TNF-α Genotypes Research Articles

IL-1β, IL-6, IL-10, and TNFα Single Nucleotide Polymorphisms in Human Influence the Susceptibility to Alzheimer’s Disease Pathology

Neuroinflammation plays an important role in Alzheimer's disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor α (TNFα) that participate in neuron damage, but also anti-inflammatory cytokines (such as IL-10), which maintain homeostasis of immune response. Previous studies showed the association of IL-1α -889C/T (rs1800587), IL-1β-1473G/C (rs1143623), IL-6 -174C/G (rs1800795), IL-10 -1082G/A (rs1800896), and TNFα -308A/G (rs1800629) polymorphisms with AD. We aimed to investigate whether people with certain IL-1α, IL-1β, IL-6, IL-10, and TNFα genotypes in these polymorphisms are more prone to develop AD-related pathology, reflected by pathological levels of cerebrospinal fluid (CSF) AD biomarkers including amyloid-β1-42, total tau (t-tau), tau phosphorylated at Thr 181 (p-tau181), Ser 199 (p-tau199), and Thr 231 (p-tau231), and visinin-like protein 1 (VILIP-1). The study included 115 AD patients, 53 patients with mild cognitive impairment, and 11 healthy controls. The polymorphisms were determined using real-time polymerase chain reaction. Levels of CSF biomarkers were determined by enzyme-linked immunosorbent assay. A significant increase in p-tau CSF levels was found in patients with the AA IL-10 -1082G/A and GG TNFα -308A/G genotypes, and in carriers of a G allele in IL-1β -1473C/G and IL-6 -174C/G polymorphisms. t-tau levels were increased in carriers of a G allele in IL-1β -1473C/G polymorphism. An increase in VILIP-1 levels was observed in patients with CG and GG IL-1β -1473C/G, GC IL-6 -174C/G, and GG TNFα -308A/G genotype. These results suggest that persons carrying certain genotypes in IL10 (-1082G/A), IL1β (1473C/G), IL6 (-174C/G), and TNFIα (-308A/G) could be more vulnerable to development of neuroinflammation, and consequently of AD.

0274 Associations of TNFα Gene Polymorphism with Resilience to Sleep Deprivation and Caffeine Sensitivity

Abstract Introduction Sleep deprivation degrades the fidelity of human brain information processing, leading to cognitive impairment. Carriers of the A allele of a single nucleotide polymorphism of the TNFα gene (G308A, rs1800629) have been found to be resilient to cognitive impairment due to sleep deprivation as compared to individuals homozygous for the G allele. Caffeine mitigates the cognitive impairment associated with sleep deprivation. We investigated whether the effects of caffeine and TNFα genotype interact. Methods In an 18-day, controlled, in-laboratory study, 12 healthy adults (age 27.4±6.9; 6 females) underwent three sessions of 48-hour total sleep deprivation (TSD), with each TSD session preceded and followed by three nights of baseline and/or recovery sleep (10 hours time in bed). In randomized, counterbalanced, double-blind, placebo-controlled fashion, during each TSD session a specific dose of caffeine (0, 200, or 300 mg) was administered four times at 12-hour intervals. Vigilant attention was measured every 2 hours during each TSD session with a psychomotor vigilance test (PVT), for which the log of the signal-to-noise ratio (LSNR) derived from the RT distribution was determined as a measure of the fidelity of information processing. Each subject’s TNFα genotype was assessed from a blood sample. Results Subjects homozygous for the TNFα G allele showed greater PVT impairment during sleep deprivation in the 0 mg caffeine (i.e., placebo) condition as compared to carriers of the A allele and as compared to the 200 and 300 mg caffeine conditions (mixed-effects ANOVA, genotype by dose interaction: F2,566=5.23, p=0.005). There was no appreciable caffeine-related difference in performance for carriers of the A allele, who were relatively resilient to TSD regardless of caffeine dose. Conclusion These results suggest non-additive, interacting effects of TNFα genotype and caffeine and a potentially shared mechanism of action with regard to the fidelity of information processing during sleep deprivation. Support This research was supported by ONR. AJB, TJB, VFC, RHR were supported by DoD MOMRP-USAMRDC. The views expressed here are those of the authors and do not represent the official policy or position of the DoD.

