线粒体DNA点突变有关的中国大家族母系遗传性高血压研究

目的 研究具有母系遗传性特点的原发性高血压中国大家系临床与遗传学特点。方法 对入选的1865例原发性高血压患者进行线粒体DNA测序分析,发现线粒体DNA点突变,对其进行家系随访,收集该家系成员临床资料进行分析,分析其遗传学特点。结果 该家系中母系成员高血压患病率高达55.6%,非母系成员高血压患病率15.6%（P＜0.01）;母系成员高血压发病年龄有提前的趋势[Ⅱ代（62.0±6.2）岁;Ⅲ代（46.3±5.8）岁;Ⅳ代（23.3±2.9）岁]母系成员血糖、总胆固醇、血钠明显高于非母系成员（P＜0.05）,而超声结果没有明显差异;遗传学分析发现母亲患病子代发病率明显高于父亲患病者（P＜0.05）,男女发病率没有差异（P＞0.05）;结论 该家系母系成员高血压发病率明显高于非母系成员,该家系符母系遗传特点,高血压发病与线粒体DNA突变有关,提示线粒体DNA突变可能与母系遗传性高血压发病有关,在高血压发病中发挥重要作用。     

DNA甲基化与原发性高血压关系研究进展

表观遗传学在原发性高血压(EH)的发病机制中发挥重要的作用,DNA甲基化是表观遗传学最明确的修饰方式,与EH的病理过程密切相关。肾素-血管紧张素系统、水盐代谢、血管内皮功能、炎性因子等相关基因启动子区域发生异常甲基化可调控基因表达,使血压升高。了解特定基因甲基化修饰在EH发生和发展中的作用,将为EH的预防和诊疗提供新的靶点。现就特定基因甲基化修饰在EH中的分子机制进行综述。     

线粒体DNA突变与衰老

衰老又称老化,通常是指在正常状况下生物发育成熟后,随年龄增加,自身功能减退,内环境稳定能力与应激能力下降,结构、组分逐步退行性改变,趋向死亡,不可逆转的现象[1].1956年,Harman首先提出来衰老的自由基假说,之后又提出人类衰老过程中线粒体DNA是自由基攻击的首要目标.19世纪80年代初Miquel等提出"细胞衰老学说",认为衰老是由于氧自由基攻击线粒体DNA引起的一个生物过程.1989年Linnane等提出线粒体衰老假说.随着时代的发展与科技的进步,人们越来越关注线粒体与衰老的关系,线粒体与衰老的关系也成为研究前沿.\     

线粒体DNA与心血管疾病相关性的研究进展

线粒体作为人体的能量工厂,具有自己独立的基因组——线粒体DNA(mtDNA)。心肌作为一种高耗能组织,线粒体的正常供能至关重要,而mtDNA在一定程度上可以影响线粒体的供能。根据最新的全球疾病负担研究,心血管疾病(CVD)是导致死亡的主要原因,冠心病是CVD患者主要的死亡原因之一。mtDNA作为一种新发现的生物标志物,与冠心病的发生机制、潜在的治疗靶点、对预后的预测等具有很强的关联性,本文就mtDNA与冠心病相关性的研究进展进行综述。     

线粒体tRNA突变与高血压关系的研究进展

线粒体基因突变与多种疾病的发生有关,虽然转移RNA（tRNA）基因只占整个线粒体基因组的10%,但它们却是研究线粒体基因突变与疾病发生关系的热点。既往高血压遗传学的研究主要集中在核基因方面,近年来研究发现线粒体DNA突变可能参与原发性高血压（EH）的发生与发展,且越来越多的线粒体tRNA也被报道与EH的发生和发展密切相关。本文对线粒体tRNA突变与高血压发病的关系及其机制进行了综述。     

线粒体DNA突变与衰老及冠心病的关系

近年来,线粒体DNA(mtDNA)与衰老和某些心脏疾病的研究发展较快,mtDNA突变不仅可导致器官老化,而且可引发多种心血管疾病,其结果可能是mtDNA突变造成线粒体氧化磷酸化(OXPHOS)功能障碍、ATP产生不足所致.本文就此作一综述.     

