Transforming Growth Factor-?1 T869C Gene Polymorphism Is Associated with Acquired Sick Sinus Syndrome via Linking a Higher Serum Protein Level.
ABSTRACT: Familial sick sinus syndrome is associated with gene mutations and dysfunction of ion channels. In contrast, degenerative fibrosis of the sinus node tissue plays an important role in the pathogenesis of acquired sick sinus syndrome. There is a close relationship between transforming growth factor-?1 mediated cardiac fibrosis and acquired arrhythmia. It is of interest to examine whether transforming growth factor-?1 is involved in the pathogenesis of acquired sick sinus syndrome.Overall, 110 patients with acquired SSS and 137 age/gender-matched controls were screened for transforming growth factor-?1 and cardiac sodium channel gene polymorphisms using gene sequencing or restriction fragment length polymorphism methods. An enzyme-linked immunosorbent assay was used to determine the serum level of transforming growth factor-?1.Two transforming growth factor-?1 gene polymorphisms (C-509T and T+869C) and one cardiac sodium channel gene polymorphism (H588R) have been identified. The C-dominant CC/CT genotype frequency of T869C was significantly higher in acquired sick sinus syndrome patients than in controls (OR 2.09, 95% CI 1.16-3.75, P = 0.01). Consistently, the level of serum transforming growth factor-?1 was also significantly greater in acquired sick sinus syndrome group than in controls (5.3±3.4 ng/ml vs. 3.7±2.4 ng/ml, P = 0.01). In addition, the CC/CT genotypes showed a higher transforming growth factor-?1 serum level than the TT genotype (4.25 ± 2.50 ng/ml vs. 2.71± 1.76 ng/ml, P = 0.028) in controls.Transforming growth factor-?1 T869C polymorphism, correlated with high serum transforming growth factor-?1 levels, is associated with susceptibility to acquired sick sinus syndrome.
Project description:BACKGROUND: Genetic factors are thought to be crucial in the pathogenesis of ankylosing spondylitis. Transforming growth factor beta 1 (TGF beta 1) is a multifunctional cytokine that plays a key role in inflammation. Two functional single nucleotide polymorphisms (SNPs) in the TGFB1 gene have been described: TGFB1 T869C and TGFB1 G915C. OBJECTIVE: To determine whether these SNPs contribute to ankylosing spondylitis susceptibility or its disease characteristics. METHODS: Genomic DNA was isolated from the peripheral blood of 134 patients with ankylosing spondylitis and 194 healthy blood donors. All subjects were unrelated and of white Dutch ethnicity. The diagnosis of ankylosing spondylitis was made according to the modified New York criteria. The TGFB1 T869C and TGFB1 G915C SNPs were genotyped by a polymerase chain reaction-single strand conformation polymorphism haplotyping method. RESULTS: No significant differences were found between patients and controls in genotype, allele, and haplotype frequencies or in the carrier rate of the rare alleles of the TGFB1 T869C and TGFB1 G915C SNPs. CONCLUSIONS: TGFB1 T869C and TGFB1 G915C SNPs are not major factors in the susceptibility to ankylosing spondylitis or its disease characteristics.
Project description:This study sought to determine if serum markers for collagen I and III synthesis, the carboxyl terminal peptide from pro-collagen I (PICP) and the amino terminal peptide from pro-collagen III (PIIINP), correlate with left atrial (LA) fibrosis and post-operative atrial fibrillation (AF).AF after cardiac surgery is associated with adverse outcomes. We recently demonstrated that LA fibrosis is associated with post-operative AF in patients with no previous history of AF.Fifty-four patients having cardiac surgery without a history of AF consented to left and right atrial biopsies and a pre-operative peripheral blood draw. Picrosirius red staining quantified the percentage of fibrosis, and reverse transcriptase polymerase chain reaction assessed atrial tissue messenger ribonucleic acid transcripts involved in the fibrosis pathway. PICP and PIIINP levels were measured using an enzyme immunosorbent assay.Eighteen patients developed AF, whereas 36 remained in normal sinus rhythm. LA fibrosis was higher in patients who developed AF versus normal sinus rhythm (6.13 ± 2.9% vs. 2.03 ± 1.9%, p = 0.03). LA messenger ribonucleic acid transcripts for collagen I, III, transforming growth factor, and angiotensin were 1.5- to 2.0-fold higher in AF patients. Serum PICP and PIIINP levels were highest in AF versus normal sinus rhythm (PICP: 451.7 ± 200 ng/ml vs. 293.3 ± 114 ng/ml, p = 0.006; PIIINP: 379 ± 286 pg/ml vs. 191.6 ± 162 pg/ml, p = 0.01). Furthermore, there was a linear correlation between LA fibrosis and serum PICP levels (R(2) = 0.2; p = 0.01), and of the markers, only PICP was independently associated with AF.This demonstrates that serum PICP and PIIINP levels correlate with the presence of LA fibrosis and may act as predictors for post-operative AF even in the absence of previous history of AF.
