The relationship between genetic liver fat and coronary heart disease is explained by apoB-containing lipoproteins

The relationship between genetically-driven liver fat and coronary heart disease (CHD) remains unclear. ApoB-containing lipoproteins are known causal factors for CHD and may explain this relationship. We conducted a genome-wide association study (GWAS) in the UK Biobank to identify genetic variants associated with liver fat. We then investigated the effects that these genetic variants had on both apoB-containing lipoproteins and CHD. Using Mendelian Randomization (MR) analyses, we examined if the relationship between genetically-driven liver fat and CHD could be attributed to its effect on apoB-containing lipoproteins. We found 25 independent liver-fat associated single-nucleotide polymorphisms (SNPs) with differing effects on lipoprotein metabolism. The SNPs were classified into three groups/clusters. The first cluster (N = 3 SNPs) displayed lipoprotein-raising effects. The second cluster (N = 12 SNPs) displayed neutral effects on lipoproteins and the third cluster (N = 10 SNPs) displayed lipoprotein-lowering effects. For every 1% higher liver fat, the first cluster showed an increased risk of CHD (OR = 1.157 [95% CI: 1.108–1.208]). The second cluster showed a non-significant effect on CHD (OR = 0.988 [95% CI: 0.965–1.012], whereas the third cluster showed a protective effect of increased liver fat on CHD (OR = 0.942 [95% CI: 0.897–0.989]). When adjusting for apoB, the risk for CHD became null. Here, we identify 25 liver-fat associated SNPs. We find that SNPs that increase, decrease or have neutral effects on apoB-containing lipoproteins show increased, decreased or neutral effects on CHD, respectively. Therefore, the relationship between genetically-driven liver fat and CHD is mediated by the causal effect of apoB. [Display omitted] •Liver fat-related genetic variants may or may not raise coronary heart disease risk.•Previous studies have shown different results using different genetic variants.•The effect on apoB-containing lipoproteins may explain previous results.•Here, we were able to directly account for the possible effect on plasma apoB.•We found that the effect on coronary heart disease risk is fully explained by apoB.