A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10 Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.
PAR-2 signaling activates macrophages and promotes vascular inflammation, increasing atherosclerosis in ApoE mice. This signaling pathway may also participate in atherogenesis in humans.
Aims Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis. Methods and results Apolipoprotein E-deficient (Apoe−/−) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe−/− mice. Genetic deletion of Sting in Apoe−/− mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe−/− mice. In contrast, bone marrow-specific STING expression in Apoe−/− mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-β) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP. Conclusion Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.
BackgroundMetabolic syndrome (MetS) is a clustering of metabolic risk factors for cardiovascular diseases and type 2 diabetes. The study aimed to estimate the prevalence of MetS, its components, and their associations among rural middle-aged population in Vietnam.MethodsA cross-sectional study with a representative sample (n = 2443) was conducted to collect data on demographic, socioeconomic, anthropometric, lifestyles, plasma glucose, and lipid profile. The age- and sex-adjusted prevalences of MetS and its components were calculated using the direct standardization. Associations of risk factors with MetS were evaluated using logistic regression, taken into account the confounding factors.ResultsThe total age- and sex-adjusted prevalence (95% CI) of MetS was 16.3% (14.0 - 18.6). The most frequent component of MetS was high triglycerides (43.2%), followed by low HDL-C (42.0%), elevated blood pressure (29.2%), high plasma glucose (14.3%), and central obesity (12.3%). Of the total population, only 17.6% did not have any component of MetS and more than 40% had at least two MetS components. The association of MetS with residence, age, body mass index, marital status, and siesta time per day was statistically significant in univariate analysis and replicated in multivariate analysis.ConclusionThe MetS prevalence and its components are common and major public health burden in the middle-aged adults in Vietnam. Habitants living in urban, being never-married, having an increase in age, BMI, and siesta time per day are significantly associated with MetS, and they should be paid much more attention for screening and implementing preventive activities.
Activated factor X (FXa) plays a central role in the coagulation cascade, while it also mediates vascular function through activation of protease-activated receptors (PARs). Here, we examined whether inhibition of FXa by rivaroxaban, a direct FXa inhibitor, attenuates endothelial dysfunction in streptozotocin (STZ)-induced diabetic mice. Induction of diabetes increased the expression of a major FXa receptor, PAR2, in the aorta (P < 0.05). Administration of rivaroxaban (10 mg/kg/day) to diabetic wild-type (WT) mice for 3 weeks attenuated endothelial dysfunction as determined by acetylcholinedependent vasodilation compared with the control (P < 0.001), without alteration of blood glucose level. Rivaroxaban promoted eNOS Ser1177 phosphorylation in the aorta (P < 0.001). Induction of diabetes to PAR2-deficient (PAR2 −/−) mice did not affect endothelial function and eNOS Ser1177 phosphorylation in the aorta compared with non-diabetic PAR2 −/− mice. FXa or a PAR2 agonist significantly impaired endothelial function in aortic rings obtained from WT mice, but not in those from PAR2 −/− mice. FXa promoted JNK phosphorylation (P < 0.01) and reduced eNOS Ser1177 phosphorylation (P < 0.05) in human coronary artery endothelial cells (HCAEC). FXa-induced endothelial dysfunction in aortic rings (P < 0.001) and eNOS Ser1177 phosphorylation (P < 0.05) in HCAEC were partially ameliorated by a JNK inhibitor. Rivaroxaban ameliorated diabetes-induced endothelial dysfunction. Our results suggest that FXa or PAR2 is a potential therapeutic target. Accumulating evidence suggests that the blood coagulation system participates in various disease processes. Activated blood coagulation factor X (FXa) plays a central role in the coagulation cascade, while it also elicits various cellular responses in vascular cells through activation of protease activated receptors (PAR) 1-5. PARs are a family of G protein-coupled, seven transmembrane domain receptors, which are activated following proteolytic cleavage of their extracellular N-terminus. Among the four subtypes of the PAR family, PAR2, one of the major receptors of FXa, is expressed in vascular cells and leukocytes, but not in platelets 6-8. Previous studies have shown that PAR2 mediates a number of physiological and pathological processes such as inflammation, angiogenesis and vasoregulation 9-14. Together with the clinical approval of direct FXa inhibitors, the role of FXa-PAR2 signaling in vascular regulation has attracted much attention. In fact, several clinical studies have shown that rivaroxaban, the first oral FXa inhibitor, reduced cardiovascular events in patients with coronary artery disease 15,16. In addition to inhibition of the coagulation cascade, several basic research studies, including our own, suggested that vascular protective properties of rivaroxaban by inhibiting FXa might play a role in these results 17-21. The vascular complications associated with atherosclerosis are the most serious manifestations in patients with diabetes. Diabetes causes endothelial dysfunction cha...
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