Project description:Transforming growth factor beta 1(TGF-?1) polymorphism was associated with radiation pneumonitis (RP) susceptibility, but their results have been inconsistent. The PubMed and CNKI were searched for case-control studies published up to Januray 01, 2016 was Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. In this meta-analysis, we assessed eight publications involving 368 radiation pneumonitis cases and 855 controls of the association between TGF-?1 T869C (rs1982073) and G915C (rs1800471) polymorphism and RP susceptibility. Our analysis suggested that TGF-?1 T869C rs1982073 polymorphism was associated with lower RP risk for CT combined CC versus TT model (OR = 0.58, 95% CI = 0.43-0.77). However, for the G915C rs1800471 polymorphism, no association was found between the polymorphism and the susceptibility to RP in GC combined CC versus GG model (OR = 0.82, 95% CI = 0.50-1.35). These results from the meta-analysis suggest that T869C rs1982073 polymorphism of TGF-?1 may be associated with RP risk, and there may be no association between G915C polymorphism and RP risk.
Project description:Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10?²?. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.
Project description:Our study investigates association between Galectin-3 levels and adverse left ventricular remodelling (LVR) at six months. Fifty-seven patients following first acute myocardial infarction (AMI) were enrolled in this study and blood samples collected on day 1 from the femoral vein and artery, the right atrium near the coronary sinus and the aortic root, and on day 30, from the cubital vein. Patients with LVESV ?20% at six months, were included in the LVR group. On day 1, Galectin-3 plasma levels in the femoral vein (10.34?ng/ml?±?3.81 vs 8.22?ng/ml?±?2.34, p?=?0.01), and near coronary sinus (10.7?ng/ml?±?3.97 vs 8.41?ng/ml?±?2.56, p?=?0.007) were higher in the LVR group. Positive correlations between Galectin-3 levels from aortic root and coronary sinus, aortic root and femoral vein, and coronary sinus and femoral vein, were observed in both groups. On day 30, Galectin-3 concentration in the cubital vein was an independent risk factor of LVR six months post-AMI, demonstrating 1.5-fold increased risk. Day-30 Galectin-3 also showed positive correlations with echocardiography parameters indicative of diastolic and systolic dysfunction. Determining Galectin-3 plasma concentration on day 30 following AMI could have beneficial prognostic value in predicting LVR.
Project description:BACKGROUND:Transforming growth factor-beta 1 (TGF-?1) is a multifunctional pleiotropic cytokine involved in inflammation and pathogenesis of cerebrovascular diseases. There is limited information on the association between variations within the TGF-?1 gene polymorphisms and risk of ischemic stroke (IS). The aim of this study was to investigate the association of the TGF-?1 gene (C509T, G800A, and T869C) polymorphisms, and their haplotypes with the risk of IS in North Indian population. METHODS:A total of 250 IS patients and 250 age- and sex-matched controls were studied. IS was classified using the Trial of Org 10172 in Acute Stroke Treatment classification. Conditional logistic regression analysis was used to calculate the strength of association between TGF-?1 gene polymorphisms and risk of IS. Genotyping was performed using SNaPshot method. RESULTS:Hypertension, diabetes, dyslipidemia, alcohol, smoking, family history of stroke, sedentary lifestyle, and low socioeconomic status were found to be associated with the risk of IS. The distribution of C509T, G800A and T869C genotypes was consistent with Hardy-Weinberg Equilibrium in the IS and control groups. Adjusted conditional logistic regression analysis showed a significant association of TGF-?1 C509T (odds ratio [OR], 2.1; 95% CI; 1.2-3.8; P = 0.006), G800A (OR, 4.4; 95% CI; 2.1-9.3; P < 0.001) and T869C (OR, 2.6; 95% CI; 1.5-4.5; P = 0.001) with the risk of IS under dominant model. Haplotype analysis showed that C509-A800-T869 and T509-G800-C869 haplotypes were significantly associated with the increased risk of IS. C509T and T869C were in strong linkage disequilibrium (D' =0.51, r2 = 0.23). CONCLUSION:Our results suggest that TGF-?1 polymorphisms and their haplotypes are significantly associated with the risk of IS in North Indian population.
Project description:To make progress in cartilage repair it is essential to optimize protocols for two-dimensional cell expansion. Chondrocytes and SDSCs are promising cell sources for cartilage repair. We previously observed that priming with a specific growth factor cocktail (1?ng/mL transforming growth factor-?1, 5?ng/mL basic fibroblast growth factor, and 10?ng/mL platelet-derived growth factor-BB) in two-dimensional culture, led to significant improvement in mechanical and biochemical properties of synovium-derived stem cell (SDSC)-seeded constructs. The current study assessed the effect of growth factor priming on the proteome of canine chondrocytes and SDSCs. In particular, growth factor priming modulated the proteins associated with the extracellular matrix in two-dimensional cultures of chondrocytes and SDSCs, inducing a partial dedifferentiation of chondrocytes (most proteins associated with cartilage were down-regulated in primed chondrocytes) and a partial differentiation of SDSCs (some collagen-related proteins were up-regulated in primed SDSCs). However, when chondrocytes and SDSCs were grown in pellet culture, growth factor-primed cells maintained their chondrogenic potential with respect to glycosaminoglycan and collagen production. In conclusion, the strength of the label-free proteomics technique is that it allows for the determination of changes in components of the extracellular matrix proteome in chondrocytes and SDSCs in response to growth factor priming, which could help in future tissue engineering strategies.
