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2016年3月4日/生物谷BIOON/–为了将降低心脏病发作风险，健康生活方式的益处是显而易见的。但是遗传仍然能够暗度陈仓。一些人的基因在抵御心脏病上具有一种天然优势或劣势。
如今，在一项新的研究中，来自美国华盛顿大学圣路易斯分校医学院、麻省理工大学和哈佛大学等机构的研究人员在190,000多人的基因数据中鉴定出两种基因当以一种特异性的方式发生改变，促进或破坏心血管健康。这些发现可能有助人们设计出新的预防性药物，就好比他汀类药物如今被用来降低“坏”胆固醇，从而降低心脏病发作风险。相关研究结果于2016年3月2日在线发表在New England Journal of Medicine期刊上，论文标题为“Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease”。
论文第一作者、华盛顿大学圣路易斯分校医学院心脏学家和医学与遗传学助理教授Nathan O. Stitziel说，“我们鉴定出几种基因发生的遗传变异与抵抗冠状动脉性心脏病相关联。我们的发现支持这种观点：聚焦在一种主要的三酸甘油脂调节通路的疗法应当有助阻止斑块在心脏冠状动脉中堆积，从而有助阻止心脏病发作。”
为了鉴定出可能在药物开发中起着重要作用的基因，研究人员研究了冠状动脉性心脏病病人和健康人的DNA数据。他们搜寻了220,000个让蛋白发生变化的基因变异以便鉴定出那些似乎影响心脏病风险的变异。蛋白中存在的错误能够产生重大的生理学影响。
作为这项研究的一部分，研究人员证实了过去的研究工作：鉴定出之前已被证实在抵抗心脏病风险中给予优势或具有更高心脏病风险的基因，而且他们还发现了两种新的基因ANGPTL4和SVEP1。基因ANGPTL4中存在的罕见错误与下降的冠状动脉性心脏病风险相关联。这种下降的幅度从当这个基因发生的小错误时的14%，到当该基因的整个拷贝都不再发挥功能时的大约50%。另外一个基因SVEP1则表现出完全相反的关联性—它的一种罕见错误能够让冠状动脉性心脏病风险增加了大约14%。
尽管ANGPTL4已是众多研究的课题，但是另一个新发现的影响心血管健康的基因SVEP1多少还有些神秘感。在这项新的研究中，Stitziel和他的同事们在他们的研究人群中证实SVEP1基因发生的这种罕见错误也与较高的血压相关联，但是其中的分子机制仍然知之甚少。
相反，人们早就知道ANGPTL4在加工三酸甘油脂—一种血液中循环流通的脂肪—中发挥着作用。尽管三酸甘油脂是否参与斑块在动脉中堆积一直充满争议，但是医生们测量它的水平作为心脏病风险的一种标志物。ANGPTL4在加工三酸甘油脂中发挥作用是因为它脂蛋白脂酶（lipoprotein lipase）通路的一个组分。阻断ANGPTL4确实打开这种通路，允许机体加工来自饮食中的三酸甘油脂，从而将它从血液中清除。
Stitziel指出靶向ANGPTL4和LPL通路中的其他组分的抑制剂正在开发中。尽管它们当中还没有一种获得临床上的批准，但是这项新的将这些基因与下降的冠状动脉性心脏病风险和降低的三酸甘油脂水平关联起来的研究提示着这种抑制剂开发是值得追求的。（生物谷 Bioon.com）
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Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators
BACKGROUND
The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets.
METHODS
Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes.
RESULTS
We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10−10) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10−8), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of- function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10−4) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10−7).
CONCLUSIONS
We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.)
Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease
BACKGROUND
Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides.
METHODS
We sequenced the exons of ANGPTL4 in samples obtain from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. We performed tests of association between lipid levels and the missense E40K variant (which has been associated with reduced plasma triglyceride levels) and other inactivating mutations. We then tested for associations between coronary artery disease and the E40K variant and other inactivating mutations in 10,552 participants with coronary artery disease and 29,223 controls. We also tested the effect of a human monoclonal antibody against ANGPTL4 on lipid levels in mice and monkeys.
RESULTS
We identified 1661 heterozygotes and 17 homozygotes for the E40K variant and 75 participants who had 13 other monoallelic inactivating mutations in ANGPTL4. The levels of triglycerides were 13% lower and the levels of high-density lipoprotein (HDL) cholesterol were 7% higher among carriers of the E40K variant than among noncarriers. Carriers of the E40K variant were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; 95% confidence interval, 0.70 to 0.92; P=0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. Carriers of other inactivating mutations also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than were noncarriers. Monoclonal antibody inhibition of Angptl4 in mice and monkeys reduced triglyceride levels.
CONCLUSIONS
Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did noncarriers. The inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. (Funded by Regeneron Pharmaceuticals.)