编码线粒体呼吸链复合物I核心组份的核基因与高血压左心室肥厚遗传易感的相关性研究

The left ventricular hypertrophy (LVH) is one of the most important organ damage targets in essential hypertension. LVH is independently associated with risk of stroke and cardiovascular motility and mortality. Despite the involvement of multiple factors, the genetic factors have been shown to have an important function in the pathogenesis of LVH. Accumulating evidence showed that energy metabolic dysfunction caused by mitochondrial impairment was involved in hypertension and cardiomyopathy pathogenesis. In this study, we will genotype 48 tag SNPs in 7 core component genes of mitochondrial respiratory chain complex I (which are encoded by nuclear genome) using the SNaPshot method. Association analyses will be performed to discern potential association of genotype, allele and haplotype of these genes with clinical expression of LVH. Further functional analyses will be carried out to unravel the molecular mechanism of risk variants/haplotypes. This study can help us to better understand the genetic basis of mitochondrial genes that affects susceptibility to LVH, and provide potential target for LVH of hypertension prevention and treatment.

左心室肥厚（LVH）是高血压病最常见的靶器官损害, 高血压继发LVH是增加心脑血管疾病发病率和死亡率的独立危险因素。高血压继发LVH为复杂疾病，遗传因素对左心室重量的影响约占60%，但其分子发病机制至今不明。线粒体能量代谢障碍在高血压病和心肌肥厚的发生发展中扮演着重要的角色。本研究拟对2000例高血压病患者（1000例高血压伴LVH和1000例高血压不伴有LVH）和1000例健康对照者开展核基因编码的线粒体呼吸链复合物I的7个核心亚基的遗传关联分析。我们对这7个基因的48个标签SNP位点进行分型，结合临床资料在基因型、等位基因和单倍型水平剖析与高血压LVH遗传易感的关系。在细胞水平对高血压继发LVH阳性相关位点进行功能验证，以期从线粒体能量代谢角度阐明高血压继发LVH的遗传易感基础，并为该病的临床防治提供新靶标。

左心室肥厚(LVH)是原发性高血压(EH)最常见的靶器官损害。线粒体功能障碍在高血压心肌肥厚的病理生理学中起着重要作用。本项目围绕“线粒体相关基因遗传变异与EH继发LVH易感”这一主题开展遗传分析，取得以下发现：1.线粒体复合物I的NDUFS1基因rs13024804位点、NDUFV2基因rs874250位点多态性及NDUFS2基因rs10908826-rs4656993-rs3924264-rs4656994-rs1136224-rs2070902-rs11421-rs4489574-rs12721035-rs5085-rs5082-rs2307424单倍型CGGGCTCCGCTT可能与EH的发病相关联；2.线粒体复合物I的NDUFS2基因rs10908826、rs2070902和rs1136224位点及NDUFV2基因rs4798765-rs12457810-rs12964485-rs8084822-rs2377961-rs874250-rs4798772-rs4797356单倍型CTTATGAT、TGCTTAGA可能与EH继发LVH发病有关；3.在EH组中，携带NDUFS8基因rs3751084、rs2075626不同基因型患者的血清镁离子和单核细胞计数比较差异有统计学意义(P<0.05)；4.在对照组中，NDUFV2基因rs12457810位点和NDUFS2基因rs5082位点不同基因型个体的脉压和红细胞平均体积比较差异有统计学意义(P<0.05)；5.通过eQTL等分析后发现与NDUFS2基因rs10908826位点完全连锁的rs3813623位点位于NDUFS2的5’UTR区，其等位基因改变影响了转录因子FXR的结合，从而调控了NDUFS2的基因表达水平；6.通过基因表达谱分析发现NDUFS2和NDUFS8并未出现表达异常，提示其遗传相关性可能有其他的作用方式；但NDUFB3、NDUFC2、NDUFS3在两种模型中均表现出表达异常，提示线粒体相关基因的表达异常确实参与了心室肥厚过程；7.线粒体MT-TP基因m.15992A>G突变是引起EH发病相关的潜在致病性突变，线粒体MT-CYB基因15077G>A可能协同m.15992A>G突变造成外显率的增高。以上研究结果丰富了我们对于EH遗传易感和发病的认识，为搞好EH的防治和遗传咨询工作提供第一手的基础资料。