Human genetic insights into lipoproteins and risk of cardiometabolic disease.
Human genetic insights into lipoproteins and risk of cardiometabolic disease.
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DOI：
10.1097/mol.0000000000000389
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发表时间：
2017-04
影响因子：
4.4
通讯作者：
Stitziel NO
中科院分区：
文献类型：
--
作者：
Stitziel NO
人类遗传学研究已成功用于鉴定与人类生物学相关的基因和途径。利用由与人类脂质性状相关的基因座组成的遗传工具，最近的研究已经开始阐明主要脂质组分在心脏代谢疾病风险中的因果作用。低密度脂蛋白胆固醇和冠心病之间的因果关系已经牢固确立。在剩下的两个主要特征中，最近的研究发现HDL胆固醇不太可能是动脉粥样硬化形成的因果颗粒，而是将因果焦点转移到富含HDL的脂蛋白上。随后的结果正在完善这一观点，表明甘油三酯本身可能不是因果关系，而是可能是富含甘油三酯的脂蛋白中因果性胆固醇含量的替代品。其他研究也使用了类似的方法来解决脂质和脂蛋白与2型糖尿病风险之间的关联。除了他汀类药物（HGMCR）靶点的遗传变异外，LDL胆固醇降低与编码与糖尿病风险增加相关的当前或预期药物靶点的多个基因相关。此外，遗传性低HDL胆固醇和低甘油三酯似乎会增加2型糖尿病的风险。这些和未来的人类遗传学研究的结果定位于提供实质性的见解脂质和人类疾病之间的因果关系，并应突出机制，为我们了解人类生物学和未来的脂质改变治疗的发展具有重要意义。
Human genetic studies have been successfully used to identify genes and pathways relevant to human biology. Using genetic instruments composed of loci associated with human lipid traits, recent studies have begun to clarify the causal role of major lipid fractions in risk of cardiometabolic disease. The causal relationship between LDL cholesterol and coronary disease has been firmly established. Of the remaining two major traits, recent studies have found that HDL cholesterol is not likely to be a causal particle in atherogenesis and have instead shifted the causal focus to triglyceride-rich lipoproteins. Subsequent results are refining this view to suggest that triglycerides themselves might not be causal but instead may be a surrogate for the causal cholesterol content within triglyceride-rich lipoproteins. Other studies have used a similar approach to address the association between lipids and lipoproteins and risk of type 2 diabetes. Beyond genetic variation in the target of statin medications (HGMCR), reduced LDL cholesterol associated with multiple genes encoding current or prospective drug targets associated with increased diabetic risk. In addition, genetically lower HDL cholesterol and lower triglycerides appear to increase risk of type 2 diabetes. Results of these and future human genetic studies are positioned to provide substantive insights into the causal relationship between lipids and human disease and should highlight mechanisms with important implications for our understanding of human biology and future lipid-altering therapeutic development.