Promoter Polymorphism Research Articles

CCR5 promoter region polymorphisms in systemic lupus erythematosus.

This study investigated the impacts of CCR5 promoter region polymorphisms on the development of systemic lupus erythematosus (SLE) by comparing CCR5 genotypes and haplotypes from SLE patients with ethnically matched controls. A total of 382 SLE patients (289 European-derived and 93 African-derived) and 375 controls (243 European-derived and 132 African-derived) were genotyped for the CCR2-64I G>A (rs1799864), CCR5-59353 C>T (rs1799988), CCR5-59356 C>T (rs41469351), CCR5-59402 A>G (rs1800023) and CCR5-59653 C>T (rs1800024) polymorphisms through polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Previous data from CCR5Δ32 analysis was included in the study to infer the CCR5 haplotypes and as a possible confounding factor in the binary logistic regression. European-derived patients showed a higher frequency of CCR5 wild-type genotype (conversely, a reduced frequency of Δ32 allele) and a reduced frequency of the HHG*2 haplotype compared to controls; both factors significantly affecting disease risk [p=.003 (OR 3.5, 95%CI 1.6-7.5) and 2.0% vs. 7.2% (residual p=2.9E-5), respectively]. Additionally, the HHA/HHB, HHC and HHG*2 haplotype frequencies differed between African-derived patients and controls [10% vs. 20.5% (residual p=.003), 29.4% vs. 17.4% (residual p=.003) and 3.9% vs. 0.8% (residual p=.023), respectively]. Considering the clinical manifestations of the disease, the CCR5Δ32 presence was confirmed as a susceptibility factor to class IV nephritis in the African-derived group and when all patients were grouped for comparison [pcorrected =.012 (OR 3.0; 95%CI 3.0-333.3) and pcorrected =.0006 (OR 6.8; 95%CI 1.9-24.8), respectively]. In conclusion, this study indicates that CCR5 promoter polymorphisms are important disease modifiers in SLE. Present data reinforces the CCR5Δ32 polymorphism as a protective factor for the development of the disease in European-derived patients and as a susceptibility factor for class IV nephritis in African-derived patients. Furthermore, we also described a reduced frequency of HHA/HHB and an increased frequency of HHC and HHG*2 haplotypes in African-derived patients, which could modify the CCR5 protein expression in specific cell subsets.

CCR5 promoter polymorphisms associated with nonsmall cell lung cancer.

C-C chemokine receptor 5 (CCR5) plays a crucial role in the regulation of immune cell activation and migration as well as the progression of many cancers. We performed an in silico analysis using public data resources and found that the lung cancer patients with higher CCR5 expression had a notably better overall survival than those with lower CCR5 expression patients and CCR5 expression level is positive correlated with the infiltration of immune cells, such as B, CD8+ T and CD4+ T cells, in both lung adenocarcinoma and lung squamous cell cancer. In the present study, we investigated the association between the promoter polymorphism of CCR5 and nonsmall cell lung cancer (NSCLC). A case-control study of 449 NSCLC patients and 516 controls of Chinese Han population was conducted, along with polymorphism detection using a sequencing method. A dual-luciferase reporter assay system was used to analyse the transcriptional activity of CCR5 promoter variations. Our results showed that the frequency of rs1799987-AA was significantly higher in the NSCLC group than in the controls in recessive model (p=.007, OR=1.66 95% confidence interval [CI]: 1.14-2.40, adjusted by sex and age); the G allele showed a significant associated with NSCLC in dominant model (p=.003, OR=1.64, 95%CI: 1.18-2.28, adjusted by sex and age). Compared with haplotype H1 rs2227010-rs2734648-rs1799987-rs1799988-rs1800023-rs1800024: A-T-G-T-G-C, haplotype H5: A-G-G-T-G-C increased the risk of NSCLC by over 10-fold (p<.0001, OR=16.09, 95%CI: 5.37-48.20, adjusted by sex and age) and notably depressed the transcriptional activity of the CCR5 promoter in 293T, A549, H1299 and HeLa cells. In conclusion, CCR5 promoter polymorphisms are significantly associated with NSCLC by affecting the transcriptional activity of the CCR5 promoter.