TNF-α gene polymorphism in Iranian Azeri population

BackgroundTumor necrosis factor (TNF-α) is one of the major cytokines in the immune system that plays a major role in the inflammation in the body. The single nucleotide polymorphism (SNP) in the gene of this cytokine at position −308A/G that occurs in the promoter affects its expression level and subsequently predisposes to some malignancies and diseases. This study was conducted to investigate the TNF-α gene polymorphism at position −308A/G in the Azeri population. Material and methodsBlood samples were collected from 240 healthy and non-relevant Azeri individuals. After DNA extraction, the frequency of TNF-α gene genotypes and alleles at -308A/G was determined by allele specific-PCR method. Then comparisons between allele frequencies and TNF-α genotypes with other populations were performed using chi-square test and P value of <0.05 was considered significant. ResultsThe frequency percentage of GG, AG and AA genotypes in TNF-α cytokines at -308A/G in Azeri population was 70.8%, 26.7% and 2.5%, respectively. The frequency percentage of G and A alleles were 84.2% and 15.8%, respectively. The occurrence of TNF-α allele A at -308A/G is associated with high expression of this cytokine. ConclusionThe frequency of AA genotype was much lower than the other two genotypes, with low prevalence observed in other populations, which had a significant association with many diseases and even cancer; therefore, there was no significant difference with most studies examining the polymorphism of this cytokine in the same position.

Association Analysis of Tumor Necrosis Factor Alpha Promoter Polymorphisms and Vitiligo Susceptibility in South Indian Tamils

Tumor necrosis factor alpha (TNF-α) has been associated with the pathogenesis of several autoimmune diseases. Also, various studies in different ethnics showed an association between TNF-α gene polymorphisms and susceptibility to vitiligo. The paucity of genetic data led us to undertake this study to evaluate the association of five TNF-α SNPs (rs1799964, rs1800630, rs1799724, rs1800629, and rs361525) with the development of vitiligo in South Indian Tamils. A total of 264 vitiligo patients and 264 healthy controls were recruited and TNF-α genotyping was performed using amplification-refractory mutation system polymerase chain reaction and TaqMan allele discrimination assay. Circulatory TNF-α levels were measured by enzyme-linked immunosorbent assay. We observed that a single polymorphic allele A in the promoter region -308 (rs1800629) conferred significant risk to develop vitiligo (p = 0.0002, OR = 1.70, 95% CI = 1.28–2.25), whereas the other polymorphisms failed to contribute to disease risk (p > 0.05). From the constructed haplotypes, TCCAG was found to be a significant risk factor for vitiligo (p < 0.05). Also, a strong linkage disequilibrium was observed between the following SNPs: (1) rs1799964 and rs1800629 (2) rs1800630 and rs1799724 (D’ = 0.90). Analysis of the influence of genotype on phenotypes revealed that the A allele of rs361525 was a risk factor for vitiligo in females (p = 0.04, OR = 0.45, 95% CI = 0.21–0.95), whilst the rs1800629 allele conferred protection against early disease onset (p < 0.05). A statistically significant difference in plasma TNF-α levels was found between cases and controls (p < 0.05). The TNF-α -308A allele and TCCAG haplotype were identified as genetic risk factors for vitiligo susceptibility in South Indian Tamils.

Cytokine gene polymorphisms in Pigeon Breeder's Disease expression.

