Relationship Between Nonalcoholic Fatty Liver Disease Susceptibility Genes and Coronary Artery Disease

Abstract

Coronary artery disease (CAD) is the principal cause of death in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to investigate whether NAFLD is causally involved in the pathogenesis of CAD. For this, previously reported NAFLD susceptibility genes were clustered and tested for an association with CAD in the Coronary Artery Disease Genome‐Wide Replication and Meta‐Analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) Consortium data set. The role of plasma lipids as a potential mediator was explored by using data from the Global Lipids Genetics Consortium. Statistical analyses revealed that the combination of 12 NAFLD genes was not associated with CAD in 60,801 CAD cases and 123,504 controls (odds ratio [OR] per NAFLD risk allele , 1.0; 95% confidence interval [CI], 0.99‐1.00). In a subsequent sensitivity analysis, a positive relationship was observed after exclusion of gene variants that are implicated in NAFLD through impaired very low‐density lipoprotein secretion (i.e., microsomal triglyceride transfer protein [ MTTP ] , patatin‐like phospholipase domain containing 3 [ PNPLA3 ] , phosphatidylethanolamine N‐methyltransferase [ PEMT ] , and transmembrane 6 superfamily member 2 [ TM6SF2 ]) (OR, 1.01; 95% CI, 1.00‐1.02). Clustering of the excluded genes showed a significant negative relationship with CAD (OR, 0.97; 95% CI, 0.96‐0.99). A substantial proportion of the observed heterogeneity between the individual NAFLD genes in relation to CAD could be explained by plasma lipids, as reflected by a strong relationship between plasma lipids and CAD risk conferred by the NAFLD susceptibility genes ( r = 0.76; P = 0.004 for low‐density lipoprotein cholesterol). Conclusion: NAFLD susceptibility genes do not cause CAD per se . The relationship between these genes and CAD appears to depend to a large extent on plasma lipids. These observations strongly suggest taking plasma lipids into account when designing a new drug to target NAFLD.

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

“…3d), they also suggest that that plasma lipids have a greater impact on CAD risk than type 2 diabetes. Indeed, we recently expanded our genetic analyses to 12 NAFLD susceptibility genes (identified by either genome-wide association studies for NAFLD or NAFLD-related traits, or meta-analyses) and showed that the effects of these variants on CAD risk are largely accounted for by plasma lipids [55]. We observed a strong relationship between plasma lipids and CAD risk conferred by these NAFLD susceptibility genes [55].…”

“…Finally, variants in the membrane-bound O-acyltransferase domain-containing 7 gene (MBOAT7), which is involved in acyl-chain remodelling of phosphatidylinositols, have consistently been associated with NAFLD [53,54]. Of interest, the rs641738 T allele was not associated with CAD, nor with plasma lipids or type 2 diabetes [45,50,55].…”

“…Indeed, we recently expanded our genetic analyses to 12 NAFLD susceptibility genes (identified by either genome-wide association studies for NAFLD or NAFLD-related traits, or meta-analyses) and showed that the effects of these variants on CAD risk are largely accounted for by plasma lipids [55]. We observed a strong relationship between plasma lipids and CAD risk conferred by these NAFLD susceptibility genes [55]. Moreover, since many of these genes, including PNPLA3 and TM6SF2, have also been associated with NASH, it is questionable whether low-grade inflammation plays a major role in the connection between NAFLD and CVD.…”

Genetics of Non-Alcoholic Fatty Liver and Cardiovascular Disease: Implications for Therapy?

“…The clustering of 12 genetic variants associated with NAFLD by weighted fixed-effects statistical modeling showed no association with CAD or MI (OR: 1.00, 95% CI 0.99-1.01, p = 0.93) (Brouwers et al, 2019). Restricting this analysis to the four most validated genes (PNPLA3, TM6SF2, GCKR, and MBOAT7) also resulted in a null association (OR: 0.99, 95% CI 0.98-1.00) (Brouwers et al, 2019).…”

“…Different endpoints have been used in NAFLD GWAS including histology, imaging-based hepatic fat content, serum liver enzymes, and presence of HCC, contributing to heterogeneity. Here we focus primarily on candidate NAFLD risk genes with consistent results in discovery GWAS or meta-analyses of GWAS, and validated using candidate gene studies, a strategy described in a recent study clustering NAFLD associated genes (Brouwers et al, 2019). We also highlight other genes not identified with GWAS, but have significant associations with CVD in retrospective studies or meta-analyses of retrospective studies, and outline their association with NAFLD ( Table 1).…”