线粒体DNA及其突变对心肌的损害

线粒体ＤＮＡ对维持细胞正常功能起重要作用，充分认识线粒体ＤＮＡ的结构，功能及遗传学特性，开展线粒体ＤＮＡ突变对心肌损害的研究，无疑对临床的诊断治疗有着十分重要的作用。     

线粒体DNA突变合并肾脏损害

目的:探讨3例线粒体病合并慢性肾脏病(CKD)患者的临床特点及预后. 方法:2011年5月至2012年9月在南京军区南京总医院全军肾脏病研究所住院的CKD患者中共3例经线粒体DNA(mtDNA)基因检测确诊线粒体病,分析其肾外受累及肾脏损害的临床表现和肾活检病理特点,并观察其预后. 结果:(1)3例患者中2例青少年(14岁),另1例30岁,全部患者均消瘦(体质量指数13 ～ 17 kg/m2).例1生长发育迟缓,例3为早产儿.例1、例2有糖尿病家族史,例2有尿毒症家族史.(2)3例患者病程3～7月,临床均表现为水肿、蛋白尿和胱抑素C增高,肾小管损伤明显,均无高血压和镜下血尿.例1和例3组织学示局灶节段性肾小球硬化(FSGS),例2肾小球轻度系膜增生伴小动脉节段透明变性.(3)3例患者中糖尿病(2例)、高乳酸血症(2例)、听力消失或下降(3例)、癫痫发作(1例)、脑梗塞(1例)、智力障碍(2例)、视野缺失(1例),心律失常(1例).(4)3例患者均经基因测序并证实mtDNA 3243 A＞G突变位点,例2母亲和弟弟也检出与患者相同突变位点.(5)经治疗3例均停免疫抑制剂,补充辅酶Q10和左卡尼汀等治疗,蛋白尿部分缓解,血清肌酐稳定. 结论:本文首次在国内报道3例伴肾脏损害的线粒体病患者,提示这类患者并非罕见,临床除肾脏受累外均伴明显的心脏和中枢神经系统损害.临床医师应加强对此类疾病的认识.     

线粒体DNA点突变与心肌病关系的研究

用聚合酶链反应（ＰＣＲ）和异源双链（ＨＥＴ）凝胶电泳检测了１５例原发性扩张型心肌病（ＤＣＭ）、１３例急性心肌炎患儿及１个肥厚型心肌病（ＨＣＭ）家系中１７例成员 的外周血线粒体ＤＮＡ（ｍｔＤＮＡ）点突变。结果显示，ＤＣＭ患儿中，６例在ｍｔＤＮＡ保守区３１０８￣３７１７位存在点突变，其中１例家族性ＤＣＭ患儿及其母亲均检出点突变，提示ｍｔＤＮＡ点突变在ＤＣＭ发病中起一定作用；１３例急性心肌炎患儿中有１例     

线粒体DNA突变和衰老研究进展

线粒体ＤＮＡ突变和衰老、老年病相关的研究，是一个较新的研究领域。近期大量文献报道ｍｔＤＮＡ突变导致器官老化并引发多种老年疾病，本文就此作一综述。     

Applications of molecular genetics to gastrointestinal and liver diseases. I. Technical approaches

Recent developments in recombinant DNA techniques have allowed an understanding of the molecular genetics of many diseases, some affecting the gastrointestinal tract and liver. DNA probes which detect sequences within or near disease genes can be selected by direct approaches, if the gene product or primary gene function is known, or by indirect methods when the chromosomal location is known. Such probes have resulted in extensive family studies which can now define risks to family members of developing a genetic disease. The development of the polymerase chain reaction will also be of considerable use in clinical genetics and in the diagnosis of some infectious diseases. The techniques are summarized and examples of their use are given. A glossary of terms is also provided.     