Background:Exaggerated immunological response to repeated inhalation of organic or chemical dusts may lead to Hypersensitivity Pneumonitis among sensitized individuals. Only a few exposed individuals became ill and disease expression pattern is highly variable which suggest that genetic factors may play a role.Aim:To investigate interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-6, transforming growth factor (TGF)-ß, and IL-10 gene polymorphisms in a cohort of pigeon breeder’s disease (PBD) patients in comparison with exposed but healthy controls and the association with different patterns of disease.Methods:We evaluated 40 PBD patients and 70 exposed controls. IFN-γ, TNF-α, IL-6, TGF-ß, and IL-10 polymorphisms were determined by polymerase chain reaction–sequence specific primer amplification.Results:Polymorphism analysis of IFN-γ, TNF-α, IL-6, TGF-ß, and IL-10 genotypes and allele frequencies showed no differences between patients and controls. IFN-γ T/T genotype frequency was increased among patients with chronic presentation (RR=2.33, p=0.047) compared with those with acute/subacute presentation. Also, chronic presenting patients had an increased frequency of IFN-γ T allele (50% vs 22.5%, RR=1.76, p=0.011). No differences were found in TNF-α, IL-6, TGF-ß, and IL-10 genotypes neither allelic frequencies between both groups of patients. IL-6 C/C genotype was more frequent in patients who showed chronic evolution (RR=2.54, p=0.017), when comparing with patients with disease resolution.Conclusion:IFN-γ T/T and the IL-6 C/C genotypes seem to play a role in HP expression due to avian exposure, as their frequencies are increased in chronic presentations or in those with chronic evolution one year after the initial diagnosis, respectively. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (3): e2020004)

Tumor necrosis factor-α polymorphism in helicobacter pylori associated gastric carcinoma

Background: Gastric cancer (GC) is the leading cause of cancer death in the world. Chronic inflammation is a predisposing factor of gastric carcinogenesis. TNF-α is a key pro-inflammatory cytokine secreted by macrophages and causes development of malignant diseases. It also plays an important role in chronic inflammation caused by Helicobacter Pylori. Therefore, TNF-α polymorphisms is studied in Helicobacter Pylori infected gastric cancer.&#x0D; Objective: To find out the high risk group of Helicobacter Pylori infected gastric cancer cases in Asian and Caucasian people.&#x0D; Methods: A total of 130 GC cases and 103 healthy controls from Jichi Medical School, Japan were studied. TNF-α genotype and allele frequency were studied by Restriction Fragment Length Polymorphism (RFLP).&#x0D; Results: Among the study population TNFa-308A was less frequent in Asian people than those of Caucasian. TNFa-238G allele was more frequent in H. pylori positive GC (p&lt;0.036) cases.&#x0D; Conclusion: Findings of the study suggest that TNF-238G polymorphism of TNF-α gene may be closely associated with susceptibility to Helicobacter Pylori infected gastric cancer in Asian patients. This might be due to high cytokine production by TNF-238G allele.

Inflammation-related genes are associated with epigenetic aging in HIV.

Chronic inflammation is characteristic of both HIV and aging ("inflammaging") and may contribute to the accelerated aging observed in people living with HIV (PLWH). We examined whether three inflammation-related single-nucleotide polymorphisms (SNPs) were risk factors for accelerated aging and HIV-associated, non-AIDS (HANA) conditions among PLWH. We examined 155 postmortem cases with HIV (mean age = 47.3, 81% male, 68% self-reported White) from the National NeuroAIDS Tissue Consortium who had pre-mortem neurobehavioral/medical/virologic data and epigenomic data from occipital cortex tissue. Accelerated aging was measured according to the Epigenetic Clock; an aging biomarker based on DNA methylation levels. Past or current age-associated HANA conditions including cerebrovascular, liver and kidney disease, chronic obstructive pulmonary disease, cancer, and diabetes were determined via self-report. Epigenetic Aging Z-scores and likelihood of past/current HANA conditions were compared between major allele homozygotes and minor allele carriers for each SNP (IL-6 - 174G>C, IL-10 - 592C>A, TNF-α - 308 G>A) separately. Analyses were adjusted for relevant demographic/clinical factors. Epigenetic aging (e.g., higher Z-scores) was significantly greater in IL-6 C allele carriers (p = .002) and IL-10 CC homozygotes (p = .02) compared to other genotype groups. The likelihood of any past/current HANA condition did not differ by IL-10 genotype but was 3.36 times greater in IL-6 C allele carriers versus others (OR = 3.36, 95%CI = 1.09-10.34, p = .03). TNF-α genotype was not associated with epigenetic aging or HANA conditions. IL-6 and IL-10 SNPs may help to identify PLWH who are at high risk for accelerated aging. These insights into pathophysiological pathways may inform interventional approaches to treat rapid aging among PLWH.

