离子通道基因TSC及CLCNK与内蒙古地区蒙古族原发性高血压家系的关联研究

3-50% of the observed variation in essential hypertension is attributable to genetic factors. The molecular basis of essential hypertension is multiple susceptibility genes and the cumulative effects of their specific combination to certain environmental factors. Although many domestic and international researchers make efforts in understanding the pathogenesis of hypertension, so far, there is no major breakthrough due to its complexity. Our previous study indicated that the mutations in TSC and CLCNKB gene encoding the ion channel protein are associated with the non-familial hypertension in the Mongolian population. Accordingly, first, we hypothesize that there may be unique hypertension susceptibility genes in Mongolian families, the gene mutation rate of the affected individuals may be different with that of the unaffected siblings. Second, we hypothesize that different risk factors and their interactions may contribute to the hypertension in this population. Therefore, we will explore the molecular epidemiological analysis and apply Haploview software to screen common SNPs with rare allele frequency. High-throughput Genotyping for the polymorphisms of CLCNKB T481S and TSC Gln904Arg will be performed using a TaqMan assay. A study in the pathogenesis of hypertension in Mongolian families is an useful approach to identify hypertension related genes. Importantly, it provides a way for better understanding of the human evolution biology and population genetics. This will also guide us in early prevention of hypertension in the Mongolian population.

原发性高血压的遗传度为3%～50%,其分子基础是多个基因及其特定组合的累积效应对某些环境因子的易感性。尽管国内外学者努力探讨其发病机制,但是,由于其存在的复杂性，迄今没有重大突破。我们前期的研究证实，编码离子通道蛋白的基因TSC以及CLCNKB变异与非家族性蒙古族高血压发生关联，据此提出假设：①蒙古族高血压家系中可能存在独特的高血压易感基因,而同胞间患病个体与未患病个体基因的突变率存在差异;②在这一群体中可能存在不同危险因素的单独与交互作用。拟将采用分子流行病学分析，Haploview软件筛选少见等位基因频率的常见SNP位点，以TaqMan技术对CLCNKB基因T481S和TSC基因Gln904Arg的多态位点进行高通量基因分型。从家系开展蒙古族高血压发病机制的研究，是确定高血压致病相关基因的较好途径，对人类进化生物学和群体遗传学的理解有着重大意义。可指导我们对该群体进行早期预防。

目前对蒙古族人群易于罹患高血压等心脑血管疾病的遗传基础尚缺乏了解。项目研究了离子通道TSC的编码基因SLC12A3变异与蒙古族高血压、血脂异常等心血管疾病发病之间的关系,并扩展了研究。.1. 蒙古族高血压508例，蒙古族正常人群246例，分析SLC12A3基因上的15个标签SNPs与蒙古族高血压的关系，研究发现SLC12A3基因上的三个SNPs位点与血压特征显著相关，分别为 rs7187932（HTN，p = 0.048）；rs2399594 (HTN，p = 0.030；SBP，p = 0.029；DBP，p = 0.050）和rs2304478（SBP，p = 0.028）。.2. 88个蒙古族高血压家系样本中发现易感SNPs位点包括位于编码区的rs5803（z =-1.95，加性模型p = 0.05,显性模型p = 0.01）；位于内含子区域的rs2304478（z = 2.36，加性模型和显性模型均为p = 0.02）。证实SLC12A3基因是蒙古族高血压发病的一个易感基因。单倍型特异性的关联分析进一步证实了这一结论。.3. 随机采集血样331例，研究四项血脂水平与SLC12A3 基因多态性的关联，显示该基因上的三个SNPs位点（rs5803,rs2010501 和 rs711746）与血清LDL-c显著相关，其单倍型分析呈现相同结果（p < 0.01）。首次证实SLC12A3 基因变异与内蒙古地区蒙古族血脂水平相关。.4. 血脂水平与SLC12A3基因多态性进行以家系为基础的关联分析，将LDL-C与SLC12A3的分析作为重点。无论在加性模型还是在显性模型中，rs5803和rs711746在家系样本中呈现与血清LDL-c显著相关。阳性位点的单倍型分析显示相同的结果。在双亲人群中比较血清水平和不同基因型的结果证实，rs5803的基因型CC携带者比等位基因T携带者具有更高的LDL-C水平； rs711746的基因型AA和等位基因G携带者之间的LDL-C水平也存在显著性差异。证实了rs5803的基因型CC和rs711746的基因型AA携带者更倾向于具有较高的LDL-C水平，从而更易于患心脑血管疾病。. 结论：SLC12A3 基因变异与蒙古族高血压密切相关；首次发现SLC12A3基因多态性与LDL-C水平显著相关，为开展群体高血压、高血脂研究提供了科学依据。