Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality

Abstract

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.

Association of AGT rs2493132 Polymorphism and the Risk of Coronary Artery Disease in Patients with Non-alcoholic Fatty Liver Disease in Chinese Han Population

“…Cheng et al showed that the TNF-α-238 gene polymorphism also increases the developing risk of CAD in NAFLD patients in Chinese Han population [27]. Moreover, variants in PNPLA3 and TM6SF2 predispose to NAFLD conferred a mild protective effect for CAD, and both TM6SF2 and PNPLA3 gene polymorphisms were associated with lower plasma lipid levels [3,28]. These results suggested that gene polymorphisms play an important role in the development of CAD in patients with NAFLD, gene polymorphisms may exert the protective or risk dangerous role for the CAD in patients with NAFLD.…”

“…Dyslipidemia is a common feature of both NAFLD and CAD patients which characterized by the elevated plasma triacylglycerol, circulating LDL particles and the reduced HDL [31][32][33][34]. Brouwers et al suggested that plasma lipids act as the major mediators in the relationship between NAFLD and CVD [3]. The characteristics of subjects in this study showed that NAFLD patients possess the higher levers of BMI, AST, ALT, TG, LDL, GGT, and decreased level of HDL compare to health controls, that is consistent with the changes of serum lipids pro les in patients with NAFLD in previous studies [32,[35][36][37].…”

“…Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, and the prevalence of NAFLD in the Asian was as high as 29.62% [1]. As a hepatic manifestation of metabolic syndrome, NAFLD has been proven to be an independent risk factor for cardiovascular disease (CVD) [2][3][4][5]. The occurrence rate of coronary artery disease (CAD) increased 4.7 times in the adult NAFLD population and the severity of CAD was also signi cantly associated with the presence of NAFLD [6].…”

“…Multiple factors contribute to the pathogenesis of NAFLD and CAD [7]. Accumulated evidence suggested that gene polymorphism is an important risk factor not only for the occurrence of NAFLD or CAD in the general population, but also for the occurrence of CAD in the NAFLD patients [3,8]. Simons et al investigated the effect of three variants in the NAFLD susceptibility genes TM6SF2, MBOAT7, and PNPLA3 on the developing risk of CAD in the NAFLD patients [9].…”

“…A recent meta-analysis (include 274,625 individuals) demonstrated a signi cant association between the GCKR rs780094 and the risk of CAD [12]. The different effects of gene polymorphisms on plasma lipids may be a vital mediator between NAFLD and the risk of CAD [3].…”