A Functional Polymorphism C-509T in <i>TGFβ-1</i> Promoter Contributes to Susceptibility and Prognosis of Lone Atrial Fibrillation in Chinese Population

<div><p>Transforming growth factor-β1 (<i>TGF-β1</i>) is an important mediator of atrial fibrosis and atrial fibrillation (AF). But the involved genetic mechanism is unknown. Herein, the <i>TGF-β1</i> C-509T polymorphism (rs1800469) was genotyped in a case-control study of 840 patients and 845 controls in Chinese population to explore the association between the polymorphism and susceptibility and prognosis of lone AF. As a result, the CT and/or TT genotypes had an increased lone AF risk [adjusted odds ratio (OR) = 1.50 for CT, OR = 3.72 for TT, and OR = 2.15 for CT/TT], compared with the <i>TGF-β1</i>CC genotype. Moreover, patients carrying CT/TT genotypes showed a higher possibility of AF recurrence after catheter ablation, compared with patients carrying CC genotype. In a genotype-phenotype correlation analysis using 24 normal left atrial appendage samples, increasing gradients of atrial <i>TGF-β1</i> expression levels positively correlated with atrial collagen volume fraction were identified in samples with CC, CT and TT genotypes. The <i>in vitro</i> luciferase assays also showed a higher luciferase activity of the -509T allele than that of the -509C allele. In conclusion, the <i>TGF-β1</i> C-509T polymorphism is involved in the etiology of lone AF and thus may be a marker for genetic susceptibility to lone AF and predicting prognosis after catheter ablation in Chinese populations. Therefore, we provide new information about treatment strategies and our understanding of <i>TGF-β1</i> in AF.</p></div

Representative photomicrographs of Masson staining showing the interstitial collagen (stained blue) (×200, bar = 50 µm).

<p>Collagen volume fraction is used to evaluate the degree of fibrosis.</p

Correlation between atrial protein expression of <i>TGF-β1</i> and collagen volume fraction in LAAs.

<p>Correlation between atrial protein expression of <i>TGF-β1</i> and collagen volume fraction in LAAs.</p

Results of Cox multivariate regression analysis on cumulative AF recurrence after catheter ablation.

<p>β, regression coefficient; HR, hazard ratio.</p><p>Results of Cox multivariate regression analysis on cumulative AF recurrence after catheter ablation.</p

Effect of the C-509 T polymorphism in the <i>TGF-β1</i> promoter activity.

<p>(A) Schematic representation of reporter plasmids containing the -509C or -509 T allele, which was inserted upstream of the luciferase reporter gene in the pGL3 basic plasmid. (B) Two constructs were transiently transfected into the mouse cardiac fibroblasts. The luciferase activity of each construct was normalized against the internal control of Renilla luciferase (blank). Values are mean±SD.</p

Baseline characteristics of subjects with LAF and controls.

<p>Values are presented as mean±SD or number of patients.</p><p>ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.</p><p>Baseline characteristics of subjects with LAF and controls.</p

Atrial expression of <i>TGF-β1</i> among different genotypes in healthy heart donors.

<p>(A) Representative Western immunoblots. (B) Gene expression in left atrial appendages (LAAs). (C) Semi-quantitative protein content in LAAs. Boxes show interquartile ranges, and bars represent the 10th and 90th percentiles.</p

Kaplan-Meier survival curves showing freedom from AF recurrence after catheter ablation according to <i>TGF-β1</i> C-509T polymorphism.

<p>(A) Survival free from AF recurrence in CC (n = 120), CT (n = 231) and TT (n = 259) groups. (B) Survival free from AF recurrence in CC (n = 120) and CT/TT (n = 490) groups.</p

Genotype and allele frequencies of the <i>TGF-β1</i> C-509T polymorphism between the cases and controls and their associations with risk of LAF.

a<p>Two-sided χ² test for either genotype distributions or allele frequencies between the cases and controls.</p>b<p>Adjusted for age, sex, body mass index, smoking status, drinking status, and hypercholesteremia in logistic regression model.</p><p>Genotype and allele frequencies of the <i>TGF-β1</i> C-509T polymorphism between the cases and controls and their associations with risk of LAF.</p

Gefitinib or Erlotinib as Maintenance Therapy in Patients with Advanced Stage Non-Small Cell Lung Cancer: A Systematic Review

<div><p>Background</p><p>Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), gefitinib and erlotinib have been tested as maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC). The studies are quite heterogenous regarding study size and populations, and a synopsis of these data could give some more insight in the role of maintenance therapy with TKI.</p> <p>Methods</p><p>In September 2012 we performed a search in the pubmed, EMBASE and Cochrane library databases for randomized phase III trials exploring the role of gefitinib or erlotinib in advanced non-small cell lung cancer. Through a rigorous selection process with specific criteria, five trials (n = 2436 patients) were included for analysis. Standard statistical methods for meta-analysis were applied.</p> <p>Results</p><p>TKIs (gefitinib and erlotinib) significantly increased progression-free survival (PFS) [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50–0.76, I² = 78.1%] and overall survival (HR 0.84, 95% CI 0.76–0.93, I² = 0.0%) compared with placebo or observation. The PFS benefit was consistent in all subgroups including stage, sex, ethnicity, performance status, smoking status, histology, EGFR mutation status, and previous response to chemotherapy. Patients with clinical features such as female, never smoker, adenocarcinoma, Asian ethnicity and EGFR mutation positive had more pronounced PFS benefit. Overall survival benefit was observed in patients with clinical features such as female, non-smoker, smoker, adenocarcinoma, and previous stable to induction chemotherapy. Severe adverse events were not frequent. Main limitations of this analysis are that it is not based on individual patient data, and not all studies provided detailed subgroups analysis.</p> <p>Conclusions</p><p>The results show that maintenance therapy with erlotinib or gefitinib produces a significant PFS and OS benefit for unselected patients with advanced NSCLC compared with placebo or observation. Given the less toxicity of TKIs than chemotherapy and simple oral administration, this treatment strategy seems to be of important clinical value.</p> </div