Frequency Evaluation of the Interleukin-6 -174G>C Polymorphism and Homeostatic Iron Regulator (HFE) Mutations as Disease Modifiers in Patients Affected by Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Autoimmune diseases are generally characterized by a multifactorial etiology and are often associated with a genetic predisposition. Both iron metabolism and the inflammatory cytokine system have been shown to play a pivotal role in the dysregulation of the immune response in many different autoimmune conditions, rheumatologic diseases included. The purpose of this work was to analyze the frequency of mutations altering the expression of IL-6 or influencing iron metabolism in patients affected by autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). In this study, 144 patients were enrolled: 77 and 67 patients were affected by RA and SLE, respectively. In these cohorts, the frequency of the IL-6 polymorphism -174G>C located in the IL-6 gene promoter was tested. Moreover, the frequencies of the three HFE gene variations associated with iron overload were analyzed: p.His63Asp, p.Ser65Cys and p.Cys282Tyr. The two mutations p.His63Asp and p.Ser65Cys in the HFE gene did not reach statistical significance in any of the comparisons, regardless of the statistical model, cohorts of patients and control populations analyzed. The frequencies of the p.Cys282Tyr mutation and the IL-6 polymorphism -174G>C were found to be overall significantly decreased in RA and SLE patients when the Dominant model and Allele contrast were adopted with both the Odds Ratio and Chi-square. Although further investigation is needed, the examination of the frequencies of the -174G>C IL-6 promoter polymorphism and HFE mutations may add some valuable information on the interplay linking iron metabolism, inflammation and immunity in autoimmune diseases such as SLE and RA.

Interleukin-10 promoter polymorphisms and haplotypes in patients with Guillain-Barré syndrome.

Interleukin-10 (IL-10) is a multifunctional cytokine that exerts both pro- and anti-inflammatory effects on the immune system as well as in the pathogenesis of Guillain-Barré syndrome (GBS). We investigated whether the three common polymorphisms -1082 G/A(rs1800896), -819 C/T(rs1800871), and -592 C/A(rs1800872) in the promoter region of IL-10 have any influence on the susceptibility, severity, and clinical outcome of GBS. IL-10 promoter polymorphisms were investigated in 152 patients with GBS and 152 healthy controls from Bangladesh using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP), and allele-specific oligonucleotide-PCR (ASO-PCR). Haplotype patterns and frequencies were analyzed using Heatmaply R-package, chi-square, and Fisher's exact test. The serum level of IL-10 was measured through enzyme-linked immunosorbent assays. p-values < 0.05 were considered statistically significant. IL-10 promoter polymorphisms -1082 G/A, -819 C/T, and -592 C/A were not associated with GBS susceptibility. The homozygous -819 TT genotype showed a tendency with susceptibility (p = 0.029; pc = 0.08) and was prevalent in axonal variants of GBS compared to demyelinating subtypes and controls (p = 0.042, OR = 8.67, 95% CI = 1.03-72.97; pc = 0.123 and p = 0.005, OR = 4.2, 95% CI = 1.55-11.40; pc = 0.015, respectively). Haplotype analysis revealed 19 patterns of genotypes and high IL-10 expression haplotype combinations (GCC/GTA, GCC/ATA, and GCC/GCA) may have influence on disease severity (p = 0.026; pc = 0.078). Serum expression of IL-10 was elevated in GBS patients ([GBS, 12.16 ± 45.71] vs. [HC, 0.65 ± 5.17] pg/mL; p = 0.0027) and varied with disease severity ([severe-GBS, 15.25 ± 51.72] vs. [mild-GBS, 3.59 ± 19.79] pg/mL, p = 0.046). The -819 TT genotypes influence axonal GBS, and high frequency of IL-10 expression haplotype combination with elevated serum IL-10 may play an important role in disease severity.

