Non-alcoholic fatty liver disease (NAFLD) is highly prevalent among individuals with type 2 diabetes. Although epidemiological studies have shown that NAFLD is associated with cardiovascular disease (CVD), it remains unknown whether NAFLD is an active contributor or an innocent bystander. Plasma lipids, low-grade inflammation, impaired fibrinolysis and hepatokines are potential mediators of the relationship between NAFLD and CVD. The Mendelian randomisation approach can help to make causal inferences. Studies that used common variants in PNPLA3, TM6SF2 and GCKR as instruments to investigate the relationship between NAFLD and coronary artery disease (CAD) have reported contrasting results. Variants in PNPLA3 and TM6SF2 were found to protect against CAD, whereas variants in GCKR were positively associated with CAD. Since all three genes have been associated with non-alcoholic steatohepatitis, the second stage of NAFLD, the question of whether low-grade inflammation is an important mediator of the relationship between NAFLD and CAD arises. In contrast, the differential effects of these genes on plasma lipids (i.e. lipid-lowering for PNPLA3 and TM6SF2, and lipid-raising for GCKR) strongly suggest that plasma lipids account for their differential effects on CAD risk. This concept has recently been confirmed in an extended set of 12 NAFLD susceptibility genes. From these studies it appears that plasma lipids are an important mediator between NAFLD and CVD risk. These findings have important clinical implications, particularly for the design of anti-NAFLD drugs that also affect lipid metabolism.

中文翻译：

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非酒精性脂肪肝和心血管疾病：评估因果关系的证据。

非酒精性脂肪肝疾病（NAFLD）在2型糖尿病患者中非常普遍。尽管流行病学研究表明，NAFLD与心血管疾病（CVD）相关，但仍不清楚NAFLD是积极的贡献者还是无辜的旁观者。血浆脂质，低度炎症，纤维蛋白溶解受损和肝因子是NAFLD与CVD之间关系的潜在介质。孟德尔随机化方法可以帮助进行因果推断。使用PNPLA3，TM6SF2和GCKR中的常见变体作为研究NAFLD与冠状动脉疾病（CAD）之间关系的研究报告了相反的结果。发现PNPLA3和TM6SF2的变体可以预防CAD，而GCKR的变体与CAD正相关。由于所有这三个基因都与非酒精性脂肪性肝炎（NAFLD的第二阶段）有关，因此出现了低度炎症是否是NAFLD与CAD之间关系的重要介体的问题。相反，这些基因对血浆脂质的差异作用（即PNPLA3和TM6SF2的脂质降低和GCKR的脂质上升）强烈表明血浆脂质解释了它们对CAD风险的差异作用。最近在扩展的12个NAFLD敏感性基因中证实了这一概念。从这些研究看来，血浆脂质是NAFLD和CVD风险之间的重要介质。这些发现具有重要的临床意义，特别是对于设计也影响脂质代谢的抗NAFLD药物。在NAFLD的第二阶段，出现了轻度炎症是否是NAFLD与CAD之间关系的重要介体的问题。相反，这些基因对血浆脂质的差异作用（即PNPLA3和TM6SF2的脂质降低和GCKR的脂质上升）强烈表明血浆脂质解释了它们对CAD风险的差异作用。最近在扩展的12个NAFLD敏感性基因中证实了这一概念。从这些研究看来，血浆脂质是NAFLD和CVD风险之间的重要介质。这些发现具有重要的临床意义，特别是对于设计也影响脂质代谢的抗NAFLD药物。在NAFLD的第二阶段，出现了轻度炎症是否是NAFLD与CAD之间关系的重要介体的问题。相反，这些基因对血浆脂质的差异作用（即PNPLA3和TM6SF2的脂质降低和GCKR的脂质上升）强烈表明血浆脂质解释了它们对CAD风险的差异作用。最近在扩展的12个NAFLD敏感性基因中证实了这一概念。从这些研究看来，血浆脂质是NAFLD和CVD风险之间的重要介质。这些发现具有重要的临床意义，特别是对于设计也影响脂质代谢的抗NAFLD药物。这些基因对血浆脂质的差异作用（即PNPLA3和TM6SF2的脂质降低和GCKR的脂质升高）强烈表明血浆脂质解释了它们对CAD风险的差异作用。最近在扩展的12个NAFLD敏感性基因中证实了这一概念。从这些研究看来，血浆脂质是NAFLD和CVD风险之间的重要介质。这些发现具有重要的临床意义，特别是对于设计也影响脂质代谢的抗NAFLD药物。这些基因对血浆脂质的差异作用（即PNPLA3和TM6SF2的脂质降低和GCKR的脂质升高）强烈表明血浆脂质解释了它们对CAD风险的差异作用。最近在扩展的12个NAFLD敏感性基因中证实了这一概念。从这些研究看来，血浆脂质是NAFLD和CVD风险之间的重要介质。这些发现具有重要的临床意义，特别是对于设计也影响脂质代谢的抗NAFLD药物。从这些研究看来，血浆脂质是NAFLD和CVD风险之间的重要介质。这些发现具有重要的临床意义，特别是对于设计也影响脂质代谢的抗NAFLD药物。从这些研究看来，血浆脂质是NAFLD和CVD风险之间的重要介质。这些发现具有重要的临床意义，特别是对于设计也影响脂质代谢的抗NAFLD药物。