Plasma levels of HDL cholesterol (HDL-C) predict the risk of cardiovascular disease at the epidemiological level, but a direct causal role for HDL in cardiovascular disease remains controversial. Studies in animal models and humans with rare monogenic disorders link only particular HDL-associated mechanisms with causality, including those mechanisms related to particle functionality rather than cholesterol content. Mendelian randomization studies indicate that most genetic variants that affect a range of pathways that increase plasma HDL-C levels are not usually associated with reduced risk of cardiovascular disease, with some exceptions, such as cholesteryl ester transfer protein variants. Furthermore, only a fraction of HDL-C variation has been explained by known loci from genome-wide association studies (GWAS), suggesting the existence of additional pathways and targets. Systems genetics can enhance our understanding of the spectrum of HDL pathways, particularly those pathways that involve new and non-obvious GWAS loci. Bioinformatic approaches can also define new molecular interactions inferred from both large-scale genotypic data and RNA sequencing data to reveal biologically meaningful gene modules and networks governing HDL metabolism with direct relevance to disease end points. Targeting these newly recognized causal networks might inform the development of novel therapeutic strategies to reduce the risk of cardiovascular disease.

高密度脂蛋白胆固醇（HDL-C）的血浆水平在流行病学水平预测了心血管疾病的风险，但是高密度脂蛋白在心血管疾病中的直接因果关系仍存在争议。在动物模型和患有罕见单基因疾病的人类中进行的研究仅将特定的与HDL相关的机制与因果关系联系起来，包括与颗粒功能而不是胆固醇含量有关的那些机制。孟德尔随机研究表明，大多数影响一系列升高血浆HDL-C水平的遗传变异通常与降低心血管疾病的风险没有关联，除了某些例外，例如胆固醇酯转移蛋白变异。此外，全基因组关联研究（GWAS）的已知基因座仅解释了一部分HDL-C变异，提示存在其他途径和目标。系统遗传学可以增强我们对HDL途径谱的理解，特别是那些涉及新的和非显而易见的GWAS基因座的途径。生物信息学方法还可以定义从大规模基因型数据和RNA测序数据中推断出的新分子相互作用，以揭示具有生物学意义的基因模块和网络，这些模块和网络可控制与疾病终点直接相关的HDL代谢。针对这些新发现的因果网络可能会为减少心血管疾病风险的新型治疗策略的开发提供信息。生物信息学方法还可以定义从大规模基因型数据和RNA测序数据中推断出的新分子相互作用，以揭示具有生物学意义的基因模块和网络，这些模块和网络可控制与疾病终点直接相关的HDL代谢。针对这些新发现的因果网络可能会为减少心血管疾病风险的新型治疗策略的开发提供信息。生物信息学方法还可以定义从大规模基因型数据和RNA测序数据中推断出的新分子相互作用，以揭示具有生物学意义的基因模块和网络，这些模块和网络可控制与疾病终点直接相关的HDL代谢。针对这些新发现的因果网络可能会为减少心血管疾病风险的新型治疗策略的开发提供信息。