TGF-β1 Genotypes Research Articles

Impacts of circulating cytokine levels and gene polymorphism predisposition on type 1 diabetes mellitus.

A wide range of cytokines has been demonstrated to be involved in the etiology of type 1 diabetes mellitus (T1DM). Gene polymorphisms may potentially contribute to a hereditary predisposition toward circulating cytokine levels as (high, intermediate, or low) since they can affect cytokine production or function. The aim of this study was to investigate the roles of cytokine levels and the association of single-nucleotide polymorphisms (SNPs) within cytokine genes with T1DM in Saudi children. Totals of 91 well-characterized T1DM patients and 91 T1DM-free control subjects were enrolled in this study. The levels of 3 circulating cytokines (transforming growth factor [TGF]-β1, interleukin [IL]-10, and IL-6) and 6 SNPs in 3 cytokine genes (TGF-β1 [rs1800470 and rs1800471], IL-10 [rs1800896, rs1800871, and rs1800872], and IL-6 [rs1800795]) that contribute to genetic susceptibility were measured by enzyme-linked immunosorbent assay and polymerase chain reaction with sequence-specific primers. Our fn dings show that TGF-β1 serum levels were signifcantly lower in the children with T1DM than in the control participants. The TGF-β1 genotypes with a high-production phenotype were signifcantly less frequent and those with a lowproduction phenotype were signifcantly more frequent in the children with T1DM compared to the control participants. respectively. Furthermore, the IL-6 genotype frequency with low level of IL-6 production were signifcantly increased in the T1DM group compared to the control group. Moreover, our data demonstrated no appreciable diferences in circulating serum level or genotype and phenotype of IL- 10 between the patients and controls. This kind of measurement, which considers the prediction of T1DM, may be useful in assessing the severity of T1DM and susceptibility to T1DM among Saudi children.

Association of <i>VEGF</i> gene rs699947 and rs2010963 polymorphisms with vascular endothelial growth factor levels in the blood serum of children with lupus nephritis

The growth factor genes VEGF and TGFB1 are involved in the normal functioning of the kidneys, and some polymorphic loci of these genes determine a genetic predisposition to the autoimmune diseases, including systemic lupus erythematosus (SLE) and its dangerous complication, lupus nephritis (LN). The products of these genes, in particular, the vascular endothelial growth factor protein and the transforming growth factor β1 protein are used in clinical practice as markers of endothelial dysfunction for early diagnosis of kidney pathology. However, the relationship between the expression of these proteins and the genotypes/alleles of the polymorphic loci of these genes has not been studied enough, which requires clarification of this issue for the child population of Belarus. In this work, we analyzed the associations of the TGFB1 (rs1800469) and VEGF (rs699947 and rs2010963) gene genotypes with the concentration of their products in the blood serum of patients with LN during exacerbation and remission of the disease. The study did not find a significant relationship between polymorphic variants of the TGFB1 gene (rs1800469) and levels of its product in the blood. An association has been established between the rs699947 and rs2010963 polymorphic variants of the VEGF gene and the serum concentration of the gene product in pediatric patients with LN during exacerbation. It was found that the homozygous minor genotype AA of the polymorphic locus rs699947 and the group of genotypes GC + CC containing at least one minor allele of the locus rs2010963 are associated with higher levels of the gene product in the blood serum of children with LN during disease exacerbation (p < 0.001 and p = 0.036, respectively). Thus, VEGF polymorphic variants associated with an increased concentration of the gene product in the blood serum during disease exacerbation can be considered as markers of the risk of disease exacerbation in patients with LN.

Haplotype Structures and Protein Levels of TGFB1 in HPV Infection and Cervical Lesion: A Case-Control Study.

This study aimed to verify the role of TGFB1 variants (c.-1638G>A, c.-1347C>T, c.29C>T, and c.74G>C) in HPV infection susceptibility and cervical lesions development, and their impact on TGFB1 cervical and plasma levels. TGFB1 genotypes were assessed with PCR-RFLP and haplotypes were inferred for 190 HPV-uninfected and 161 HPV-infected women. TGFB1 levels were determined with immunofluorimetric assay. Case-control analyses were performed with logistic regression adjusted for possible confounders. Women carrying -1347TT or -1347CT+TT as well as those with 29CT, 29CC, or 29CT+CC were more likely to have HPV than -1347CC and 29TT carriers, respectively. Regarding haplotypes, the most frequent were *4 (GCTG) and *3 (GTCG). Women *4/*4 were less likely to have HPV than those with no *4 copy. Comparing the inheritance of *3 and *4, carriers of *3/*4 or *3/*3 were more susceptible to HPV than *4/*4. The TGFB1 plasma and cervical levels were higher in the infected patients. Plasma levels were also higher in infected women with low-grade lesions. HPV-infected patients carrying *3/Other and *3/Other+*3/*3 presented lower TGFB1 plasma levels than those with no copy of *3. TGFB1 variants could contribute to the comprehension of the TGFB1 role in HPV-caused cervical disease.

