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首页> 外文期刊>Nature >Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction
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Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction

机译：外显子组测序可鉴定出罕见的LDLR和APOA5等位基因，可导致心肌梗死

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摘要

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤ 50 years in males and ≤ 60 years in females) along with MI free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol ＞ 190 mg dl~(-1). At apo-lipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipo-protein lipase and apolipoprotein C-Ⅲ (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.%Sekar Kathiresan及同事通过对近10,000人进行外显子组测序来在人口层面上研究一个基因内的多个罕见突变对心肌梗塞风险的贡献。他们发现，“低密度脂蛋白受体”(LDLR)或“阿朴脂蛋白A-V”(APOA5)的突变与患病风险相关。当与非携带者相比较时，LDLR突变携带者血浆LDL胆固醇水平较高，而APOA5突变携带者血浆甘油三脂水平较高。除了证实APOA5是一个心肌梗塞基因外，这项工作还能为有关复杂疾病的罕见变异体关联研究的设计和进行提供信息。
机译：心肌梗塞（MI）是世界上主要的死亡原因，显示出复杂的遗传模式。当MI在生命的早期发生时，遗传是风险的主要组成部分。以前，低密度脂蛋白（LDL）基因的罕见突变已显示出对个体家庭MI风险的贡献，而超过45个基因座的常见变异已与人群MI风险相关。在这里，我们评估了罕见突变如何导致人群中早期MI风险。我们对来自MI患者的9 793个基因组的蛋白质编码区域进行了测序（年龄在男性（≤50岁，女性在≤60岁）以及无MI的对照中。我们确定了两个基因，其中MI病例中的罕见编码序列突变在外显子组范围内的重要性高于对照组。在低密度脂蛋白受体（LDLR）下，罕见的非同义突变携带者发生MI的风险增加了4.2倍。 LDLR上无效等位基因携带者的风险更高（相差13倍）。大约2％的早期MI病例在LDLR中具有罕见的破坏性突变。这一估算值与40年前使用总胆固醇分析得出的估算值相似。在对照组中，约有217位患者中有1位带有LDLR编码序列突变，血浆LDL胆固醇> 190 mg dl〜（-1）。在载脂蛋白A-V（APOA5）处，罕见的非同义突变携带者发生MI的风险增加了2.2倍。与非载体相比，LDLR突变载体的血浆LDL胆固醇更高，而APOA5突变载体的血浆甘油三酸酯更高。最近的证据表明，MI风险与功能上与APOA5相关的两个基因的编码序列突变有关，即脂蛋白脂肪酶和载脂蛋白C-Ⅲ（参考文献18、19）。综合来看，这些观察结果表明，富含甘油三酸酯的脂蛋白以及低密度脂蛋白胆固醇的代谢异常也会导致MI风险。％Sekar Kathiresan和同事通过对近10,000人进行外显子组放置来在人口众多上研究一个基因内他们发现，“低密度脂蛋白受体”（LDLR）或“阿朴脂蛋白AV”（APOA5）的突变与患病风险相关。当与非携带者相比较时，LDLR突变携带者血浆LDL水平水平较高，而APOA5突变携带者血浆甘油三脂水平较高。此外，APOA5是一个心肌梗塞基因外，因而工作仍为有关复杂疾病的罕见变异体关联研究的设计和进行提供信息。

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  • 来源
    《Nature》 |2015年第7537期|102-106a1-a2|共7页
  • 作者

    Ron Do; Nathan O. Stitziel; Hong-Hee Won; Anders Berg Jorgensen; Stefano Duga; et al;

  • 作者单位

    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA,Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA,Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA,Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA,Division of Statistical Genomics, Washington University School of Medicine, St Louis, Missouri 63110, USA;

    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA,Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA,Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA,Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen 1165, Denmark;

    Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Universita degli Studi di Milano, Milano 20122, Italy;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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