我国傣族高血压病人群线粒体基因突变和遗传背景影响发病的研究

Essential hypertension (EH) is one of the most common cardiovascular diseases and affects one-quarter of the world's adult population. The exact molecular pathogenesis of EH has not been fully elucidated to date. The EH patients with maternally inherited model were observed in clinic. Dai population is currently distributed in Yunnan Province and has a high prevalence of EH (10.79%), much higher than those of other minor ethnic groups located in the same region, such as Hani (4.82%) and Yi (3.28%). To uncover the exact reason for the high prevalence of EH in Dai population has great importance for both prevention and treatment of EH. In this study, We plan to recruit 1000 Dai EH patients and 1000 matched healthy controls. We will classify the haplogroup of each individual by sequencing the mtDNA control region sequence. Fisher's exact test will be performed to show the statistical significance, and further to discern the mtDNA haplogroup effect on the clinical expression of EH. We will sequence the entire mtDNA genome of the patients with obviously maternal inheritance of EH and identify potentially pathogenic mutation by using a phylogenetic method. The immortalized lymphoid cell lines of the patients and healthy controls will be established and be measured for parameters of mitochondrial function, to further validate the potentially deleterious effect of certain pathogenic mutation. Our results will provide essential information to understand the intrinsic connection between mtDNA mutation and EH, and offer important implications for prevention, cure and genetic counselling of this disease in Dai population.

高血压病（EH）是严重危害人类健康的常见疾病，其病因和发病机制尚未完全明确。临床上观察的部分EH患者存在母系遗传特征。傣族主要聚居在云南，高血压发病率高达10.79%，远远高于居住在同一地区的其他少数民族如哈尼族（4.82%）和彝族（3.28%）。探索傣族人群EH高发病因与发病机理，对于指导傣族EH的防治工作具有重要的意义。本研究将采集傣族EH患者（实验组）和血压正常的对照个体（对照组）各1000例，通过对两组线粒体DNA(mtDNA)遗传背景进行比较，确定影响EH的单倍型类群。通过对有母系遗传特征的傣族EH患者mtDNA全基因组进行测定，采用系统发育进化分析方法识别潜在的致病性突变，并在EH患者和正常对照个体的永生化细胞株上开展相关的线粒体功能指标测定，验证突变的致病性。研究结果将从母系遗传这个角度揭示我国傣族EH发病的内在原因，为EH的防治和遗传咨询提供依据。

高血压病（EH）是一种严重危害人类健康的常见疾病，临床发病存在种族、民族和地区差异。为进一步明确傣族EH高发的原因，我们对云南农村地区的傣族人群开展了EH流行病学调查和围绕线粒体遗传背景、线粒体DNA突变与EH发病的相关性开展遗传分析等研究工作，取得以下发现：1．云南省傣族高血压家系人群收缩压和舒张压平均水平分别为134.31 mmHg和80.27 mmHg。直系人群正常高值血压构成比大，是发展为高血压的主要后备人群。高血压患病率直系高于旁系，提示存在高血压家族聚集性。直系和旁系高血压知晓率、治疗率、控制率均低，其中低年龄组（<35岁）和高年龄组（>65岁）的治疗率更低。遗传模式估计显示：高血压家系患病不符合单基因隐性遗传，存在单基因显性遗传或多基因遗传性疾病的可能。2．我们已对采集到的802个傣族高血压患者和825个傣族无关对照个体进行了mtDNA控制区测序和单倍型类群划分，结果显示单倍型类群D增加高血压的易感性（P＜0.05）。3．对22个表现出母系遗传特征的傣族高血压家系进行了研究，遗传度分析显在这些家系中有明显的母系遗传效应存在； mtDNA世系树枝端私有变异的分析结果显示m.5512A>G、m.6651G>A、m.3394T>C、m.9655G>A等四个变异存在潜在的致病性，并为其建立了永生化淋巴细胞系；通过对携带m.5512A>G突变的EH家系进行深入研究发现该家系先证者及母系成员均携带该突变，该突变会使得原来的WC碱基配对消失，导致氨基酸接受臂不稳定；临床关联性分析显示m.5512A>G突变独立于高血压与大动脉硬化及左心室重构相关联，且突变携带者存在运动不耐受（短时内静息心率增快到最大心率、短的运动持续时间和摄氧量的降低）。4．磁共振测量傣族高血压患者主动脉扩张度的研究显示：MRI可用于高血压等病变过程中主动脉扩张度的监测，从而有望指导高血压的诊治。以上研究结果大大地丰富了我们对于傣族EH患者遗传易感和发病的认识，为搞好傣族EH的防治和遗传咨询工作提供第一手的基础资料。项目执行期间共发表论文3篇。培养硕士研究生3名，博士后1名。