Manipulation of Interleukin-6 (IL-6) and Transforming Growth Factor Beta-1(TGFβ-1) towards viral induced liver cancer pathogenesis.

Hepatocellular carcinoma (HCC) is the most common liver malignancy. Early diagnosis of HCC has always been challenging. This study aims to assess the pathogenicity and the prevalence of IL-6 -174G/C (rs1800795) and TGFβ-1 +29C/T (rs1800470) polymorphisms in HCV-infected HCC patients. Experimental strategies are integrated with computational approaches to analyse the pathogenicity of the TGFβ-1 +29C/T and IL-6–174 G/C polymorphisms in HCV-induced HCC. AliBaba2 was used to predict the effect of IL-6–174 G/C on transcription factor binding site in IL-6 gene. Structural changes in the mutant TGFβ-1 structure were determined through project HOPE. To assess the polymorphic prevalence of IL-6 -174G/C and TGFβ-1 +29C/T genotypes in HCC and control subjects, amplification refractory mutation system PCR (ARMS-PCR) was performed on 213 HCC and 216 control samples. GraphPad Prism version 8.0 was used for the statistical analysis of the results. In-silico analysis revealed the regulatory nature of both IL-6 -174G/C and TGFβ-1 +29C/T polymorphisms. ARMS-PCR results revealed that the individuals carrying TT genotype for TGFβ-1 gene have an increased risk of developing HCC (p<0.0001, OR = 5.403, RR = 2.062) as compared to individuals with CT and CC genotype. Similarly, GC genotype carriers for IL-6 gene exhibit an increased risk of HCC susceptibility (p<0.0001, OR = 2.276, RR = 1.512) as compared to the people carrying the GG genotype. Genotype TT of TGFβ-1 gene and genotype GC of IL-6 gene are found to be associated with HCV-induced HCC. IL-6 polymorphism may alter its transcription that leads to its pathogenicity. TGFβ-1 polymorphism may alter protein structure stability.

COMPLEX ANALYSIS OF THE ROLE OF CYTOKINE GENE POLYMORPHISMS AS PROGNOSTIC FACTOR OF THE RISK OF PLASMA CELL MYELOMA IN PERSONS SUFFERED AFTER THE CHORNOBYL NPP ACCIDENT.

to provide a comparative characterization of the prevalence of polymorphic variants of cytokine genes in plasma cell myeloma (PCM) patients suffered after the Chornobyl disaster and patients who were in contact with ionizing radiation within the natural radiation background, based on comparison with population controls to determine their contribution as genetic markers of disease risk. Molecular genetic studies of polymorphism of cytokine genes (TNF-α, TGF-β1, IL-6, IL-10, IFN-γ) and complex frequency analysis of occurrence in three-, four-, and five-locus combinations of their allelic variants as prognostic markers of the risks of plasma cell myeloma was carried out in 102 patients - 56 victims of the Chornobyl nuclear power plant accident and 46 patients irradiated within the limits of the natural radiation background, in comparison with the control group (364 practically healthy people, residents of the Central geno-geographical region of Ukraine). The same probable increase in the prevalence of the TGF-β genotype codon10 T/T of the TGF-β1 gene was established in the groups of patients irradiated after the Chornobyl NPP accident and non-irradiated patients. In patients with plasma cell myeloma a protective effect for IL-10 -1082 A/G and an association with the risk of disease occurrence for IL-10 -1082 G/G were determined. Probable difference in the frequency of the TGF-β1 genotype codon10 T/T of the TGF-β1 gene in the observed groups relative to the control group provides grounds for considering this single-nucleotide polymorphism of the TGF-β1 gene as an immunogenetic factor of predisposition to the development of PCM independent of exogenous factors. The study of the contribution of multigene combinations of «gene-gene» interaction indicates their role in the mechanisms of plasma cell myeloma occurrence and confirms the presence of an additive interaction.

IL-10 and TGF-β1 gene polymorphisms in Greek patients with recurrent aphthous stomatitis.