Insulin-like growth factor binding protein 3 promoter variant (rs2854744) is associated with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and a growing global epidemic. In NAFLD, liver fat surpasses 5% of hepatocytes without the secondary causes of lipid accumulation or excessive alcohol consumption. Given the link between NAFLD and insulin resistance, the possible association between the rs2854744 (-202 G>T) promoter polymorphism of insulin-like growth factor binding protein 3 (IGFBP3) gene and NAFLD was investigated in this study. In this genetic case-control association study, the IGFBP3 rs2854744 genotypes of 315 unrelated individuals, including 156 patients with biopsy-proven NAFLD and 159 controls, were determined using polymerase chain reaction/restriction fragment length polymorphism analyses. The "GT+TT" genotype of the IGFBP3 rs2854744 polymorphism, compared with the "GG" genotype, was associated with a 2.7-fold increased risk of NAFLD after adjustment for confounding factors (P = 0.009; odds ratio [OR] = 2.71; 95% confidence interval [CI] = 1.19-3.18). Additionally, the IGFBP3 rs2854744 "T" allele, in comparison with the "G" allele, was significantly overrepresented in NAFLD patients than the controls (P = 0.008; OR = 1.85; 95%CI = 1.23-2.94). Our findings first indicated that the IGFBP3 rs2854744 "GT+TT" genotype is a marker of increased NAFLD susceptibility; however, it needs to be supported by further investigations in other populations.

Investigation of Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G promoter polymorphism and other thrombophilia genes in patients with acute pulmonary embolism

Abstract Background Venous thromboembolism (VTE) is a serious threat to life and health, commonly known as the silent killer. Recent study has found that VTE is a polygenetic disease and more than 60% of deep vein thrombosis risk is influenced by genetic factors [1]. PAI-1 is a serine protease with negative feedback to fibrinolysis, activating and inhibiting coagulation [2]. The aim of this study was to elucidate the clinical impact of the PAI-1 4G/5G polymorphism and other thrombophilia in patients with acute PE. Methods A total of 58 subjects with acute PE and 60 healthy controls, were recruited in Institute of Cardiology. The accuracy of the RT-PCR method for detecting F5 G1691A (FVL) and PAI-1 4G/5G polymorphisms was evaluated by using sequencing method as the gold standard. Moreover, the association of the PAI-1 4G/5G polymorphism with susceptibility, treatment efficacy and recurrence status were explored. Eventually, we evaluated the association with inherited thrombophilia genes, such as the coagulation Factor V Leiden, prothrombin G20210A, FGB-455 G/A and methylenetetrahydrofolate reductase C677T and 1298 A/C. Results It was noted that the vast majority of patients with acute PE (87.9%) present polymorphism in the PAI-1 gene (29.3% homozygous (4G/4G) and 58.6% heterozygous (5G/4G)). Eleven patients out of 58 (19% of patients) showed factor V Leiden mutation and 19 patients out of 58 (32,7% of patients) showed mutation in FGB-455 G/A (2 homozygotes); MTHFR C677T gene mutation was found in 55,2%, while prothrombin 20210A gene mutation was presented in 6 patients (10.3% of patients). Nine patients (15,5% of patients) presented with chronic complication of VTE and 38.7% of patients showed recurrent pulmonary embolism. More than a half of patients (51.9%) had multiple gene mutation and only one presented with mutations in three studied genes. It showed a significant difference in the occurrence of other thromboses in the body and significant increase in the recurrence of pulmonary embolism and residual complications in these patients. It was also observed that individuals with the 4G/5G genotype had lower neutrophil counts and neutrophil-to-lymphocyte ratio (NLR) than the 5G/5G genotype. Furthermore, it was underlined that the patients with the 5G/5G genotype were more likely to achieve complete recanalization compared to the 4G/4G genotype. Individuals carrying the 5G/5G genotype were more likely to develop a recurrence-free status as compared to those with the 4G/4G or 4G/5G genotypes. PAI-1 antigen levels in the VTE group were significantly higher than those in the HC group. Conclusion The PAI-1 4G/5G polymorphism has potential value in assessing the prognosis of patients with VTE. This study has laid the foundation for the application of PAI-1 4G/5G polymorphism in the personalized management and monitoring of patients with VTE. According to this study results PAI-1 4G/5G polymorphism could be included in laboratory testing panel of thrombophilia.

