高血压基因研究及应用前景

单基因遗传性高血压疾病的基因诊断 自上世纪九十年代以来,已有十种左右的单基因性继发性高血压疾病的致病基因被克隆,如Liddle综合征、糖皮质激素可治性醛固酮增多症、多发性内分泌瘤、表征性盐皮质激素增多症、11β-羟化酶缺乏症、17α-羟化酶缺乏症和Gordon综合征等疾病.由于上述疾病的致病基因和致病突变已经明确,因此临床上可以通过基因突变筛查实现基因诊断.     

单基因糖尿病的研究进展

单基因糖尿病在儿童糖尿病中约占1％～4％,大部分易被误诊为1型或2型糖尿病.目前已发现40余种单基因糖尿病的致病基因,其通过复杂的转录因子网络调控等途径影响胰腺的发育、分化、功能和形态的完整性等.单基因糖尿病的临床表型、遗传方式不尽相同,其确诊依靠基因诊断,基因诊断明确后可以针对性的开展个体化治疗和遗传咨询.     

2型糖尿病易感基因对中国人2型糖尿病遗传易感性影响的系统评价

2型糖尿病（T2DM）是遗传异质性疾病,从遗传模式上讲可分为单基因遗传性糖尿病和多基因遗传性糖尿病。前者往往由一个作用较强的基因突变导致,发病较早,呈现孟德尔遗传模式;后者由多个作用较弱的基因再加上环境因素共同导致疾病的发生。在T2DM中,由于基因诊断技术还不能广泛应用,     

2022《EHRA/HRS/APHRS/LAHRS心血管疾病基因检测专家共识》要点解读

遗传性心血管疾病是指由基因变异引起，符合孟德尔遗传规律的一系列心血管疾病，常表现出家族性聚集。相关疾病包括长QT综合征、短QT综合征、Brugada综合征等遗传性心律失常综合征，肥厚型心肌病、扩张型心肌病、致心律失常性心肌病等结构性心肌病。随着基因筛查在临床中的应用，临床医生应该如何认识基因筛查的重要性和局限性 2022《EHRA/HRS/APHRS/LAHRS心血管疾病基因检测专家共识》概述了基因检测的基本原则，并介绍了遗传性心律失常综合征、心肌病等疾病的基因检测现状，对临床工作具有重要指导意义。     

肾素-血管紧张素-醛固酮系统基因多态性与心血管疾病关系的研究进展

肾素-血管紧张素-醛固酮系统在心血管疾病的发生和发展中发挥重要的作用,由遗传决定的该系统基因多态性对心血管疾病的影响成为近年来人们研究的热点之一,某些心血管疾病与某个单基因或多基因多态性密切相关。     

基因多态性与动脉粥样硬化性心血管疾病相关性的研究进展

心血管疾病是影响人类生命和健康的重要疾病。导致心血管病发病的因素有很多,其中遗传方面的因素近几年来渐被重视,特别是与心血管病发病过程紧密相关的基因多态性倍受关注,且已取得可喜成果,但也存在不少问题。本研究简要介绍心血管疾病相关基因多态性研究进展,并就常见问题提出一些看法,供同道参考。     

中国人单基因突变糖尿病及肥胖病的研究

对糖尿病和肥胖病病因学研究的不断发展使许多单基因糖尿病和肥胖病被发现。对中国人已开展的青少年发病型成人糖尿病、线粒体糖尿病、黑皮素4受体(MC4R)及部分伴糖尿病的遗传综合征的研究提示,单基因肥胖病及糖尿病存在种族、遗传和临床特点的异质性。对这些特殊类型糖尿病和肥胖病的深入认识将有助于对疾病的病因细致分类和个体化治疗的指导。     

遗传,环境和心血管疾病

普通慢性多因素疾病对医疗服务的需求最为明显。在两方国家里，它导致的死亡率位居第一。这些疾病包括心血管疾病、癌症、糖尿病和精神紊乱症。它们在家族中呈现遗传分离，但不符合孟德尔单基因分离规律。多个易感基因和多种环境因素作用通过动态的、外源的、调节机制最终整合成疾病的表型，这直接导致了疾病在个体、家族和群体中的分布特点。多因素疾病的遗传分析是目前人类遗传学家面临的最复杂最困难的研究。     