GENETIC POLYMORPHISM OF TUMOR NECROSIS FACTOR ALPHA (TNF-Α) AND TUMOR NECROSIS FACTOR BETA (TNF-Β) GENES AND RISK OF ORAL PRE CANCER AND CANCER.

Background Inflammatory cytokines such as TNF-α andTNF-β may play a pathogenic role in the development of oral precancerous lesions and oral cancer. Genetic polymorphisms of in these genes are known to predispose to malignant disease. We hypothesized that the risk of oral precancerous lesions and oral cancer might be associated with polymorphisms in these two inflammatory genes. Methodology A total 500 patients with oral pre cancer &cancer and 500 healthy volunteers were genotypes for the TNF-α (-238) G/A and TNF-β (252) A/G gene polymorphism. Genotypes were identified by polymerase chain reaction (PCR) restriction fragment length polymorphism(RFLP). Genotype frequencies were evaluated by Chi-square test. Results Compared to the GG genotype the GA genotype of TNF-α (G238A) polymorphism has been found to significantly increase the risk of oral disease (OR= 1.99) and especially the risk of Lichenplanus and oral malignancy (OR= 2.805 and 5.790 respectively). The risk of overall oral disease, Lichenplanus and oral malignancy were also high with allele A compared to allele G of TNF-α (G238A) polymorphism (OR =1.88, 2.34, 4.42) and respectively). Similarly, the risk of oral disease was also more in the heterzygote (AG) than the common allele homozygote (AA) of TNF-β (A252G) polymorphism (OR= 1.483). Conclusions We conclude that the TNF-α (-238) G/A, TNF-β(252) A/G polymorphism were significantly associated with Oral pre cancer & cancer.

Determination of TNF-a Gene Polymorphisms on Skeletal Pattern in Class II Malocclusion.

Bone development and growth is a non-going, life-long process, varying greatly among individuals and much of this variation could be modulated by genetic factors. The purpose of this study was to evaluate the association between the polymorphisms in the TNF-a gene and skeletal class II malocclusion. Single nucleotide polymorphisms in TNF-a (rs1799724; rs1800629) gene were studied in 79 skeletal class II malocclusion and 102 skeletal class I malocclusion subjects from Straight Wire Group of Studies on Orthodontics and Functional Orthopedics for Maxillary from Rio de Janeiro, Brazil. The Genotyping of these selected polymorphisms was carried out by TaqMan real-time PCR using genomic DNA extracted from buccal cells. All allele and genotype frequencies were compared between the groups using the PLINK® software in a free, in a dominant and in a recessive model using a chi-square test (p≤0.05). There was no significant association of TNF-a (rs1799724; rs1800629) genotype and allele distribution with skeletal class II malocclusion. Regardless of the dominant or recessive genetic model, the preferential genotype associations for rs1799724 and rs1800629 was insignificant. In conclusion, no evidence of association is apparent between genetic polymorphisms involving TNF-a and skeletal class II malocclusion or the position of the maxilla and mandible in the postero-anterior direction.

TNF-α gene polymorphisms: association with age-related macular degeneration in Russian population.