TPO Gene Expression in Relation with Promoter SNPs in Iraqi Patients with Hyperthyroidism

Background: Thyroid peroxidase (TPO) gene mutations are one of the most common causes of thyroid disorders. Objective: To investigate the effect of genetic polymorphisms in the TPO promoter region on gene expression in early-diagnosed hyperthyroid patients. Methods: Genomic DNA was extracted from 100 blood samples (75 hyperthyroid patients and 25 healthy controls), then the TPO promoter region was amplified and sequenced for genotyping rs2071399, rs2071400, and rs2071403 SNPs. Total RNA was also isolated, and cDNA synthesis was performed to determine quantitatively the expression of TPO by using qPCR. The level of TPO antibodies in serum was determined by using an enzyme-linked immunosorbent assay (ELISA). Results: The prevalence of hyperthyroidism in women was significantly higher than in men, as were serum levels of TPO-Abs. There was a significant increase in serum TPO-Abs in hyperthyroid patients (235.29 IU/ml) compared with healthy controls. Genotypes of three SNPs (rs2071399 G/A, rs2071400 C/T, and rs2071403 A/G) in the TPO promoter region were TPO rs2071399 AG and GG, and rs2071400 CT and TT genotypes were more frequent in hyperthyroid patients. There are no significant differences between rs2071403 polymorphic and non-polymorphic genotypes among hyperthyroid patients and healthy controls. The rs2071399 G/A and rs2071400 C/T gene promoter polymorphism significantly down-regulated constitutive TPO gene expression in hyperthyroid patients, but rs2071403 A/G has no major effect on gene expression. Conclusion: There was an association between the mutation in the promoter region of TPO and the incidence of hyperthyroidism.

Design and deep learning of synthetic B-cell-specific promoters.

Synthetic biology and deep learning synergistically revolutionize our ability for decoding and recoding DNA regulatory grammar. The B-cell-specific transcriptional regulation is intricate, and unlock the potential of B-cell-specific promoters as synthetic elements is important for B-cell engineering. Here, we designed and pooled synthesized 23640 B-cell-specific promoters that exhibit larger sequence space, B-cell-specific expression, and enable diverse transcriptional patterns in B-cells. By MPRA (Massively parallel reporter assays), we deciphered the sequence features that regulate promoter transcriptional, including motifs and motif syntax (their combination and distance). Finally, we built and trained a deep learning model capable of predicting the transcriptional strength of the immunoglobulin V gene promoter directly from sequence. Prediction of thousands of promoter variants identified in the global human population shows that polymorphisms in promoters influence the transcription of immunoglobulin V genes, which may contribute to individual differences in adaptive humoral immune responses. Our work helps to decipher the transcription mechanism in immunoglobulin genes and offers thousands of non-similar promoters for B-cell engineering.

The transcription factor MYB110 regulates plant height, lodging resistance, and grain yield in rice.