高血压病的药物基因组学研究

高血压是冠心病、脑卒中等心脑血管疾病及终末期肾功能衰竭的独立危险因素 ,严重危害人类身体健康。流行病学显示 ,原发性高血压病主要受遗传和环境因素影响 ,但它并非孟德尔单基因遗传 ,而受多基因控制。目前对于高血压的治疗主要依据医生的临床经验或各种用药指南 ,然而不同患者使用相同的降压药物后常常表现出不同的疗效 ,副作用亦可能千差万别。随着分子生物学研究的飞速发展 ,人们发现这种个体差异的本质源于基因差异。自从 1 990年“人类基因组计划”启动以来 ,所有基因测序工作已基本完成 ,对于许多与遗传相关的疾病 ,人们期望能从基…     

应用生命科学的新成就推动心血管疾病的临床和基础研究

虽然不同的心血管疾病 (如冠心病、心肌梗死、高脂血症等 )的临床表型和发病机制上都是不一样的。但是 ,他们之间包含着许多内在的联系 ,例如 ,脂质紊乱、氧化应激、炎症和血栓形成等。这些疾病的发生、形成包含着大量的基因功能改变、基因与基因的相互作用、基因与环境的相互影响。因此 ,引入生命科学新理念 ,应用其新技术、新方法是推动和提高心血管疾病临床和基础研究水平的关键所在。一、应用单核苷酸多态性和单倍型研究成果开展心血管疾病研究基因多态性或称为单核苷酸多态性 (singlenucleotidepolymorphism ,SNP)是指在基因组水平上…     

Phenotypic and genotypic characterization of inflammatory bowel disease in children under six years of age in China

AIM To analyze clinical differences between monogenic and nonmonogenic very-early-onset inflammatory bowel disease(VEO-IBD) and to characterize monogenic IBD phenotypically and genotypically via genetic testing. METHODS A retrospective analysis of children aged 0 to 6 years diagnosed with VEO-IBD in a tertiary hospital in southern China from 2005 to 2017 was performed. Clinical data for VEO-IBD patients were collected, and genetic characteristics were analyzed using whole exome sequencing or target gene panel sequencing. RESULTS A total of 54 VEO-IBD patients were included in this study. A diagnosis of Crohn's disease(CD) or CDlike intestinal manifestations accounted for 72.2% of the VEO-IBD cases. Nine patients(16.7%) were identified by genetic testing as having monogenic IBD. The median age of diagnosis in the monogenic group was younger than that of the nonmonogenic IBD group, at 18 mo(interquartile range(IQR): 4 to 78) and 43.5 mo(IQR: 3 to 173), respectively; the P-value was 0.021. The incidence of perianal disease in the monogenic group was higher than that in the nonmonogenic group(P = 0.001). However, there were no significant differences between weight-forage and height-for-age Z-scores between the two groups, and similar laboratory results were obtained for the two groups. Five patients were found to have IL10 receptor mutation, two patients had chronic granulomatous disease, one patient had common variable immunodeficiency disease, and one patient had X-linked inhibitor of apoptosis protein deficiency. CONCLUSION A high proportion of monogenic IBD was observed in the VEO-IBD group, especially with disease onset before the age of 6 mo. Monogenic IBD and nonmonogenic IBD exhibited similar clinical features. Furthermore, next-generation sequencing played an important role in the diagnosis of monogenic IBD, and IL10 receptor mutation was predominant in this cohort.     

Genetic Testing in Inherited Arrhythmias: Approach,Limitations, and Challenges

Genetic testing is playing an ever-expanding role in cardiovascular care and is becoming part of the “toolkit” for the cardiovascular clinician. In patients with inherited arrhythmias, genetic testing can confirm a suspected diagnosis, establish a diagnosis in unexplained cases, and help facilitate cascade family screening. Many inherited arrhythmia syndromes are monogenic diseases arising from a single pathogenic variant involved in the structure and function of cardiac ion channels or structural proteins. As such, “arrhythmia gene panels” will often cast a wide net for such heritable diseases. However, challenges may arise when genetic testing results are ambiguous, or when genetic testing results (genotype) and clinical phenotypes do not match. In cases of “genotype-phenotype matching,” genetic results complement the clinical phenotype and genetic testing can be used in diagnosis, family screening, and occasionally prognostication. It becomes more challenging when genetic results are negative or noncontributory and “contradict” the clinical phenotype. “Genotype mismatches” can also occur when genotype-positive patients have no clinical phenotype, or when genetic testing results point towards a completely different disease than the clinical phenotype. We discuss an approach to genetic testing and review the challenges that may arise when interpreting genetic testing results. Genetic testing has opened a wealth of opportunities in the diagnosis, management, and cascade screening of inherited arrhythmia syndromes, but has also opened a “Pandora’s box” of challenges. Genetic results should be interpreted with caution and in a multidisciplinary clinic, with support from genetic counsellors and an expert with a focused interest in cardiovascular genetics.     

