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Hepatol Commun. 2019 Feb 11;3(4):587-596. doi: 10.1002/hep4.1319. eCollection 2019 Apr.

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

Author information

1
Department of Internal Medicine, Division of Endocrinology Maastricht University Medical Center Maastricht the Netherlands.
2
Cardiovascular Research Institute Maastricht, Maastricht University Maastricht the Netherlands.
3
Department of Internal Medicine, Division of General Internal Medicine, Laboratory for Metabolism and Vascular Medicine Maastricht University Medical Center Maastricht the Netherlands.
4
Department of Internal Medicine, Division of General Internal Medicine Maastricht University Medical Center Maastricht the Netherlands.
5
Department of Internal Medicine, Division of Gastroenterology and Hepatology Maastricht University Medical Center Maastricht the Netherlands.
6
School of Nutrition and Translational Research in Metabolism Maastricht University Maastricht the Netherlands.
7
Department of Surgery, Klinikum Rheinisch-Westfälische Technische Hochschule Aachen Germany.
8
Maastricht Center for Systems Biology Maastricht University Maastricht the Netherlands.
9
Department of Biochemistry Maastricht University Maastricht the Netherlands.

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.

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