The high-yielding Green Revolution varieties of cereal crops are characterized by a semidwarf architecture and lodging resistance. Plant height is tightly regulated by the availability of phosphate (Pi), yet the underlying mechanism remains obscure. Here, we report that rice (Oryza sativa) R2R3-type Myeloblastosis (MYB) transcription factor MYB110 is a Pi-dependent negative regulator of plant height. MYB110 is a direct target of PHOSPHATE STARVATION RESPONSE 2 (OsPHR2) and regulates OsPHR2-mediated inhibition of rice height. Inactivation of MYB110 increased culm diameter and bending resistance, leading to enhanced lodging resistance despite increased plant height. Strikingly, the grain yield of myb110 mutants was elevated under both high- and low-Pi regimes. Two divergent haplotypes based on single nucleotide polymorphisms in the putative promoter of MYB110 corresponded with its transcript levels and plant height in response to Pi availability. Thus, fine-tuning MYB110 expression may be a potent strategy for further increasing the yield of Green Revolution cereal crop varieties.

Investigating Association Level of CXCL12 with its SDF-1α 3'A Genetic Variant and CXCL10 with its 1443 Promoter Polymorphism in Type-1 Diabetes.

Type-1 Diabetes Mellitus (T1DM) is an autoimmune and heterogeneous disorder. In the present study, we aimed to examine whether there exists an association between serum CXCL10 (IP-10) level and its promoter polymorphism at position-1443 along with CXCL12 and its known SDF-1 3' A genetic variant as an angiogenesis chemokine in T1DM patients. Blood specimens were collected from 209 unrelated T1DM patients and 189 healthy subjects. The DNA samples were extracted from the subjects and analyzed for CXCL10 and CXCL12 polymorphisms using PCR-RLFP. The serum concentrations of CXCL10 and CXCL12 were also analyzed with ELISA. Following expert opinion and data analysis, we found significant differences between A/A, A/G, and G/G genotypes with A and G alleles of polymorphisms at position +801 (SDF-1α3'A) in CXCL12. No association was reported between CXCL10/-1443 promoter polymorphism and T1DM. In our assessment of promoter polymorphism, both T1DM patients and controls had GG genotypes in CXCL10/-1443. When patients were compared with controls, both serum CXCL10 and CXCL12 levels were found to be increased in type 1 diabetes with complications. Levels were not increased in patients without complications. Both CXCL10 and CXCL12 play fundamental roles in T1DM pathogenesis. Only the CXCL12 3'A (SDF-1α3'A) polymorphism is possibly necessary for the pathogenesis of T1DM, while the CXCL10-1443 promoter polymorphism is not.

PO32 Investigation of Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G Promoter Polymorphism and Other Thrombophilia in Patients with Acute Pulmonary Embolism: A Case-Control Study

PO32 Investigation of Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G Promoter Polymorphism and Other Thrombophilia in Patients with Acute Pulmonary Embolism: A Case-Control Study

Study on association of nuclear factor kappa B gene polymorphism with bacterial load in pulmonary tuberculosis

Objectives: Pulmonary tuberculosis (PTB) is a leading infectious disease and a major public health concern. Out of susceptible genes, nuclear factor kappa B (NF-κB) gene influences inflammation and hence the progression of the disease. A single nucleotide polymorphism of functional NF-κB1 promoter −94 ins/del ATTG (rs28362491) has a regulatory effect on the NF-κB1 gene. The aim of our study was to ascertain the bacterial load and to find the association with NF-κB gene polymorphism. Methodology: One hundred two diagnosed and microbiologically confirmed cases of PTB patients between 18 and 69 years of age and 102 healthy age, sex, and socioeconomic status–matched volunteers were taken as controls. Sputum from cases and blood samples from cases and controls were collected. Bacterial load estimation was done from the sputum sample. Genomic deoxyribonucleic acid (DNA) was extracted for NF-κB gene. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were performed. Results: The genotypic frequency of ins/del was found to be 54.9% in PTB patients which was more than that of the other genotype frequencies in the case group and also from the control genotype frequencies, although it was found to be insignificant (P value = 0.098). On analysis of bacterial load with NF-κB gene polymorphism, a significant association was found more particularly for ins/del versus del/del. Conclusion: The bacterial load showed significant variation among the del/del genotype, ins/del genotype, and ins/ins genotype which was statistically significant. The del/del genotype exhibited the highest bacterial load in and greater statistical significance was found between ins/del and del/del genotypes. This implies the association between NF-κB gene polymorphism and bacterial load.

