Heteroplasmic mitochondrial DNA variants in cardiovascular diseases.
Heteroplasmic mitochondrial DNA variants in cardiovascular diseases.
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心血管疾病中的杂质线粒体DNA变体。
DOI：
10.1371/journal.pgen.1010068
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发表时间：
2022-04
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
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作者：
线粒体与心血管疾病（CVD）的发病机制有关，但其原因尚不清楚。影响所有线粒体DNA分子（同质）的母系遗传群体线粒体DNA（mtDNA）变异与心脏代谢特征和发生心血管疾病的风险相关。然而，目前尚不清楚仅影响一部分mtDNA分子（异质性）的mtDNA突变是否也起作用。为了解决这个问题，我们对1,399名高血压（HTN）患者、1,946名缺血性心脏病（IHD）患者、2,146名缺血性中风（IS）患者和723名健康对照者的血液DNA进行了高深度（~1000倍）mtDNA测序。我们发现异质性单核苷酸变异（mtSNVs）的个体负担随着年龄的增长而增加。低水平异质性（异质性分数，HF，5-10%）的年龄效应更强，可能反映了基于三核苷酸突变特征的获得性体细胞事件。校正年龄和其他混杂因素后，中间异质性（HF 10-95%）在高血压中更常见，特别是涉及改变必需呼吸链蛋白氨基酸序列的非同义变体。这些发现提出了异质性mtSNV在高血压病理生理学中发挥作用的可能性。影响所有线粒体DNA（mtDNA）分子的遗传同质变异与心血管疾病有关，但引起mtDNA混合群体（异质性）的变异的作用尚不清楚。在这里，我们试图通过对包括健康对照在内的5，491名个体的整个mtDNA分子进行深度测序，来表征mtDNA异质性变体在高血压，缺血性心脏病和缺血性中风中的作用。我们测量了在不同基因组区域注释的低水平和中等水平异质性单核苷酸变异（mtSNV）的负担。除了与年龄相关的异质性mtDNA变异积累外，我们还发现高血压患者的mtSNVs变异负担更大，特别是在中等异质性水平（HF 10-95%）时。这些mtSNV大多涉及编码关键呼吸链蛋白的线粒体DNA基因中的非同义变体。这些发现提出了线粒体DNA异质性通过影响线粒体呼吸链功能而参与高血压发病机制的可能性。
Mitochondria are implicated in the pathogenesis of cardiovascular diseases (CVDs) but the reasons for this are not well understood. Maternally-inherited population variants of mitochondrial DNA (mtDNA) which affect all mtDNA molecules (homoplasmic) are associated with cardiometabolic traits and the risk of developing cardiovascular disease. However, it is not known whether mtDNA mutations only affecting a proportion of mtDNA molecules (heteroplasmic) also play a role. To address this question, we performed a high-depth (~1000-fold) mtDNA sequencing of blood DNA in 1,399 individuals with hypertension (HTN), 1,946 with ischemic heart disease (IHD), 2,146 with ischemic stroke (IS), and 723 healthy controls. We show that the per individual burden of heteroplasmic single nucleotide variants (mtSNVs) increases with age. The age-effect was stronger for low-level heteroplasmies (heteroplasmic fraction, HF, 5–10%), likely reflecting acquired somatic events based on trinucleotide mutational signatures. After correcting for age and other confounders, intermediate heteroplasmies (HF 10–95%) were more common in hypertension, particularly involving non-synonymous variants altering the amino acid sequence of essential respiratory chain proteins. These findings raise the possibility that heteroplasmic mtSNVs play a role in the pathophysiology of hypertension. Inherited homoplasmic variants affecting all mitochondrial DNA (mtDNA) molecules are associated with cardiovascular diseases, but the role of variants causing a mixed population of mtDNA (heteroplasmy) is not well understood. Here we sought to characterize the role of mtDNA heteroplasmic variants in hypertension, ischemic heart disease, and ischemic stroke, by deep-sequencing of the whole mtDNA molecule in 5,491 individuals including healthy controls. We measured the burden of low and intermediate level heteroplasmic single-nucleotide variants (mtSNVs) annotated in different genomic regions. In addition to an age-related accumulation of heteroplasmic mtDNA variants, we show that hypertensive individuals have a greater burden of mtSNVs variants particularly at intermediate heteroplasmy levels (HF 10–95%). These mtSNVs mostly involve non-synonymous variants in mtDNA genes coding for critical respiratory chain proteins. These findings raise the possibility that mtDNA heteroplasmy contributes to the pathogenesis of hypertension through an effect on mitochondrial respiratory chain function.