To study polymorphisms in promotor regions of tumor necrosis factor (TNF)-α TNF-863A/C (rs1800630), TNF-308A/G (rs1800629), and TNF-238A/G (rs361525) in patients with age-related macular degeneration (AMD) and associations of complex TNF-α genotypes with AMD. One hundred and two patients (82 women, 20 men; mean age 64.2±1.2y) with AMD and 100 healthy age- and sex-matched controls (82 women, 18 men; 60±1.4y) were included in the study. All subjects were Caucasian, all subjects and their parents were inhabitants of Russia. Genomic DNA was obtained from EDTA-preserved blood using the standard phenol-chloroform method. Polymorphisms were detected by polymerase chain reaction followed by the restriction fragment length polymorphism method. The following TNF-α genotypes were studied: TNF-α-238 AA, GA, GG, TNF-α-308 AA, GA, GG, TNF-α-863 AA, CA, CC. Differences in TNF-α-863 and TNF-α-238 genotypes frequencies in patients with AMD and healthy controls were not found. The distribution of TNF-α-308 AA and TNF-α-308 GA genotypes was significantly different between the studied group and the controls [odds ratios (OR) =0.22, P=0.0287 and OR=2.91, P=0.0063, respectively]. TNF-863CC/TNF-308GA and TNF-308GA/TNF-238GG genotypes were associated with the increased risk of AMD (OR=2.48, P=0.0332 and OR=2.51, P=0.0187, respectively). Five genotypes combinations appeared to be protective. In the present study, single nucleotide polymorphisms and complex polymorphisms of one of the key inflammatory cytokines TNF-α, and a number of significant associations of these polymorphisms with AMD in Russian population have been shown. Complex analysis of genotypes could be important in AMD risk factors detection and studying pathogenesis.

TGF-β1 polymorphism in American tegumentary leishmaniasis in a Southern Brazilian population.

Genetic polymorphisms define the cytokine production leading to susceptibility or resistance to diseases. We studied the cytokine polymorphism in the development of tegumentary leishmaniasis (TL). Genotyping of TNF-α, TGF-β1, IFN-γ, IL-6, and IL-10 were performed by polymerase chain reaction assay. G and C alleles of TGF- β1 (codon 25) were the most common in controls and patients, respectively. G/G was the most frequent genotype in controls, and G/C and C/C in patients. G/G genotype of codon 25 in TGF-β1 appeared to confer resistance, and G/C and C/C genotypes, susceptibility to TL in this population.

Association of the TNF-α -308G/A polymorphism with lipid profile changes in response to aerobic training program

Promoter polymorphism of the tumor necrosis factor-α (TNF-α) gene is associated with obesity-related traits, although the role of its potential modifying effect on changes in obesity-related parameters achieved through a training program is still unknown. The aim of the present study was to examine whether the TNF-α-308G/A polymorphism (rs1800629) influences the effects of a training program. Accordingly, we studied the alleles and genotypes distribution in a group of 168 Polish Caucasian women measured for selected body mass and composition, as well as biochemical parameters before and after the realization of a 12-week aerobic training program. Our results showed that TNF-α genotypes can modulate training-induced biochemical parameter changes such as lipid profile. We demonstrated that carriers of the GG genotype are associated with decreases in post-training high-density lipoprotein cholesterol (HDL-C) levels (p<0.001). Additionally, we revealed that participants with the GG genotype had a higher low-density lipoprotein cholesterol (LDL-C) level (p=0.046) during the entire study period. It could be concluded that harboring the GG genotype of rs1800629 may be considered to be a disadvantageous factor in the context of training-induced effects on lipid profile changes in young female participants.

Genetic variability of the mtDNA control region and the intron of the nuclear gene tumor necrosis factor alpha in graylings, Thymallus

Genetic variability of the mtDNA control region and the intron of the nuclear gene tumor necrosis factor alpha in graylings, Thymallus

Genetic variation of TNF-α and IL-10, IL-12, IL-17 genes and association with torque teno virus infection post hematopoietic stem cell transplantation.