Background Recurrent aphthous stomatitis (RAS) is one of the most frequent inflammatory disorders of the oral mucosa. Cytokines, which play an important role in RAS pathogenesis, participate directly or indirectly in normal, immunological and inflammatory processes and are secreted from cells belonging to innate and adaptive immunity as a consequence of microbial and antigenic stimuli. Gene polymorphisms in specific cytokines may predispose to RAS development. The aim of this study was the investigation and association of IL-10 and TGF-β1 gene polymorphisms with RAS.Material and Methods Study’s cohort consisted of 60 Greek patients diagnosed with RAS, including 40 patients with minor, 10 patients with major and 10 with herpetiform aphthous ulcers. Forty age- and sex-matched control subjects were included in this study. DNA was extracted from whole blood samples of all patients and sequence-specific primers (SSP)-based polymerase chain reaction (PCR) was used for genotyping. Gene polymorphisms for cytokines IL-10 at loci -592 and -819 and for TGF-β1 at codon 10 were detected.Results Significant differences between patients with minor RAS and healthy controls were recorded for IL-10 genotypes distribution at position -592 (p=0.042) and -819 (p=0.045) with predominance of C/A and C/T genotypes in RAS patients, respectively. Also, in patients with minor and herpetiform aphthous ulcerations, heterozygous TGF-β1 genotype C/T at codon 10 was associated with increased risk of RAS (p=0.044 and p=0.020, respectively).Conclusions These data provide evidence that genetic predisposition for RAS and possibly its specific clinical variants is related with the presence of gene polymorphisms for specific cytokines, including IL-10 and TGF-β1, which, in turn, may vary according to geographic origin and genetic background. Key words:Recurrent aphthous stomatitis, aphthae, IL-10, TGF-β, gene polymorphisms, oral mucosa.

The association of transforming growth factor beta 1 gene polymorphisms with arthritis: a systematic review and meta-analysis.

The objective of this study was to explore the association between transformation growth factor beta 1 (TGF-β1) gene polymorphisms and different types of arthritis. PubMed, Medline, Web of Science, Cochrane Library, Biosis and four Chinese databases: China Biology Medicine, China National Knowledge Infrastructure, Wanfang and CQVIP, were searched. Studies that analyzed the association of the TGF-β1 polymorphisms with different types of arthritis were included. OR, 95% confidence interval and P value were calculated in three models including allele, dominant and recessive models, using D + L method. The Newcastle-Ottawa Scale was used to assess the quality of the included studies. TGF-β1 869T > C polymorphism was significantly associated with rheumatoid arthritis (RA) in allele and recessive models, but not in dominant model (allele model T vs. C: OR = 1.30, 95% CI = 1.13-1.49, P < 0.001; recessive model CC vs. TT + TC: OR = 0.57, 95% CI = 0.43-0.76, P < 0.001; dominant model TT vs. TC + CC: OR = 1.20, 95% CI = 0.99-1.45, P = 0.063). Additionally, allele and recessive models showed that TGF-β1 -509C > T was significantly correlated with RA susceptibility, while dominant model revealed nonsignificant correlation (allele model: C vs. T: OR = 1.51; 95% CI = 1.00-2.28; P = 0.049; recessive model: TT vs. CC + TC: OR = 0.52, 95% CI = 0.37-0.72, P = 0.000; dominant model: CC vs. TT + TC: OR = 1.48; 95% CI = 0.79-2.76; P = 0.223). However, no significant association was found between TGF-β1 polymorphisms and ankylosing spondylitis (AS) or osteoarthritis (OA) risk. This study demonstrated that 869T > C, -509 C > T polymorphisms of TGF-β1 gene were associated with increased susceptibility of RA, while polymorphisms of TGF-β1 gene were not associated with OA and AS. These findings suggest that studying TGF-β1 genotype may be useful in the prevention and management of RA. However, more studies are needed to evaluate the association of TGF-β1 gene polymorphisms with the susceptibility of OA and AS.