A gene-environment interaction model of stress-induced hypertension

The case for a gene-environment interaction model of stress-induced hypertension is detailed in this paper. We hypothesize that repeated exposure to stress in combination with an environmentally and/or genetically mediated susceptibility may lead to the development of essential hypertension. Previously, we reviewed the evidence for a genetic influence on the two major intermediate phenotypes of our model: cardiovascular reactivity to psychological stress and stress-induced sodium retention, representing the cardiovascular and renal stress response, respectively. Here we first describe how genes underlying the physiological systems mediating the stress response of heart, vasculature, and kidney (i.e., the sympathetic nervous system, renin-angiotensin-aldosterone system and sodium reabsorption, and the endothelial system) may increase vulnerability to stress and confer susceptibility to development of essential hypertension. Next, we extend our model and review genes underlying three additional systems that may mediate the influence of stress on the development of essential hypertension: the parasympathetic nervous system, the serotonergic system, and the hypothamamus-pituitary-adrenal axis. The elucidation of our gene-environment interaction model of stress-induced essential hypertension will improve the understanding of the contribution of stress to the development of essential hypertension. This knowledge may lead to more effective primary and secondary prevention programs involving lifestyle interventions in which the role of stress, both acute and chronic, will be taken into account, particularly for individuals at increased genetic risk of essential hypertension. This study was supported by National Heart Lung and Blood Institute Grants HL56622 and HL69999.     

Association of the level of heteroplasmy of the 15059G>A mutation in the MT-CYB mitochondrial gene with essential hypertension

AIM: To examine whether the heteroplasmy level for 15059G>A mutation in the mitochondrial genome might be associated with essential hypertension. METHODS: This cross-sectional study involved 196 unrelated participants randomly selected from general population (90 males and 106 females) who underwent a regular medical check-up at the Institute for Ath-erosclerosis Research (Moscow, Russia). One hundred and twenty of them (61%) had essential hypertension, and 76 (39%) were apparently healthy normotensive persons. The level of heteroplasmy for 15059G>A mutation occurring in the coding region of cytochrome b gene (MT-CYB) of mtDNA isolated from the blood leukocytes, was quantified using DNA pyrosequencing method. RESULTS: The 15059G>A heteroplasmy level ranged between 4% and 83%, with a median level of 31%. Between the upper and lower quartiles of 15059G>A heteroplasmy distribution, significant differences were observed for patients’ age, systolic blood pressure, and triglyceride levels. 15059G>A heteroplasmy correlated both with age (r = 0.331, P < 0.001) and the presence of hypertension (r = 0.228, P = 0.002). Regression analysis revealed that the age explains 12% variability of 15059G>A heteroplasmy, and hypertension independently explains more 5% variability. The 15059G>A heteroplasmy exceeding 31% was found to be significantly associated with a higher risk of essential hypertension (odds ratio 2.76; P (Fisher) 0.019]. The study participants with high 15059G>A heteroplasmy level were found to have significantly higher age (P < 0.001) and the prevalence of essential hypertension (P = 0.033), as compared to those with low 15059G>A heteroplasmy level. These observations suggested a positive correlation between the level of 15059G>A heteroplasmy and essential hypertension. CONCLUSION: This study provides the evidence of association of mtDNA 15059G>A mutation heteroplasmy with essential hypertension.     

高血压病与炎症反应相关性的研究进展

越来越多的证据表明,炎症反应与原发性高血压病之间存在相关性。炎症因子会增加高血压病的患病率,并影响高血压病患者的诊断、治疗和预后。因此,采用一种新的治疗途径去干扰炎症反应和氧化应激可能会改善高血压患者的预后,延缓和减少血管并发症的发生。     

