The Correlation Between Epigenetic Regulation Of Hypertension And Target Organ Damage Stroke And The New Mutation Of FBN1 Gene Lead To Cardiovascular Phenotype Of Marfan Syndrome

Background and Purpose:In 2005, the American Stroke Association’s Task Force made recommendations for the establishment of stroke systems of care to optimize patient care and management processes, as well as improve patient outcomes. A fully functional stroke system of care would reduce stroke-related deaths by 2% to 3% annually. Poststroke disability would also be reduced, which would improve the quality of life and reduce the burden on patients, their families, and governments. Stroke system of care plays key roles both in providing effective therapies and in improving the overall outcome of patients with stroke. Our purpose was to develop and evaluate the system in Chinese rural areas.Methods:A stroke system of care was developed from November 2009 to November 2010 in 3 townships in Ganyu County. An additional 3 matched townships were invited as controls. We first investigated stroke management in these townships and then implemented stroke system of care and an education campaign in the 3 intervention townships. The effectiveness of the system was then evaluated.Results:There were 1036 patients with new stroke among 344345 subjects in the 6 rural communities. The incidence of stroke in the rural areas was 301/100000, and the mortality rate was 55/100000. During the 2-year follow up, the proportions significantly increased in the intervention communities after the implementation of the stroke system of care and education campaign when compared with the control communities, including patients presenting at rural hospitals within 3 hours of symptom onset (in 2012:12.01% versus 8.13%; P=0.044; in 2013:15.15% versus 9.70%, P=0.008), diagnosed by computed tomographic scanning within 24 hours of admission (in 2012:61.70% versus 55.08%; P=0.036; in 2013:69.09% versus 61.98%; P=0.017), and received thrombolytic treatment (in 2012:2.07% versus 1.02%; P=0.181; in 2013:3.03% versus 1.14%; P=0.034). In 2012,43 (8.90%) patients with stroke in the intervention communities and 48 (9.76%) in the control communities died. In 2013, the case fatality in the intervention communities significantly decreased compared with the control communities (6.06% versus 9.70%; P=0.032). The disability rate of stroke was significantly reduced in the intervention communities at postintervention (45.25% versus 51.52%; P=0.045).Conclusions:This is the first study to develop, implement, and evaluate a stroke system of care in Chinese rural areas. We also confirmed that this system is reliable and practical. Community education can increase public knowledge of stroke and shorten the period of time between stroke onset and hospital presentation. Implementation of the system led to more patients with stroke receiving thrombolytic treatment.Clinical Trial Registration-URL:http://www.chictr.org.Unique identifier:ChiCTR-RCH-13003408.Purpose:Overweight and obesity are becoming more widespread with global projections of more than 2.16 billion overweight and 1.12 billion obese individuals by 2030. It is also correlated with an increased risk of type-2-diabetes, cardiovascular disease, cancer and overall mortality. Despite intensive research, current efforts to reduce obesity by diet, exercise, education, surgery and drug therapies are failing to provide effective long-term solutions. At an individual level, obesity occurs when abnormal amounts of triglycerides are stored in adipose tissue and released from adipose tissue as free fatty acids with detrimental effects. Obesity is an independent risk factor of essential hypertension. Patients with obesity-related hypertension have high morbidity and mortality from cardiovascular diseases and different comorbidities (chronic kidney disease, diabetes, apnea and atherosclerosis). Obesity increases tubular absorption of sodium and promotes a compensatory shift in the pressure natriuresis curve towards higher blood pressure in response to elevated plasma sodium levels. In humans with diabetes mellitus and animal models with obesity, sodium-glucose cotransporter-2 expression is increased in the proximal convoluted tubule, which correlates with increased glucose reabsorption, leading to elevated plasma glucose levels and sodium reabsorption, which also contributes to sodium retention. Obesity produced by high-fat diet leads to increased activating phosphorylation of Na+-KT-2C1-cotransporter (NKCC2) and activity of NKCC2 in vivo as contributors to the pathogenesis of obesity-related hypertension. So obesity-related hypertension might be resulted from activation of sodium channels and increased sodium reabsorption via multiple pathways. The goal of this study was to characterize DNA methylation profile in peripheral blood leukocytes in two groups of simple obese group, control group, hypertensive group and obesity-related