Little is known about the role of genetic variation in the genes for cytokines and susceptibility to viral infection especially torque teno virus (TTV) following allogeneic hematopoietic stem cell transplantation. In this study, the association between interleukin-12, interleukin-17, interleukin-10 (IL-12,-17,-10) and tumor necrosis factor-α (TNF-α) polymorphisms was evaluated in patients with TTV infection who underwent allogeneic hematopoietic stem cell transplantation from South of Iran. The single nucleotide polymorphisms in the cytokine genes including IL-12 (-1188A/C), IL-17 (-197G/A), IL-10 (-1082G/A, -819C/T and -592C/A) and TNF-α (-308 G/A) were analyzed by PCR-RFLP methods. While our results did not show any association between IL-17, IL-12 and IL-10 (-819C/T and -1082G/A) polymorphisms and TTV infection status, heterozygote genotype of IL-10 (-592C/A) had direct correlation with TTV infection and A allele of TNF-α (-308G/A) showed a protective effect against TTV infection (P=0.05 and P=0.025, respectively). Within the group of patients who experienced acute graft-versus-host disease, the AA genotype and the A allele of IL-17 (-197 G/A) were significantly higher in non-infected patients compared to infected ones (P=0.024 and P=0.057, respectively). It was also observed that among infected patients, the GG genotype of IL-17 and AA genotype of TNF-α were significantly increased in hematopoietic stem cell transplanted patients with low grade (grade I+II) acute graft-versus-host disease compared to high grade (grade III and IV) disease (P=0.056 and P=0.056, respectively). Taken together, genetic variation of IL-10 (-592C/A) and TNF-α (-308G/A) genes might be associated with susceptibility to TTV infection post hematopoietic stem cell transplantation. Keywords: TNF-α; interleukins; torque teno virus (TTV); hematopoietic stem cell transplantation (HSCT); graft versus host disease (GvHD).

The association gene’s TNFα G(308) with quantity of TNFα and degree of liver’s fibrosis in patients with chronic hepatitis C

The data on the polymorphism of cytokine genes associated with individual reactivity on the effects of hepatitis C virus, predict the rate of progression of liver fibrosis. The purpose of this work is study the association of the polymorphic marker G308A of the TNFα gene with its quantitative content and degree of liver fibrosis in patients with chronic hepatitis C. A total of 100 patients with CSF were examined. The polymorphism of G308A gene’s TNFα was studied by amplification of the corresponding genome zones by PCR. The assessment of the degree of fibrosis was performed using the non-invasive Fibrotest method. The study of the quantity of TNFα cytokine in serum of patients was performed by ELISA. The distribution of genotypes on the investigated polymorphic loci was verified using Pearson's χ2 criterion. The frequencies of alleles and genotypes in the groups were compared using Pearson's χ2 criterion with Yates correction for continuity with the number of degrees of freedom 1. In order to detect the correlation dependencies between the individual parameters, the Spearman correlation coefficient was applied. It was found that a smaller degree of fibrosis was observed in carriers of the GG TNFα genotype, and a greater degree of fibrosis in the carriers of the genotype AA TNFα (moderate feedback between the degree of fibrosis and the genotypes of TNFα). The higher content of TNFα is noted in the carriers of the AA genotype TNFα, the lower content of TNFα - in the carriers of the GG TNFα genotype (moderate feedback between the TNFα genotypes and the TNFα content). It has been established that a higher TNFα content is observed in patients with F1-F0 fibrosis, a lower TNFα content in patients with F2-F3 fibrosis (a strong correlation between the degree of fibrosis and the amount of TNFα cytokine). It is assumed that the production of the cytokine is determined at the genetic level, and the severity of changes in the cytokine profile in chronic hepatitis C affects the course of the pathological process. An increase in the TNFα content in chronic hepatitis C may be a marker for significant morphological changes in the hepatic tissue and high activity of the inflammatory process.