The impact of tumor necrosis factor-α (-308 G/A) and transforming growth factor beta 1 (-509C/T) gene polymorphism in Egyptian children with primary nephrotic syndrome

Background: Nephrotic syndrome (NS) is a disease affecting both children and adults. Cytokines act as inflammatory mediators in childhood NS. Excretion of too much protein in patients' urine as well as reduction in albumin levels in their blood are the most common symptoms of NS. Aim of the Study: The aim is to assess the potential relationship of tumor necrosis factor (TNF)-α (−308 G/A) and transforming growth factor beta 1 (TGF-β1) (−509C/T) genes with the incidence of NS. Subjects and Methods: In this study, 99 healthy children and 98 children with NS have been included. Polymerase chain reaction was used to detect the gene polymorphism of both TNF-α-G308A and TGF-β1 (−509C/T). Results: The TNF-α G308A showed a significant different genotype distribution among children with NS compared with the healthy volunteers (GG vs. AA, P = 0.0009; [odds ratio [OR] 95% CI = 25.2 [2.45–259.23]); GG vs. GA, P = 0.001; (OR 95% CI = 4.84 [1.74–13.5]); as well as alleles distribution of G vs. A, P = 0.022; (OR 95% CI = 1.06 [1.068–2.42]). However, there is a non-significant variation in the frequency of TGF-β1 (-509C/T) genotypes (CC, CT and TT) respectively (11.4%, 78.5% and 10.1) in NS patients, compared with their corresponding levels in healthy control subjects (15.5%, 68% and 16.5). Conclusion: TNF-α-G308A polymorphism may help to early predict the incidence of NS in children, while TGF-β1 showed no effect on the disease incidence.

Quantitative 3-Dimensional Photographic Assessment of Breast Cosmesis After Whole Breast Irradiation for Early Stage Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial

PurposeOur purpose was to use 3-dimensional (3D) surface photography to quantitatively measure breast cosmesis within the framework of a randomized clinical trial of conventionally fractionated (CF) and hypofractionated (HF) whole breast irradiation (WBI); to identify how 3D measurements are associated with patient- and physician-reported cosmesis; and to determine whether objective measures of breast symmetry varied by WBI treatment arm or transforming growth factor β 1 (TGFβ1) status. Methods and MaterialsFrom 2011 to 2014, 287 women age ≥40 with ductal carcinoma in situ or early-stage invasive breast cancer were enrolled in a multicenter trial and randomized to HF-WBI or CF-WBI with a boost. Three-dimensional surface photography was performed at 3 years posttreatment. Patient-reported cosmetic outcomes were recorded with the Breast Cancer Treatment Outcome Scale. Physician-reported cosmetic outcomes were assessed by the Radiation Therapy Oncology Group scale. Volume ratios and 6 quantitative measures of breast symmetry, termed F1-6C, were calculated using the breast contour and fiducial points assessed on 3D surface images. Associations between all metrics, patient- and physician-reported cosmesis, treatment arm, and TGFβ1 genotype were performed using the Kruskal-Wallis test and multivariable logistic regression models. ResultsAmong 77 (39 CF-WBI and 38 HF-WBI) evaluable patients, both patient- and physician-reported cosmetic outcomes were significantly associated with the F1C vertical symmetry measure (both P < .05). Higher dichotomized F1C and volumetric symmetry measures were associated with improved patient- and physician-reported cosmesis on multivariable logistic regression (both P ≤ .05). There were no statistically significant differences in vertical symmetry or volume measures between treatment arms. Increased F6C horizontal symmetry was observed in the CF-WBI arm (P = .05). Patients with the TGFβ1 C-509T variant allele had lower F2C vertical symmetry measures (P = .02). ConclusionsQuantitative 3D image-derived measures revealed comparable cosmetic outcomes with HF-WBI compared with CF-WBI. Our findings suggest that 3D surface imaging may be a more sensitive method for measuring subtle cosmetic changes than global patient- or physician-reported assessments.

Investigation of TGFB1 -1347C>T variant as a biomarker after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic option for malignant hematopoietic diseases. Cytokines including transforming growth factor β1 (TGFβ1) play a pivotal role in immune reconstruction, and the development of graft versus host disease (GvHD) or infections. The aim of this study was to investigate the role of TGFB1 gene -1347C>T variant in the outcome of HSCT in a cohort of 409 adult recipient-donor pairs. TGFB1 variant was analysed from genomic DNA with LightCycler hybridisation probe method. In case of myeloablative conditioning, donor TGFB1 genotype correlated with overall survival (60-month OS for CC: 62.1 ± 4.8%; CT: 46.8 ± 4.8%; TT: 35.6 ± 9.3%; p = 0.032), which was independent of age, donor type and GvHD prophylaxis in multivariate analysis (HR:2.35, 95%CI:1.35-4.10, p = 0.003). The cumulative incidence of acute GvHD grade III-IV [CC:10%; CT:17%; TT:24%], and non-relapse mortality was higher in TT-carriers (24-month NRM: CC:24%; CT:26%; TT:46%, p = 0.035). We did not find any association between recipient TGFB1 -1347C>T polymorphism and HSCT outcome. Our results suggest that donor TGFB1 -1347C>T may exert an adverse influence on the outcome of myeloablative conditioning transplantation.