Causal role of a promoter polymorphism in natural variation of the Arabidopsis floral repressor gene FLC

Noncoding polymorphism frequently associates with phenotypic variation, but causation and mechanism are rarely established. Noncoding single-nucleotide polymorphisms (SNPs) characterize the major haplotypes of the Arabidopsis thaliana floral repressor gene FLOWERING LOCUS C (FLC). This noncoding polymorphism generates a range of FLC expression levels, determining the requirement for and the response to winter cold. The major adaptive determinant of these FLC haplotypes was shown to be the autumnal levels of FLC expression. Here, we investigate how noncoding SNPs influence FLC transcriptional output. We identify an upstream transcription start site (uTSS) cluster at FLC, whose usage is increased by an A variant at the promoter SNP-230. This variant is present in relatively few Arabidopsis accessions, with the majority containing G at this site. We demonstrate a causal role for the A variant at -230 in reduced FLC transcriptional output. The G variant upregulates FLC expression redundantly with the major transcriptional activator FRIGIDA (FRI). We demonstrate an additive interaction of SNP-230 with an intronic SNP+259, which also differentially influences uTSS usage. Combinatorial interactions between noncoding SNPs and transcriptional activators thus generate quantitative variation in FLC transcription that has facilitated the adaptation of Arabidopsis accessions to distinct climates.

Association of VEGF-116G/A Promoter Polymorphism with Esophageal Cancer Risk: A Case-Control study and an Updated Meta-Analysis on Gastrointestinal Tract Cancers.

The present study aimed to investigate the potential association of VEGF-116G/A promoter polymorphism with esophageal cancer risk in North-West Indians and to perform a comprehensive meta-analysis of VEGF-116G/A polymorphism in Gastrointestinal Tract (GIT) cancers. A total of 679 DNA samples (333 esophageal cancer patients and 346 healthy controls) were genotyped for VEGF-116G/A polymorphism using Sanger sequencing. In silico analysis was carried out to predict the impact of VEGF-116G/A polymorphism on transcription factor binding sites. Ten studies including 2157 patients and 2307 controls on different GIT cancers were included in the meta-analysis. Results: The AA genotype and A allele of VEGF -116G/A polymorphism was significantly associated with an increased risk of esophageal cancer. In silico analysis predicted that A allele of VEGF-116G/A polymorphism created new binding sites for STAT4, c-Ets-1 and Elk-1 transcription factors. The meta-analysis results showed that VEGF-116G/A polymorphism was associated with an increased risk of GIT cancer under the recessive and AA vs GG genetic model in the overall population. Stratification of the studies by ethnicity revealed an increased risk of GIT cancers in Asians under allele contrast, recessive, AA vs GG and AA vs AG model. Analysis based on cancer type revealed an increased risk of esophageal cancer under allele contrast, recessive, AA vs GG and AA vs AG comparison model and increased risk of oral cancer was observed under the allele contrast model and dominant model. VEGF-116G/A polymorphism was associated with esophageal cancer risk in North- West Indians. The findings of the present meta-analysis showed a significant association of VEGF-116G/A polymorphism with GIT cancer risk.

CLL-268 Frequency of MDM2 Promoter Polymorphism del1518 (rs3730485) and its Correlation With Clinic-Haematological Features and Treatment Response in Chronic Lymphocytic Leukemia in Sudanese Patients

CLL-268 Frequency of MDM2 Promoter Polymorphism del1518 (rs3730485) and its Correlation With Clinic-Haematological Features and Treatment Response in Chronic Lymphocytic Leukemia in Sudanese Patients

Investigation of MIF gene promoter variations and their haplotypes in the Alzheimer disease in Turkish population