Genotypes of the genes of vegf, tnf-a and tnf-b in patients with bladder cancer in the t1n0m0 stage and their association with the degree of neoplasia of the tumor

36 patients with bladder cancer in the T1N0M0 stage were selected in the study Of the 36 patients, there were 20 men and 16 women. The age of men was 57.1±5.0, women 54.2± 5.1 years. Thirty healthy individuals constituted a control group, gender characteristics and age consistent with those of patients with bladder cancer. 36 patients with RSM G1 were diagnosed in 2 patients, G2 in 30 patients, G3 in 4 patients. The ratio of GG / GC / CC GEG / GC / CC gene of VEGF patients to the C-r bladder in the T1 stage was 46.7% / 40.1% / 13.3%, in the group of healthy subjects 43.3% / 46.7% / 10%. The ratio of the genotypes of the GC / GA / AA gene of TNF-a to patients with C-r bladder in the T1 stage is 43.75% / 56.25% / 0% in the group of healthy subjects, 43.3% / 46% / 10%. The ratio of TT / TC / SS genotypes of the TNF-b gene in patients with C-r bladder in the T1 stage is 12.5% †/ 56.2% / 31.25%, respectively, in healthy 13.3% / 50% / 36.7%. Of the 36 patients with Cr with bladder Cr in the T1 stage, 83.3% of patients showed G2 neoplasia, 11.1% found G3 neoplasia and 5.5% G1 in G1 patients. With T1G2 bladder cancer, the GG VEGF genotype was detected in 40 % of patients, GC in 26.7%, TNF-a genotype and GA were detected in 50% of patients, GG at 31.25%, and TNF-b gene genotype 43.7% and CC in 25% of patients.

TNFα −857 C/T and TNFR2 +587 T/G polymorphisms are associated with cystic fibrosis in Iranian patients

Identification of modifier genes influencing phenotype of cystic fibrosis (CF) patients has become a challenge in CF pathophysiology, prognostic estimations and development of new therapeutic strategies. The aim of this study was to explore the association between four genetic polymorphisms of three modifier genes with CF, by comparing their alleles, genotypes and haplotype frequencies in patients and controls. In this favor, two regulatory polymorphic loci in TNFα promoter (−857C/T, rs1799724 and -238A/G, rs361525) and two functional polymorphic loci in TNFR1 (+36A/G, rs767455) and TNFR2 (+587T/G, rs1061622) were genotyped in 70 patients and 79 controls, using PCR-RFLP. Clinical pulmonary data were also recorded from all studied patients. Results indicated that an association was observed between both T allele and CT/TT genotypes of TNFα (P = 0.0005, OR = 7.06, 95% CI = 3.71–13.45) with CF under dominant model of inheritance. GG genotype of TNFR2 +587 (P = 0.0005, OR = 4.92, 95%CI = 2.34–10.34) was significantly associated with CF using recessive model. Consistently, more severe pulmonary disorder was found for patients carrying either T dominant allele of TNFα −857 or GG genotype of TNFR2 +587 polymorphic sites. Despite an association of A-T and G-T haplotypes with CF, no significant association was found between these haplotypes and clinical parameters of CF. Overall, TNFα −857 T allele and GG genotype of TNFR2 +587 were more frequent in CF patients compared to healthy controls and hence, they showed an association with CF and severe pulmonary phenotype in Iranian patients.