Association of single nucleotide polymorphisms at HSPB1 rs7459185 and TGFB1 rs11466353 with radiation esophagitis in lung cancer

Background and purposeRadiochemotherapy (RCT) success in lung cancer (LC) can be limited due to the onset of adverse effects in the adjacent normal tissue such as radiation-induced esophageal toxicity (RIET). Therefore, specific biomarkers to customize the RCT dose administration and esophageal toxicity prediction are necessary to improve treatment effectiveness. Materials and methods247 LC patients prospectively recruited between 2012 and 2016 from 3 institutions were genotyped for 7 SNPs along TGFB1 and HSPB1 genes seeking an association with RIET risk development. Kaplan–Meier cumulative probability and Cox proportional hazards analyses were used to evaluate the effect of TGFB1 and HSPB1 genotypes on such risk. ResultsMultivariate analyses showed that patients carrying the HSPB1 rs7459185 CC genotype were associated with a significantly higher risk of acute grade 3 RIET than those carrying the GG/GC genotypes (HR = 17.73; 95% CI = 2.896–108.49; p = 0.002). LC patients who received higher (>median) volume of esophagus exposed to 30 Gy and harboring the rs7459185 GG/GC genotypes showed a significantly lower RIET incidence (p < 0.001). Additionally, LC patients carrying the TGFB1 rs11466353 GG genotype were found to be associated with a lower risk of late grade 2 RIET compared with those with the TT/TG genotypes (HR = 0.29; 95% CI = 0.103–0.830; p = 0.021). Patients receiving a high (>60 Gy) radiation dose who presented the rs11466353 GG genotype had a significantly lower RIET incidence (p = 0.025). ConclusionThe presence of different rs7459185/rs11466353 genotypes in LC patients associated with RIET risk and may be useful biomarkers along with other risk factors for guiding therapy intensity in an individualized therapy.

Association of Transforming Growth Factor β Polymorphism C−509T With Radiation-Induced Fibrosis Among Patients With Early-Stage Breast Cancer

Whether genetic factors can identify patients at risk for radiation-induced fibrosis remains unconfirmed. To assess the association between the C-509T variant allele in the promoter region of TGFB1 and breast fibrosis 3 years after radiotherapy. This is an a priori-specified, prospective, cohort study nested in an open-label, randomized clinical trial, which was conducted in community-based and academic cancer centers to compare hypofractionated whole-breast irradiation (WBI) (42.56 Gy in 16 fractions) with conventionally fractionated WBI (50 Gy in 25 fractions) after breast-conserving surgery. In total, 287 women 40 years or older with pathologically confirmed stage 0 to IIA breast cancer treated with breast-conserving surgery were enrolled from February 2011 to February 2014. Patients were observed for a minimum of 3 years. Outcomes were compared using the 1-sided Fisher exact test and multivariable logistic regression. A C-to-T single-nucleotide polymorphism at position -509 relative to the first major transcription start site (C-509T) of the TGFB1 gene. The primary outcome was grade 2 or higher breast fibrosis as assessed using the Late Effects Normal Tissue/Subjective, Objective, Medical Management, Analytic scale (range, 0 to 3) three years after radiotherapy. Among 287 women enrolled in the trial, TGFB1 genotype and 3-year radiotherapy-induced toxicity data were available for 174 patients, of whom 89 patients (51%) with a mean (SD) age of 60 (8) years had at least 1 copy of C-509T. Grade 2 or higher breast fibrosis was present in 12 of 87 patients with C-509T (13.8%) compared with 3 of 80 patients without the allele variant (3.8%) (absolute difference, 10.0%; 95% CI, 1.7%-18.4%; P = .02). The results of multivariable analyses indicated that only C-509T (odds ratio, 4.47; 95% CI, 1.25-15.99; P = .02) and postoperative cosmetic outcome (odds ratio, 7.09; 95% CI, 2.41-20.90; P < .001) were significantly associated with breast fibrosis risk. To date, this study seems to be the first prospective validation of a genomic marker for radiation fibrosis. The C-509T allele in TGFB1 is a key determinant of breast fibrosis risk. Assessing TGFB1 genotype may facilitate a more personalized approach to locoregional treatment decisions in breast cancer. ClinicalTrials.gov identifier: NCT01266642.

Transforming Growth Factor-β Protects against Inflammation-Related Atherosclerosis in South African CKD Patients.