In Alzheimer’s disease, which is characterized by amyloid plaques and neurofibrillary tangles in the brain tissue, many components such as acute phase proteins, cytokines, and proteases contribute to the progression of the disease or are part of the pathological process. The macrophage migration inhibitory factor (MIF) gene encodes a cytokine, which is secreted by lymphocytes, and has a role in the pathogenesis of autoimmune/inflammatory diseases such as rheumatoid arthritis. The purpose of this study to investigate the association between Alzheimer disease and MIF gene promoter polymorphisms. The 205 patients with Alzheimer disease (AD) and 130 age-sex matched healthy individuals were investigated in terms of MIF -173 G/C and MIF −794 CATT polymorphisms. The genotyping of MIF -173 G/C was determined using the RT-PCR method. MIF-794 CATT polymorphism was analyzed using PCR and DNA Sequencing. In terms of binary genotypes and haplotypes, the 5/5-GC (p = 0.004), 6/7-GG (p = 0.02) and, 6/6-GG (p = 0.026) binary genotypes, and 5-C (p = 0.003), 7-G (p = 0.026) and 6-G (p = 0.025) haplotypes were differed significantly between the patients and the controls. This is the first study investigating the relationship between AD and MIF in terms of different genotypes, haplotypes and, alleles. The fact that the binary genotype and allele distributions are significantly different between the patient and control group, suggests that this MIF variants may play a role in the pathogenesis of AD.

Polymorphism Detection of VKORC1 (Vitamin K Epoxide Reductase Complex, Subunit 1) Gene for Warfarin Dose Adjustment in Egyptian Patients with Budd Chiari and/or Portal Vein Thrombosis: A Single Center Experience

Background Budd–Chiari syndrome is a heterogeneous group of disorders characterized by hepatic venous outflow obstruction at the level of the hepatic venules, the large hepatic veins, the inferior vena cava till its junction with the right atrium. The classic triad of abdominal pain, ascites, and hepatomegaly is observed in the vast majority of patients with Budd-Chiari syndrome, but it is nonspecific. Warfarin was introduced into clinical practice in the 1950s, and has been the most widely prescribed oral anti-coagulant for prevention and treatment of thrombotic diseases despite its significant side effects as (bleeding tendency, drug drug interaction). Vitamin K epoxide reductase complex subunit1 (VKORC1), a membrane protein located in hepatocytes, has an important role in the anabolism of vitamin K, which is essential for blood coagulation. Objectives The aim beyond this study is to evaluate effect of the allelic frequency of the VKORC1 (G1639A) polymorphic genes by real time PCR on response of Egyptian patients with Budd–Chiari syndrome or PVT to Warfarin. Patients and Methods The studied patients were selected from patients presented to Budd chiari study group clinic.tropical medicine department in Ain Shams University hospitals. Within 6 months from july 2020 to December 2020, total number of cases during the study period was 50 cases fulfilling the inclusion criteria Results The mean age of the patients was (32.40 ± 9.69) slightly more common in males. The chronic presentation represented 60% of the patients and the acute represented 32%.The most common cause of budd chiarri syndrome was MTHFRD (52%) followed by FVLM (36%) then Primary ant phospholipid antibody syndrome (26%). Patients with the −1639 promoter polymorphism GG genotype had lower dose requirements, whereas the AG/AA genotypes had higher dose. Conclusion Identifying these polymorphisms in patients prior to starting the therapy may help clinicians choose the appropriate warfarin dose &amp; decrease its adverse effects.

Race-specific association of an IRGM risk allele with cytokine expression in human subjects

