【观点】IMPROVE-IT研究启示：利用基因变异寻找新药的可能性大大提高

在《新英格兰医学杂志》11月27日发表的研究中，作者们使用基因测序的方法在29 954例冠心病患者及83 140例对照患者中鉴别了非活动性NPC1L1突变的携带者。每650例患者中约有1例为杂合子携带者，定义为15个特征性突变中至少发现1处突变。与非携带者相比，NPLC1L1失活性突变的携带者其LDL胆固醇水平的均值较低（P = .04），冠心病风险相对降低53%（P = .008）。NPC1L1发生失活性突变与血浆LDL胆固醇水平及冠心病风险降低相关。哈佛医院Paul D Thompson博士对此结果进行了点评。

专家评述

哈佛医院Paul D Thompson博士

依折麦布通过干预Niemann-Pick C1-like 1（NPC1L1）受体介导的肠道对胆固醇的吸收而使低密度脂蛋白胆固醇（LDL-C）水平下降了15%-20%。但依折麦布在减少动脉粥样硬化性心血管疾病（ASCVD）方面的应用却受到质疑，因为ENHANCE试验（依折麦布联合辛伐他汀治疗高胆固醇血症可增进动脉粥样硬化恢复）未能证明家族性高胆固醇血症患者在使用他汀类药物加用依折麦布或安慰剂治疗后颈动脉内膜厚度有所不同。为检验依折麦布是否能减少ASCVD，心肌梗死遗传学研究联合会在欧洲、非洲和南亚的7364例ASCVD患者和14 728例对照者中对NPC1L1基因的失活性突变进行了检测。结果发现22  590例ASCVD患者和68 412例对照者具有单一失活性突变的基因型（p.Arg406X）。

这类基因突变及其罕见，每650人中仅发现1例。研究未观察到纯合子或混合型杂合子，提示NPC1L1吸收胆固醇和其他甾醇类的能力对于个体存活而言是不可或缺的。具有遗传变异的个体其LDL-C水平降低了12 mg/dL，ASCVD的发生率降低了53%。这些结果都说明，减少胆固醇的吸收降低了ASCVD的发生率。该结果支持了依折麦布等药物可减少ASCVD的观点，但却未能对此提供证明。其他与基因相关的因素可促成这一结果的发生，而依折麦布可能具有治疗目标之外的作用，这限制了其应用。然而这些遗传学结果，或者所谓的“自然临床试验”结果支持了“包含他汀类在内的药物有降低ASCVD风险的作用”这一观点。

该研究发表后仅1周，IMPROVE-IT研究结果就在美国心脏协会年会上发布了。IMPROVE-IT研究表明，依折麦布在与他汀类药物联用时减少了复发性心血管事件的发生。这些遗传学发现与IMPROVE-IT研究结果相符，因而利用基因变异寻找药物研发甚或药物批准新途径的可能性大大提高。人抗PCSK9（胆固醇水平修饰基因，首先发现于LDL-C低水平患者中）单克隆抗体的研发已经在遵循这一步骤进行。

TAKE-HOME MESSAGE

The authors used genetic sequencing to identify carriers of non-activatingNPC1L1 mutations in 29,954 patients with coronary heart disease and 83,140 control patients. Approximately 1 in every 650 patients was determined to be a heterozygous carrier for at least 1 of the 15 distinct mutations identified. Carriers of NPLC1L1 inactivating mutations had lower mean LDL cholesterol levels (P = .04), and a 53% relative reduction in the risk for coronary heart disease compared with non-carriers (P = .008).

The presence of inactivating mutations in NPC1L1 was associated with reduced plasma LDL cholesterol levels and a reduced risk for coronary heart disease.

Expert Comment

Ezetimibe reduces lower-density lipoprotein cholesterol (LDL-C) by 15% to 20% by interfering with intestinal cholesterol absorption mediated by the Niemann-Pick C1-like 1 (NPC1L1) receptor. However, the utility of ezetimibe for reducing atherosclerotic cardiovascular disease (ASCVD) was questioned when the ENHANCE trial (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) failed to show any difference in carotid intimal thickness when ezetimibe or placebo was added to a statin in patients with familial hypercholesterolemia. To examine whether ezetimibe would reduce ASCVD, the Myocardial Infarction Genetics Consortium Investigators identified 15 inactivating mutations in the NPC1L1 gene among 7364 patients with ASCVD and 14,728 controls of European, African, and South Asian ancestry. They then genotyped for a single inactivating mutation (p.Arg406X) in 22,590 patients with ASCVD and 68,412 controls.

The genetic mutations were extremely rare, found in only 1 in 650 individuals. No homozygotes or compound heterozygotes were identified, suggesting that the ability to absorb cholesterol and other sterols by NPC1L1 is necessary for survival. LDL-C levels were 12 mg/dL lower in individuals with the genetic variant, and the incidence of ASCVD was 53% lower. Both results suggest that reducing cholesterol absorption reduces ASCVD. Such results support the concept that drugs such as ezetimibe will reduce ASCVD, but they do not prove it. Other factors associated with the gene could contribute to the results, and ezetimibe may have off-target effects that limit its utility. Nevertheless, these genetic results, or what one could label “natural clinical trials” support the concept that drugs besides statins have a role in ASCVD risk reduction.

This study was published only a week before the IMPROVE-IT results were presented at the American Heart Association annual meeting. IMPROVE-IT documented that ezetimibe reduced recurrent cardiovascular events when added to a statin. The agreement between these genetic findings and IMPROVE-IT raises the possibility that genetic variants will be used to identify novel pathways for drug development and perhaps drug approval. This process is already underway with the development of human monoclonal antibodies against PCSK9, a cholesterol-level modifier first identified in patients with low levels of LDL-C.

The New England Journal of Medicine

Inactivating NPC1L1 Mutations and Protection From Coronary Heart Disease

N. Engl. J. Med 2014 Nov 27; 371(22)2072-2082, The Myocardial Infarction Genetics Consortium Investigators

This abstract is available on the publisher's site.

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