hypertensive group using a genome wide approach. Identification of methylation changes in specific genes will provide important targets for further study into the mechanisms of obesity’s effect on epigenetic modification of epithelial sodium channel gene.Methods:A cohort of 100 subjects was recruited in 2012, including 25 patients with obesity,25 patients with hypertension,25 patients with obese-related hypertension, and 25 controls. All the subjects with 50-74 years had no cardiovascular and cerebrovascular diseases. Obesity was defined as BMI 27 kg/m2 or more; the control group had normal body weight (18.5 kg/m2≤BMI≤24 kg/m2) and normal blood pressure (systolic blood pressure less than 140 mmHg and diastolic blood pressure less than 90 mmHg). In thisPurpose:Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue primarily affecting cardiovascular, ocular and skeletal systems. It is estimated that the prevalence of this disease is 1/5000-1/10000 with 25% sporadic cases. Extensive studies have demonstrated that different mutations in the fibrillin-1 gene (FBN1) coding for fibrillin-1 cause MFS. The FBN1 mutation disrupts the extracellular processing of profibrillin to fibrillin, and then the unprocessed profibrillin is not incorporated into microfibrils. Patients with MFS show marked phenotypic variation in cardiovascular, ocular and skeletal systems. In this study, we reported two Chinese families with MFS which resulted from new FBNl mutations, mainly contributing to their cardiovascular manifestations.Methods:Two patients (patient-1 and patient-2) were admitted to our hospital due to aortic aneurysm surgery and diagnosed as MFS according to the revised Ghent criteria. Peripheral blood samples were collected and genomic DNAs were isolated from available cases, namely, patient-1 and his daughter and son, and patient-2 and his parents. The patient-1 pedigree had typical phenotypes of Marfan syndrome, so we only detected mutations in the FBN1 gene. Two generation sequencing was performed to identify the causative gene. FBN1 mutations were confirmed by sequencing.Results:The sequencing results from proban-1 and his daughter revealed a novel heterozygous frameshift mutation in exon 12 of FBNl, c.1560-1566 (GAGCACA) deletion, which resulted in a change from amino acid 520, termination codon occurred at amino acid 575, the subsequent amino acids deleted. Moreover, no mutation was observed in his son. In patient-2, one novel missense mutation, c.6575T>C, p.2068C＞R in exon 50 of FBN1 was identified. In addition, no mutation was observed in his parents.Conclusions:Two novel mutations in exon 12 and 50 of FBN1 were identified respectively in two Chinese family members with MFS. Importantly, these mutations might be responsible for cardiovascular manifestations. Our findings expanded the FBN1 mutation spectrum and provided more knowledge on genotype-phonotype correlations underlying FBN1 mutations. study, hypertensive patients had systolic blood pressure≥160 mmHg or diastolic blood pressure≥100 mmHg or taking antihypertensive drugs; obesity-related hypertension was fulfilled with the criteria of obesity and hypertension. According to the results of quality control, genome-wide methylation analysis was performed using Illumina 450k BeadChip in 58 DNA samples and gene expression profiling analysis was performed using Affymetrix Human Gene 2.0ST Array in 52 RNA samples. DNA methylation and mRNA expression profiles were investigated in differentially hypomethylated and hypermethylated CpG sites.Results:DNA methylation and mRNA expression showed that 4 hypomethylated (cg01601×××× cg08330×××, cgl6819×××,cg19651×××(cg12623×××) and 1 hypermethylated (cg02193×××) CpG site were identified in obese group (G1) compared to the control group (G2),5 hypomethylated CpG sites (cg01601×××,cg08330×××, cg16819×××,cg19651×××,cgl2623xxx) in hypertensive group (G3) compared with the control group and 1 hypomethylated CpG site (cg02193×××) in the obesity-related hypertensive group (G4) compared with the obese group. Importantly,3 hypomethylated CpG sites (cg01601×××, cg08330××××,Cg19651×××) located in the body region of A gene were identified in G1 vs. G2 and G2 vs. G3, which was related to mRNA up-regulation or down-regulation of A gene. One CpG site (cg02193×××) located in 5’UTR of B gene was hypermethylated in Gl vs. G2 and hypomethylated in G4 vs. G1, which was associated with increased mRNA expression of B gene.Conclusions:DNA methylation profiles and mRNA expression pattern were investigated in the peripheral blood cells in obese patients, hypertensive patients, obesity-related hypertensive patients and health controls. Our results showed that 4 CpG sites (cg01601×××, cg08330×××, cg19651×××,cg02193×××) had methylation alteration both in obesity and hypertension and resulted in upregulation or downregulation of A and B gene mRNA, suggesting that these methylation sites might be associated with obesity-related hypertension.