Background Transforming growth factor-β (TGF-β) may inhibit the development of atherosclerosis. We evaluated serum levels of TGF-β isoforms concurrently with serum levels of endotoxin and various inflammatory markers. In addition, we determined if any association exists between polymorphisms in the TGF-β1 gene and atherosclerosis in South African CKD patients. Methods We studied 120 CKD patients and 40 healthy controls. Serum TGF-β1, TGF-β2, TGF-β3, endotoxin, and inflammatory markers were measured. Functional polymorphisms in the TGF-β1 genes were genotyped using a polymerase chain reaction-sequence specific primer method and carotid intima media thickness (CIMT) was assessed by B-mode ultrasonography. Results TGF-β isoforms levels were significantly lower in the patients with atherosclerosis compared to patients without atherosclerosis (p<0.001). Overall, TGF-β isoforms had inverse relationships with CIMT. TGF-β1 and TGF-β2 levels were significantly lower in patients with carotid plaque compared to those without carotid plaque [TGF-β1: 31.9 (17.2 – 42.2) versus 45.9 (35.4 – 58.1) ng/ml, p=0.016; and TGF-β2: 1.46 (1.30 – 1.57) versus 1.70 (1.50 – 1.87) ng/ml, p=0.013]. In multiple logistic regression, age, TGF-β2, and TGF-β3 were the only independent predictors of subclinical atherosclerosis in CKD patients [age: odds ratio (OR), 1.054; 95% confidence interval (CI): 1.003 – 1.109, p=0.039; TGF-β2: OR, 0.996; 95% CI: 0.994–0.999, p=0.018; TGF-β3: OR, 0.992; 95% CI: 0.985–0.999, p=0.029). TGF-β1 genotypes did not influence serum levels of TGF-β1 and no association was found between the TGF-β1 gene polymorphisms and atherosclerosis risk. Conclusion TGF-β isoforms seem to offer protection against the development of atherosclerosis among South African CKD patients.

Transforming growth factor beta 1 (TGFβ1) polymorphisms and haplotype structures have dual roles in breast cancer pathogenesis.

Despite the documented dual role of TGFβ1 in breast cancer (BC) pathogenesis, the subtype-specific influences of its polymorphisms remain undocumented. The present study investigated the effects of the TGFB1 promoter region (rs1800468 or G-800A and rs1800469 or C-509T) and signal peptide (rs1800470 or C29T and rs1800471 or G74C) single nucleotide polymorphisms (SNPs) and their haplotype structures on the susceptibility and clinicopathological presentation of BC subtypes. TGFB1 genotypes were assessed by PCR-RFLP and haplotype structures were inferred for 323BC patients and 405 neoplasia-free women, and case-control analyses were performed by logistic regression adjusted by age. Clinicopathological parameters (age at diagnosis, tumor size, histopathological grade, lymph node metastasis, proliferation index and disease stage) were tested for correlation with TGFB1 variants. All statistical analyses were two-tailed with an alpha level of 0.05. Variants related to increased TGFβ1 production (C-509T SNP and GTCG haplotype) were associated with increased susceptibility to HER2+ tumors and correlated with worse prognostic parameters in HER2+ and triple-negative (TN) BCs, but correlated negatively to Ki67 in ER/PR+HER2- tumors. Conversely, low TGFβ1 production variants (C29T SNP and GCTG haplotype) were protective against HER2+ tumors and correlated negatively with prognostic parameters in HER2+ and TN BCs, while indicating higher proliferation rates in ER/PR+HER2- tumors. Furthermore, the GCCG haplotype was associated with decreased susceptibility to ER/PR+HER2- tumors, but correlated positively with Ki67 in this subgroup. The present study indicates that TGFB1 variants have subtype-specific roles in BC and may switch from tumor suppressor to promoter during tumor development, consistent with TGFβ1 dual role in BC pathogenesis.

Association of cytokine gene polymorphisms with the complications of allogeneic haematopoietic stem cell transplantation

The purpose of our study was to confirm the prevalence of the association between single nucleotide polymorphisms present in genes encoding cytokines and the complications occurring after haematopoietic stem cell transplantation (HSCT). 108 recipients and 81 donors were typed for TNF-α (−308), TGF-β1 (codon 10, 25), IL-10 (−1082, −819, −592), IL-6 (−174) and INF-γ (+874). Our studies have shown a tendency toward association between the occurrence of acute form of graft versus host disease (aGVHD) and IL-6 genotype. Homozygote C/C was less likely to develop aGVHD (p=0,09). Genotype GCC/ATA in IL-10 recipient gene alone had protective effect against the occurrence of aGVHD (p=0,01). Furthermore, GCC/ATA protected the host against developing the disease in the clinically relevant grades (II-IV) (p=0,03). In addition, the recipient’s T/T G/G genotype (TGF-β1) predisposed to the development of both acute (p=0,06 – trend) and chronic (p=0,04) GVHD and also severe aGVHD (p=0,004). We also observed a statistically significant association between the genotype of recipient and the risk of infection – the protective function of the G/C IL-6 in the bloodstream infections (p=0,001). Our results suggest that IL-6, IL-10 and TGF-β1 genotypes of recipient are the most associated with the risk of complications after HSCT.