Role of Adipokines in Development of Metabolic Syndrome

Visceral adipose tissue releases a variety of adipokines which together determine a comprehensive cardiometabolic risk profile. Estrogen deficiency leads to central fat deposition in postmenopausal women. However, premenopausal women are also running high risk of central obesity owing to unhealthy lifestyles, making them prone to development of metabolic syndrome which leads to infertility, polycystic ovary syndrome (PCOS), insulin resistance, and type 2 diabetes (T2D). Premenopausal women with (n=30) and without (n=30) central obesity were studied. Metabolic risk factors and circulatory adipokines were measured. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Adipokines' gene polymorphisms were studied by polymerase chain reaction and mRNA expression of leptin, adiponectin, resistin, and interleukin-6 (IL-6). Tumour necrosis factor-α (TNF-α), acylation stimulating protein (ASP) receptor gene (C5L2) were done by real time-polymerase chain reaction in visceral (VAT) and subcutaneous (SAT) adipose tissues was also obtained. Significant high circulating leptin, IL-6, TNF-α, resistin and their VAT mRNA expression and significant low circulating adiponectin and VAT mRNA expression were found in women with metabolic syndrome, irrespective of their menopausal status. Carriers of mutant genotype of TNF-α 308 AA, IL-6 174 CC, resistin 420 GG, leptin 2549 AA, adiponectin 276 TT and C5L2 698 CT had significant association with metabolic syndrome. Conclusively changes in fat distribution modulate the secretion profile of adipokines, therefore elevated circulating leptin, IL-6, TNF-α, ASP, resistin, and low adiponectin may serve as surrogate markers for metabolic syndrome and related morbidities in women with central obesity.

342. Association between Tumor Necrosis Factor Alpha (TNF-α) polymorphisms and haplotypes and preeclampsia risk

Introduction Preeclampsia is a multi-system disorder of pregnancy characterized by hypertension and proteinuria. Excessive release of pro-inflammatory cytokines, particularly tumour necrosis factor alpha (TNF-α) has been demonstrated to contribute to endothelial activation and default of trophoblasts invasion that result in the clinical symptoms of preeclampsia. Genetic polymorphisms of TNF-α could regulate its production and may play an important role in the pathogenesis of this disease. Objective/hypothesis The aim of this study was to evaluate the association of five different TNF-α gene promoter single nucleotide polymorphisms (SNPs), or their haplotype combinations, with the development of preeclampsia. Methods This a case-control study conducted on 300 women with PE and 300 age-matched women with normal pregnancy from Tunisian hospitals. Genotyping of TNF-α −1031T/C, −376G/A, −308G/A, −238G/A, and + 488C/T SNPs was performed on DNA extracted from blood samples. TNF-α genotyping was assessed using PCR-restriction fragment-length polymorphism (RFLP) analysis. Statistical analysis was performed using the chi-square test. P values less than 0.01 were considered statistically significant. Results Our results demonstrated a higher frequency of the minor allele − 1031C (p ⧹ A is associated with lower systolic blood pressure while the minor allele is associated with increased diastolic blood pressure. Discussion These results demonstrate that TNF-α polymorphisms, in particular − 1031C/A and − 376 G/A, are significantly associated with preeclampsia. In addition, we found a protective effect of the major allele G of − 308 G ⧹ A SNP on systolic blood pressure while increased diastolic blood pressure can be found in carriers of the minor allele A.

Lack of Association Between TNF-α, IFN-γ, IL-10 Gene Polymorphisms and Rheumatic Heart Disease in South Indian Population

Background: Proinflammatory and anti-inflammatory cytokines play a crucial role in the development and maintenance of immune mediated inflammatory diseases including rheumatic heart disease (RHD). Polymorphisms in tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-10 genes influence the differential cytokine expression as well as the pathogenesis of various inflammatory and autoimmune diseases. Objective: The aim of the study is to investigate the association between TNF-α, IFN-γ, and IL-10 gene polymorphisms and RHD in South Indian population. Materials and Methods: TNF-α (–308, –238), IFN-γ (+874), and IL-10 (–1082, –819, –592) gene polymorphisms were determined in 100 patients with RHD and 127 healthy siblings by PCR. Results: There was no significant difference in the genotype, allele, and haplotype frequencies of TNF-α, IFN-γ, and IL-10 polymorphisms between RHD patients and healthy siblings. Conclusion: The present study suggests that TNF-α, IFN-γ, and IL-10 gene variants may not be associated with the development of RHD in South Indian population.