β3肾上腺素能受体基因Trp64Arg多态性与蒙古族原发性高血压病相关性分析

目的检测蒙古族原发性高血压人群中β3肾上腺素能受体基因Trp64Arg多态性,探讨其与蒙古族人群原发性高血压病(EH)和其他心血管病危险因素的关系。方法应用PCR技术检测原发性高血压病患者102例,健康体检者93例。比较两组Trp64Arg突变基因型和临床特征。结果高血压病组与对照组β3-AR基因突变频率两者差异无统计学意义(P>0.05),基因Trp64Arg突变者的体质量指数显著高于正常基因型(P<0.05),突变者在三酰甘油、血糖、胰岛素、尿酸方面差异有统计学意义(P<0.05)。结论 Trp64Arg基因突变可能不是蒙古族原发性高血压病发生的决定因素,但该基因变异可能与肥胖、脂代谢、糖代谢等危险因素有关。     

线粒体转运RNA基因突变与原发性高血压的相关研究

目的探究线粒体转运RNA(tRNA)基因突变与母系遗传原发性高血压(EH)的关联性。方法依据EH诊断和母系遗传判别标准,筛选2015年1月至2018年12月解放军总医院心血管内科收治的母系遗传EH患者17例(A组)、非母系遗传EH患者65例(B组)。选取同期来院进行健康体检的正常对照人群33名(C组)。对全线粒体DNA(mtDNA)进行测序并与线粒体基因文库MitoMap的修正剑桥序列进行比对,分析3组受试者线粒体tRNA基因突变率差异及其与母系遗传EH发生的关系。应用SPSS 19.0软件对数据进行分析。结果纳入人群中母系遗传EH占总EH 20.7%(17/82)。mtDNA序列对比分析发现,与C组(0.04%)比较,A组(0.28%,P=0.024)及B组(0.12%,P=0.046)患者线粒体tRNA基因总变异率明显升高,但A与B组间比较差异无统计学意义(P=0.076)。对A组患者进一步分析显示,仅有1个线粒体tRNA基因位点突变的先证者A06、A11和A13所在3个家系分别发生mtDNA A5823G、mtDNA T4386C与mtDNA C15910T突变,三个家系母系成员EH发病率分别为53.8%(7/13)、87.5%(7/8)和75.0%(9/12),发病率均较高,提示这3个位点突变可能与母系遗传EH发生密切关联。另外,mtDNA 5597缺失在A组(4例,23.5%)、B组(14例,21.5%)和C组(1例,3.0%)均出现。与C组比较,A组(P=0.002)与B组(P=0.002)患者mtDNA 5597缺失率均显著升高,但A组与B组间比较差异无统计学意义(P=0.127)。结论 mtDNA A5823G、mtDNA T4386C与mtDNA C15910T突变与母系遗传EH有较好的关联性,但mtDNA 5597缺失与母系遗传EH关系不大。     

A T1083C polymorphism in the human adenosine A2a receptor gene is not associated with essential hypertension

The adenosine A2a receptor (A2aAR) gene is thought to be involved in essential hypertension because adenosine elicits vasodilation and decreases arterial blood pressure via this receptor, and because disruption of the A2aAR gene increases blood pressure in mice. Therefore, using a restriction fragment length polymorphism (RFLP) of the A2aAR gene, we performed an association study in patients with essential hypertension. One hundred forty-two patients with essential hypertension and 142 age-matched subjects with normal blood pressure were studied. Polymerase chain reaction (PCR) was applied to amplify the T1083C polymorphic site in the A2aAR gene, and restriction analysis of the PCR product was employed to score the T and C alleles. Overall distributions of allele frequencies in the two groups were not significantly different. Thus, the alleles detected by this RFLP polymorphism in the A2aAR gene are not associated with essential hypertension.     

The concept of crosstalk‐directed embryological target mining and its application to essential hypertension treatment failures

This review aims to introduce the novel concept of embryological target mining applied to interorgan crosstalk network genesis, and applies embryological target mining to multidrug‐resistant essential hypertension (a prototype, complex, undertreated, multiorgan systemic syndrome) to uncover new treatment targets and critique why existing strategies fail. Briefly, interorgan crosstalk pathways represent the next frontier for target mining in molecular medicine. This is because stereotyped stepwise organogenesis presents a unique opportunity to infer interorgan crosstalk pathways that may be crucial to discovering novel treatment targets. Insights gained from this review will be applied to patient management in a clinician‐directed fashion.