Association between TGFβ1 polymorphisms and chronic hepatitis B infection in an Iranian population.

Transforming growth factor-beta 1 (TGFβ1) is a potent suppressive cytokine that contributes to chronic hepatitis B (CHB) infection. Disparities in TGFβ1 production among individuals have been attributed to TGFβ1 genetic polymorphisms. We examined whether three putative polymorphisms in TGFβ1[-509 C/T (rs1800469), +869 C/T (rs1800470), and +11929 C/T (rs1800472)]are associated with CHB infection in a South-Eastern Iranian population. In total, 341 subjects were recruited, including 178 patients with CHB and 163 healthy individuals as controls. Genotyping of the three TGFβ1 SNPs was performed by tetra amplification refractory mutation system-PCR. TheTGFβ1 +869 TT vs.CC genotype in codominant (OR=0.445, p=0.012) and TT vs. TC+CC in the recessive (OR=0.439, p=0.003) model as well as the variant allele T vs. C(OR=0.714, p=0.038) were associated with lower CHB infection risk. However, the +11929 C/T polymorphism was associated with increased CHB risk, and the CT vs. CC genotype (OR=2.77, P=0.001) and T variant allele (OR=2.53, P=0.002) were risk factors for CHB. Furthermore, TTT (+869/-509/+11929) and CCC haplotypes were risk and protective factors for CHB, respectively. We found no significant association between viral DNA load and TGFβ1 genotype or hepatic enzyme levels (p >0.05). Results indicated that the TGFβ1+869TT genotype and T allele were protective factors, whereas the +11929 CT genotype and T allele were risk factors for CHB infection.

The Synergistic Effect of TNFα -308 G/A and TGFβ1 -509 C/T Polymorphisms on Hepatic Fibrosis Progression in Hepatitis C Virus Genotype 4 Patients.

Tumor necrosis factor-alpha (TNFα) and transforming growth factor-beta (TGFβ1) cytokines are highly implicated in liver fibrosis. Polymorphisms in these cytokines affect their expression, secretion, and activity. This study aimed to evaluate the influence of TNFα -308 G/A and TGFβ1 -509 C/T polymorphism on hepatic fibrosis progression in Egyptian patients with hepatitis C virus (HCV) genotype 4. Genotyping of TNFα -308 G/A and TGFβ1 -509 C/T was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 122 subjects (50 healthy controls and 72 HCV patients). Also, serum TNFα and TGFβ1 levels were detected by enzyme-linked immunosorbent assay (ELISA). The genotyping results of early (F0-F1, n = 36) and late (F2-F4, n = 36) HCV fibrosis patients showed that late fibrosis patients had higher TNFα -308 AA genotype and TGFβ1 -509 TT genotype than early fibrosis patients (p = 0.016, 0.028, respectively). Moreover, the TNFα and TGFβ1 serum levels were significantly higher in HCV patients with TNFα A containing genotypes (GA+AA) (p = 0.004) and patients with TGFβ1 T containing genotypes (CT+TT) (p = 0.001), respectively. The combined unfavorable TNFα (GA/AA) and TGFβ1 (CT/TT) genotypes were highly associated with abnormal liver function parameters and were significantly higher in high activity (A2-A3) and late fibrosis (F2-F4) HCV patients (p = 0.023, 0.029). The multivariate analysis results confirmed that the combined TNFα-308 (AA) and TGFβ1 -509 (TT) unfavorable genotypes increased the risk of hepatic fibrosis progression by 6.4-fold than combined favorable genotypes (odds ratio: 6.417, 95% confidence interval [1.490-27.641], p = 0.013). In conclusion, both TNFα -308 G/A and TGFβ1 -509 C/T polymorphisms synergistically influence the hepatic fibrosis progression and can be used as potential biomarkers to predict hepatic disease progression in chronic hepatitis C patients.