Project description:Loss-of-function mutations in Na(v)1.5 cause sodium channelopathies, including Brugada syndrome, dilated cardiomyopathy, and sick sinus syndrome; however, no effective therapy exists. MOG1 increases plasma membrane (PM) expression of Na(v)1.5 and sodium current (I(Na)) density, thus we hypothesize that MOG1 can serve as a therapeutic target for sodium channelopathies.Knockdown of MOG1 expression using small interfering RNAs reduced Na(v)1.5 PM expression, decreased I(Na) densities by 2-fold in HEK/Na(v)1.5 cells and nearly abolished I(Na) in mouse cardiomyocytes. MOG1 did not affect Na(v)1.5 PM turnover. MOG1 small interfering RNAs caused retention of Na(v)1.5 in endoplasmic reticulum, disrupted the distribution of Na(v)1.5 into caveolin-3-enriched microdomains, and led to redistribution of Na(v)1.5 to noncaveolin-rich domains. MOG1 fully rescued the reduced PM expression and I(Na) densities by Na(v)1.5 trafficking-defective mutation D1275N associated with sick sinus syndrome/dilated cardiomyopathy/atrial arrhythmias. For Brugada syndrome mutation G1743R, MOG1 restored the impaired PM expression of the mutant protein and restored I(Na) in a heterozygous state (mixture of wild type and mutant Na(v)1.5) to a full level of a homozygous wild-type state.Use of MOG1 to enhance Na(v)1.5 trafficking to PM may be a potential personalized therapeutic approach for some patients with Brugada syndrome, dilated cardiomyopathy, and sick sinus syndrome in the future.
Project description:Mesenchymal stem cells (MSCs) are proposed to be useful in cartilage regenerative medicine, however, canine MSCs have been reported to show poor chondrogenic capacity. Therefore, optimal conditions for chondrogenic differentiation should be determined by mimicking the developmental process. We have previously established novel and superior canine MSCs named bone marrow peri-adipocyte cells (BM-PACs) and the objective of this study was to evaluate the effects of growth factors required for in vivo chondrogenesis using canine BM-PACs. Spheroids of BM-PACs were cultured in chondrogenic medium containing 10 ng/ml transforming growth factor-?1 (TGF-?1) with or without 100 ng/ml bone morphogenetic protein-2 (BMP-2), 100 ng/ml growth differentiation factor-5 (GDF-5) or 100 ng/ml insulin-like growth factor-1 (IGF-1). Chondrogenic differentiation was evaluated by the quantification of glycosaminoglycan and Safranin O staining for proteoglycan production. The expression of cartilage matrix or hypertrophic gene/protein was also evaluated by qPCR and immunohistochemistry. Spheroids in all groups were strongly stained with Safranin O. Although BMP-2 significantly increased glycosaminoglycan production, Safranin O-negative outer layer was formed and the mRNA expression of COL10 relating to cartilage hypertrophy was also significantly upregulated (P<0.05). GDF-5 promoted the production of glycosaminoglycan and type II collagen without increasing COL10 mRNA expression. The supplementation of IGF-1 did not significantly affect cartilaginous and hypertrophic differentiation. Our results indicate that GDF-5 is a useful growth factor for the generation of articular cartilage from canine MSCs.
Project description:BACKGROUND: Transforming growth factor-?1 (TGF-?1) is a multifunctional cytokine involved in inflammation and pathogenesis of atherosclerosis. There is scant information on the relation between variations within the TGF-?1 gene polymorphisms and risks of ischemic cerebrovascular diseases. Therefore, this case-controlled study was carried out to investigate the possible association of the TGF-?1 gene C-509T and T869C polymorphisms, and their combined genotypes with the risk of atherosclerotic cerebral infarction (CI) in the Chinese population. RESULTS: We recruited 164 CI patients and 167 healthy control subjects who were frequency-matched for age and gender. The frequencies of the -509TT genotype and T allele gene were significantly higher in the CI group (P = 0.007, P = 0.006). The frequencies of +869CC genotype and C allele were higher in the CI group (P = 0.002, P = 0.004). In the CI group, the individuals with -509TT genotype had a significantly higher level of plasma triglyceride (TG) (P = 0.017). +869CC genotype correlated significantly with higher level of plasma low density lipoprotein cholesterol (LDL-c) in the CI group (P = 0.015). With haplotype analysis, the frequency of the -509T/+869C combined genotype was significantly higher in the CI group than in controls (P < 0.001). CONCLUSIONS: Our study suggests that C-509T and T869C gene polymorphisms in TGF-?1 may be a critical risk factor of genetic susceptibility to CI in the Chinese population.