Current perspectives in genetic cardiovascular disorders: from basic to clinical aspects

We summarize recent advances in the clinical genetics of hypercholesterolemia, hypertrophic cardiomyopathy (HCM), and lethal arrhythmia, all of which are monogenic cardiovascular diseases being essential to understanding the heart and circulatory pathophysiology. Among the issues of hypercholesterolemia which play a pivotal role in development of vascular damages, familial hypercholesterolemia is the common genetic cardiovascular disease; in addition to identifying the gene mutation coding low-density lipoprotein receptor, lipid kinetics in autosomal recessive hypercholesterolemia as well as in proprotein convertase subtilisin/kexin 9 gene mutation were recently demonstrated. As for HCM, some gene mutations were identified to correlate with clinical manifestations. Additionally, a gene polymorphism of the renin–angiotensin system in development of heart failure was identified as a modifier gene. The lethal arrhythmias such as sudden death syndromes, QT prolongation, and Brugada syndrome were found to exhibit gene mutation coding potassium and/or sodium ion channels. Interestingly, functional analysis of these gene mutations helped to identify the role of each gene mutation in developing these cardiovascular disorders. We suggest considering the genetic mechanisms of cardiovascular diseases associated with hyperlipidemia, myocardial hypertrophy, or lethal arrhythmia in terms of not only clinical diagnosis but also understanding pathophysiology of each disease with therapeutic aspects.     

Phenomics, lipodystrophy, and the metabolic syndrome

The metabolic syndrome (MetS) is a common multiplex cluster of phenotypes strongly related to cardiovascular disease that includes central obesity with hypertension, dyslipidemia, and type 2 diabetes. The core molecular defect of the MetS is insulin resistance; indeed, the terms "MetS" and "insulin resistance syndrome" often are used interchangeably. The successful translation to clinical medicine of molecular genetic research on other rare monogenic metabolic disorders has stimulated the evaluation of such rare monogenic forms of insulin resistance as partial lipodystrophy resulting from mutations in either LMNA or PPARG genes. Careful phenotypic evaluation of carriers of monogenic insulin resistance using a range of diagnostic methods--an approach sometimes called "phenomics"--may help to find early presymptomatic biomarkers of cardiovascular disease, which, in turn, may uncover new pathways and targets for interventions for the common MetS, diabetes, and atherosclerosis.     

Molecular genetics of heart diseases. A familial approach

Cardiovascular diseases are the result of the interaction of genetic and environmental factors and constitute a complex group of monogenic and, above all, polygenic pathologies. The possibility of localising the responsible genetic factors on the chromosomes by the study of families may eventually enable a predictive diagnosis, better orientation of treatment and a fuller understanding of the interaction of the different cardiovascular risk factors. The family approach allows the confirmation or the elimination of the role of a given gene of major or minor expression because of the polymorphisms of DNA.     

Clinical, diagnostic, and therapeutic aspects of familial hypercholesterolemia

Heterozygous familial hypercholesterolemia (FH) is a common inherited disorder of lipoprotein metabolism. FH is characterized by elevated levels of low-density lipoprotein cholesterol, the presence of tendon xanthomas, and premature cardiovascular disease. The underlying molecular defect of FH consists of mutations in the gene coding for the low-density-lipoprotein-receptor protein, detection of which provides the only unequivocal diagnosis. Although the cause of FH is monogenic, there is wide variation in the onset and severity of atherosclerotic disease in these patients. Additional atherogenic risk factors of environmental, metabolic, and genetic origin are presumed to influence the clinical phenotype in FH. Criteria used to identify individuals with FH include a combination of clinical characteristics, personal and family history of early coronary artery disease, and biochemical parameters. Since the introduction in 1989 of statins, which have been shown to be effective and to delay or prevent the onset of cardiovascular disease, drug treatment of FH has greatly improved. New lipid-lowering agents are presently being developed for clinical use. This review provides an update on the clinical, diagnostic, and therapeutic aspects of heterozygous familial hypercholesterolemia.     

