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Completing the genetic spectrum influencing coronary artery disease: from germline to somatic variation

机译:完成影响冠状动脉疾病的遗传谱:从种系为躯体变化

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摘要

Genetic and environmental factors influence the development of coronary artery disease (CAD). Genetic analyses of families and the population continue to yield important fundamental insights for CAD. For the past four decades, CAD human genetic research focused largely on the study of germline genetic variation in CAD and its risk factors. The first genes associated with CAD were discovered using basic Mendelian principles and pedigree analysis. Mapping of the human genome and advancement in sequencing technology sparked further discovery of novel genetic associations through exome sequencing and genome wide association analysis in increasingly larger populations. While prior work implicated in situ DNA damage as a feature of atherosclerosis, more recently, somatic mutagenesis in and clonal expansion of haematopoietic stem cells was found to influence risk of CAD. Mutations observed for this condition, termed clonal haematopoiesis of indeterminate potential, frequently occur within epigenetic regulator genes (e.g. DNMT3A, TET2, ASXL1, etc.), which are also implicated in leukaemogenesis. Hypercholesterolaemic mice with Tet2 bone marrow deficiency are predisposed to the development of atherosclerosis that may be partly related to inflammatory cytokines. As the genetic basis of CAD expands from the germline to somatic genome, our fundamental understanding of CAD continues to evolve; these new discoveries represent new opportunities for risk prediction and prevention, and a new facet of cardio-oncology.
机译:遗传和环境因素影响冠状动脉疾病(CAD)的发展。对家庭和群体的遗传分析继续为CAD提供重要的基本见解。在过去的四十年里,CAD人类遗传学研究主要集中在CAD的种系遗传变异及其危险因素的研究上。使用基本孟德尔原理和系谱分析发现了第一批与CAD相关的基因。人类基因组图谱的绘制和测序技术的进步通过外显子组测序和全基因组关联分析在越来越多的人群中进一步发现了新的基因关联。虽然之前的研究表明原位DNA损伤是动脉粥样硬化的一个特征,但最近发现,造血干细胞的体细胞突变和克隆性扩增会影响CAD的风险。在这种情况下观察到的突变称为潜在不确定的克隆性造血,通常发生在表观遗传调节基因(如DNMT3A、TET2、ASXL1等)内,这些基因也与白血病发生有关。Tet2骨髓缺乏的高胆固醇血症小鼠易患动脉粥样硬化,这可能部分与炎性细胞因子有关。随着CAD的遗传学基础从种系扩展到体细胞基因组,我们对CAD的基本理解不断发展;这些新发现代表了风险预测和预防的新机会,以及心脏肿瘤学的一个新方面。

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