Immunity-related GTPase family M (IRGM), located on human chromosome 5q33.1, encodes a protein that promotes autophagy and suppresses the innate immune response. The minor allele of rs13361189 (−4299T>C), a single nucleotide polymorphism in the IRGM promoter, has been associated with several diseases, including Crohn’s disease and tuberculosis. Although patterns of linkage disequilibrium and minor allele frequency for this polymorphism differ dramatically between subjects of European and African descent, studies of rs13361189 have predominantly been conducted in Europeans and the mechanism of association is poorly understood. We recruited a cohort of 68 individuals (30 White, 34 African American, 4 other race) with varying rs13361189 genotypes and assessed a panel of immune response measures including whole blood cytokine induction following ex vivo stimulation with Toll-like Receptor ligands. Minor allele carriers were found to have increased serum immunoglobulin M, C-reactive protein, and circulating CD8+ T cells. No differences in whole blood cytokines were observed between minor allele carriers and non-carriers in the overall study population; however, minor allele status was associated with increased induction of a subset of cytokines among African American subjects, and decreased induction among White subjects. These findings underline the importance of broad racial inclusion in genetic studies of immunity.

Association of IL6 and IL10 gene promotor polymorphisms with susceptibility to acute necrotizing encephalopathy.

Acute necrotizing encephalopathy (ANE) is a severe complication of infectious diseases affecting the brain and systemic organs. The main pathogenesis is cytokine storm, in which interleukin-6 (IL-6) and interleukin-10 (IL-10) are candidates for key cytokines. To further elucidate their roles in the etiology and pathogenesis of ANE, we studied polymorphisms in the promotor regions of the IL6 and IL10 genes by genetic and functional analyses. We first conducted a case-control association study of four IL6 and three IL10 polymorphisms. We genotyped 31 Japanese ANE cases and compared the results with those of approximately 200 Japanese controls. For the two polymorphisms showing a possible association, we next studied whether the polymorphisms alter the production of IL-6 or IL-10 by lymphoblasts upon phorbol 12-myristate 13-acetate (PMA) stimulation. The frequencies of IL6 rs1800796G allele and IL10 rs1800871/rs1800872 CC/CC diplotype were significantly higher in ANE cases than in controls. The IL10 CC/CC diplotype was associated with low IL-10 production, whereas the IL6 GG genotype was not associated with IL-6 production. IL10 rs1800871/rs1800872 CC/CC diplotype may predispose Japanese children to ANE by altering IL-10 production in the early phase of infection. Etio-pathogenetic significance of IL6 rs1800796G remains to be elucidated.

The importance of SOCS1 - 1478 CA/del polymorphism and expression in breast cancer: a case-control study in the north of Iran.

This project aimed to evaluate the relationship between the suppressor of cytokine signaling-1 (SOCS1) - 1478 CA > del genetic variation and breast cancer susceptibility. Moreover, we investigated the SOCS1 mRNA expression level in cancerous tissues. A total of 100 patients with breast cancer and 120 healthy individuals were selected. Genomic DNA was extracted from blood. SOCS1 genotyping and relative gene expression were performed using ARMS-PCR (Amplification-Refractory Mutation System-Polymerase Chain Reaction) and real-time PCR, respectively. In breast cancer patients, the prevalence of genotype frequencies of SOCS1 (- 1478 CA > del) CA/CA, CA/del, and del/del was 52, 31, and 17%, respectively. Among controls, the distribution of CA/CA, CA/del, and del/del was 63, 15, and 22%, respectively. The chi-square test reported that a significant difference was observed in the genotypic distribution of SOCS1 (- 1478 CA > del) polymorphism between cases and controls (χ2 = 8.08, P = 0.01). In addition, the presence of the CA/del genotype was associated with an elevated risk of breast cancer (in the codominant model: OR 2.51; 95% CI 1.27-4.96, P = 0.007 and in the over dominant model: OR 2.54; 95% CI 1.32-4.90, P = 0.005). However, there was no significant difference in allelic distributions between the groups (P > 0.05). There was no significant difference in the breast cancer risk associated with the dominant and recessive genetic models when the reference was CA/CA and CA/CA + CA/del genotype, respectively (P = 0.09 and P = 0.38). Moreover, the expression of SOCS1 decreased in cancerous tissues as compared to the adjacent non-cancerous tissues (P < 0.0001). In conclusion, a functional SOCS1 promoter polymorphism (- 1478 CA > del) may affect breast cancer susceptibility.