Personalisierte Therapie in der Kardiologie

Improved therapy and prophylaxis of cardiovascular diseases have contributed to an increase in life expectancy like no other field of medicine. However, many cardiological diseases remain untreatable and standard therapies often work only in a minority of patients or cause more harm than benefit. Personalized approaches appear to be a promising solution. Monogenic heart diseases are paradigmatic for this approach and can in rare cases be treated mutation specifically. Overall, however, success remains limited. Next generation sequencing will facilitate the identification of mutations causing diseases. Cell culture models based on induced pluripotent stem cells open the perspective of individualized testing of disease severity and pharmacological or genetic therapy. In contrast to monogenic diseases genetic testing plays no practical role yet in the management of multifactorial cardiovascular diseases. Biomarkers can identify individuals with increased cardiovascular risk. Furthermore, biomarker-guided therapy represents an attractive option with troponin-guided therapy of acute coronary syndromes as a successful example. Individual responses to drugs vary and are partly determined by genes. Simple genetic analyses can improve response prediction and minimize side effects in cases such as warfarin and high doses of simvastatin. Taken together personalized approaches will gain importance in the cardiovascular field but this requires the development of better methods and research that quantifies the true value of the new knowledge.     

Reducing cardiovascular risk in patients with familial hypercholesterolemia: Risk prediction and lipid management

Familial hypercholesterolemia (FH) is a frequent genetic disorder characterized by elevated low-density lipoprotein (LDL)-cholesterol (LDL-C) levels and early onset of atherosclerotic cardiovascular disease. FH is caused by mutations in genes that regulate LDL catabolism, mainly the LDL receptor (LDLR), apolipoprotein B (APOB) and gain of function of proprotein convertase subtilisin kexin type 9 (PCSK9). However, the phenotype may be encountered in individuals not carrying the latter monogenic defects, in approximately 20% of these effects of polygenes predominate, and in many individuals no molecular defects are encountered at all. These so-called FH phenocopy individuals have an elevated atherosclerotic cardiovascular disease risk in comparison with normolipidemic individuals but this risk is lower than in those with monogenic disease. Individuals with FH are exposed to elevated LDL-C levels since birth and this explains the high cardiovascular, mainly coronary heart disease, burden of these subjects. However, recent studies show that this risk is heterogenous and depends not only on high LDL-C levels but also on presence of previous cardiovascular disease, a monogenic cause, male sex, smoking, hypertension, diabetes, low HDL-cholesterol, obesity and elevated lipoprotein(a). This heterogeneity in risk can be captured by risk equations like one from the SAFEHEART cohort and by detection of subclinical coronary atherosclerosis. High dose high potency statins are the main stain for LDL-C lowering in FH, however, in most situations these medications are not powered enough to reduce cholesterol to adequate levels. Ezetimibe and PCSK9 inhibitors should also be used in order to better treat LDL-C in FH patients.     

Genetic information in the diagnosis and treatment of hypertension

Advancement in cardiovascular science should be measured by a number of new diagnostic and therapeutic options applied in clinical practice as a result of translational research. Hypertension genetics is a good example of such a successful transfer of knowledge from bench to bedside. There are genetic methods currently used as diagnostic tools in patients presenting with secondary forms of hypertension, including primary hyperaldosteronism, Cushing’s syndrome, pheochromocytoma, and chronic kidney disease. Directed treatment that corrects pathophysiologic abnormalities is available for several monogenic forms of hypertension as a result of uncovering their underlying genetic mechanisms. Progress in hypertension pharmacogenetics and pharmacogenomics brings closer a perspective of personalized antihypertensive treatment and gene transfer strategies, which, although still considered as innovative approaches, may soon become options to treat, control, and, possibly, cure hypertension.     

Genetics 101 for Cardiologists: Rare Genetic Variants and Monogenic Cardiovascular Disease

Monogenic diseases have a distinctive familial inheritance that follows Mendel's laws, showing patterns like dominant, recessive, or X-linked. There are > 7000 monogenic diseases curated in databases, and together they account for up to 10% of all illnesses encountered in the emergency room or clinic. Despite the rarity of individual monogenic conditions, mapping their causative genes and mutations is important for several reasons. First, knowing the causative gene and mutation could provide actionable information for genetic counselling. Sometimes, knowing the gene and mutation allows for early diagnosis in affected families, which is important if there is an evidence-based intervention. Second, the implication of a mutant gene as being causative for a clinical phenotype provides strong evidence of the importance of the gene product in a cellular or biochemical pathway. Discovery of new molecular pathways in families with rare diseases can serve as the first step toward developing rational therapies to help not only affected families, but also patients with less extreme, nongenetic forms of the same condition. For instance, the study of rare patients with familial hypercholesterolemia helped in developing statin drugs, initially as a treatment for familial hypercholesterolemia but now a widely used therapy to reduce low-density lipoprotein cholesterol and cardiovascular disease risk.