular genotyping of TNF-?, TNF-?, and IL-10 gene polymorphisms was performed to analyze the alleles and genotypes distribution in 272 Saudi subjects, including BD patients (61) and healthy controls (211). The frequencies of allele A and genotype GA of TNF-? (-308G/A) were significantly higher, whereas those of allele G and genotypes GG were significantly lower in BD patients than controls, indicating that A allele and GA genotype are susceptible, while G allele and GG genotype may be refractory to BD. The distribution of frequencies of alleles and genotype of TNF-? (+252A/G) promoter polymorphism was not significantly different between BD patients and healthy controls. Genotypes 1082GG, -819TT, and 592AA of IL-10 polymorphisms are significantly associated with susceptibility risk of BD, while genotypes 1082AA, 1082GA, 819CC, 819CT, 592CC, and 592CA are resistant to BD. This study indicates that TNF-? (-308G/A) and IL-10 (-1082G/A, -819C/T, and -592C/A) polymorphisms are associated with risk of BD susceptibility in Saudi patients. However, larger scale studies in Saudi population as well as in other ethnicities are needed to confirm this association.