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2015年2月8日讯 /生物谷BIOON/ –近日，来自美国的科学家在著名国际期刊Nature发表了他们的最新研究成果，他们通过对心肌梗死病人进行外显子测序发现两个蛋白编码基因的罕见突变可能会导致心肌梗死患病高风险。这项研究对临床预测心肌梗死发病，针对性开发治疗药物具有重要意义。
研究人员指出，心肌梗死（MI）是全世界范围内致死率非常高的一种疾病，具有复杂的遗传模式。对于早发性MI，基因遗传是一个主要的风险因素。之前已有研究证明LDL基因中的罕见突变能够增加个别家庭发生MI的风险，同时有超过45个位点的常见突变与人群的MI发生风险具有相关性。但罕见突变是如何增加人群中早发性MI发生风险仍不清楚。
研究人员对MI早发病人基因组中9793个蛋白编码区域进行了测序，发现了两个编码序列中的罕见突变在MI早发病人中出现频率更高。携带了罕见非同义突变的LDLR基因能够增加4.2倍MI患病风险，携带无效等位基因的LDLR甚至可增加更高倍数的倍患病风险。携带了罕见非同义突变的APOA5基因能够增加2.2倍MI患病风险。
综上所述，这篇文章通过对早发性MI病人进行外线则测序发现了可能导致早发性MI高风险患病的两个蛋白编码区域（LDLR基因和APOA5基因）的罕见突变。这些发现表明脂蛋白-甘油三酯以及LDL-胆固醇代谢紊乱会增加MI患病风险，同时对临床预测MI患病风险以及开发针对性治疗方法具有重要意义。（生物谷Bioon.com）
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Exome sequencing identifies rare LDLR andAPOA5 alleles conferring risk for myocardial infarction
Ron Do, Nathan O. Stitziel, Hong-Hee Won, Anders Berg J?rgensen, Stefano Duga, Pier Angelica Merlini, Adam Kiezun, Martin Farrall, Anuj Goel, Or Zuk, Illaria Guella, Rosanna Asselta, Leslie A. Lange, Gina M. Peloso, Paul L. Auer, NHLBI Exome Sequencing Project,Domenico Girelli, Nicola Martinelli, Deborah N. Farlow, Mark A. DePristo, Robert Roberts,Alexander F. R. Stewart, Danish Saleheen, John Danesh, Stephen E. Epstein et al.
Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1, 2. When MI occurs early in life, genetic inheritance is a major component to risk1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3, 4, 5, 6, 7, 8, whereas common variants at more than 45 loci have been associated with MI risk in the population9, 10, 11, 12, 13, 14, 15. 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 cholesterol16. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl?1. At apolipoprotein 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 lipoprotein lipase15, 17 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.