The Relationship between VEGFA and TGFB1 Polymorphisms and Target Lesion Revascularization after Elective Percutaneous Coronary Intervention.

Background and Aim The specific association between genetic variation and in-stent restenosis is still only partly understood. The aim of this study is to analyze the relationship between functional polymorphisms in the genes encoding vascular endothelial growth factor A (VEGF-A; rs699947) and transforming growth factor beta 1 (TGF-β1; rs1800470) and target lesion revascularization (TLR) risk. Methods A total of 676 patients (805 lesions) with stable coronary artery disease (SCAD) who received elective percutaneous coronary intervention (PCI) with at least one bare-metal stent implantation were included. The primary study endpoint was TLR at a 4-year follow-up. Results The TLR rate was higher in patients with the VEGFA A/A genotype (15.4%) than in patients with the VEGFA A/C (7.9%) and C/C (8.9%) genotypes (p = 0.009). The VEGFA A/A genotype, after adjustment for clinical and procedural covariates, remained significantly and independently associated with the TLR (hazard ratio—2.09 [95% confidence interval 1.32–3.33, p = 0.0017]). However, we found no association between TLR and the TGFB1 genotype. Conclusion The VEGFA A/A genotype is significantly and independently associated with TLR risk in Polish SCAD patients who received elective PCI with bare-metal stent implantation.

The TGFβ1 Promoter SNP C-509T and Food Sensitization Promote Esophageal Remodeling in Pediatric Eosinophilic Esophagitis.

BackgroundEosinophilic esophagitis (EoE) is a chronic antigen mediated disease associated with substantial esophageal remodeling and fibrosis. The functional TGFβ1 promoter SNP C-509 associates with renal fibrosis and asthma. The effect of TGFβ1 genotype and EoE severity or potential gene-environment interactions have not been previously reported in EoE.MethodsGenotype at TGFβ1 C-509T and remodeling was analyzed in 144 subjects with EoE. The severity of remodeling and inflammation was analyzed in the context of IgE sensitization to food antigens and C-509T genotype.ResultsThe TGFβ1 promoter C-509 genotypes CC, CT, and TT were 35%, 52%, and 13%, respectively. Sixty-six percent of subjects were sensitized to foods by positive skin prick test (SPT) or serum specific IgE. TT genotype subjects had significantly more TGFβ1 (CC subjects = 1300 per mm2; TT = 2250 per mm2) (p<0.05) and tryptase (CC subjects = 145 per mm2: TT = 307 per mm2) (p<0.05) positive cells and higher epithelial remodeling scores (2.4 vs 3.7, p<0.001) than CC subjects. The differences in TGFβ1 and tryptase positive cells as well as fibrosis were significantly increased when there was concurrent food sensitization. Food sensitization alone did not associate with any parameters of inflammation or remodeling.ConclusionsOur data support a gene-environment interaction between food and genotype at C-509 that modulates disease severity in EoE. Since EoE subjects often continue to consume foods to which they are sensitized, these findings may have clinical relevance for disease management.

Polymorphism in TGFB1 is associated with worse non-relapse mortality and overall survival after stem cell transplantation with unrelated donors

Transforming growth factor β-1, encoded by the TGFB1 gene, is a cytokine that plays a central role in many physiological and pathogenic processes. We have sequenced TGFB1 regulatory region and assigned allelic genotypes in a large cohort of hematopoietic stem cell transplantation patients and donors. In this study, we analyzed 522 unrelated donor-patient pairs and examined the combined effect of all the common polymorphisms in this genomic region. In univariate analysis, we found that patients carrying a specific allele, 'p001', showed significantly reduced overall survival (5-year overall survival 30.7% for p001/p001 patients vs. 41.6% others; P=0.032) and increased non-relapse mortality (1-year non-relapse mortality: 39.0% vs. 25.4%; P=0.039) after transplantation. In multivariate analysis, the presence of a p001/p001 genotype in patients was confirmed as an independent factor for reduced overall survival [hazard ratio=1.53 (1.04-2.24); P=0.031], and increased non-relapse mortality [hazard ratio=1.73 (1.06-2.83); P=0.030]. In functional experiments we found a trend towards a higher percentage of surface transforming growth factor β-1-positive regulatory T cells after activation when the cells had a p001 allele (P=0.07). Higher or lower production of transforming growth factor β-1 in the inflammatory context of hematopoietic stem cell transplantation may influence the development of complications in these patients. Findings indicate that TGFB1 genotype could potentially be of use as a prognostic factor in hematopoietic stem cell transplantation risk assessment algorithms.