Lifelong, genetically high liver fat content was not causally associated with risk of ischaemic heart disease (OR 0.98; 95% CI 0.96-1.00 per M-allele vs I-allele).
Meta-Analysis (n=279,013)
Does genetically determined high liver fat content or NAFLD cause ischaemic heart disease?
Despite observational associations, lifelong genetically high liver fat content is not causally associated with the risk of ischaemic heart disease, suggesting observational findings are due to confounding or reverse causation.
Odds Ratio: 0.98 (95% CI 0.96–1)
Aims: In observational studies, non-alcoholic fatty liver disease (NAFLD) is associated with high risk of ischaemic heart disease (IHD). We tested the hypothesis that a high liver fat content or a diagnosis of NAFLD is a causal risk factor for IHD. Methods and results: In a cohort study of the Danish general population (n = 94 708/IHD = 10 897), we first tested whether a high liver fat content or a diagnosis of NAFLD was associated observationally with IHD. Subsequently, using Mendelian randomization, we tested whether a genetic variant in the gene encoding the protein patatin-like phospholipase domain containing 3 protein (PNPLA3), I148M (rs738409), a strong and specific cause of high liver fat content and NAFLD, was causally associated with the risk of IHD. We found that the risk of IHD increased stepwise with increasing liver fat content (in quartiles) up to an odds ratio (OR) of 2.41 (1.28-4.51)(P-trend = 0.004). The corresponding OR for IHD in individuals with vs. without NAFLD was 1.65 (1.34-2.04)(P = 3×10-6). PNPLA3 I148M was associated with a stepwise increase in liver fat content of up to 28% in MM vs. II-homozygotes (P-trend = 0.0001) and with ORs of 2.03 (1.52-2.70) for NAFLD (P = 3×10-7), 3.28 (2.37-4.54) for cirrhosis (P = 4×10-12), and 0.95 (0.86-1.04) for IHD (P = 0.46). In agreement, in meta-analysis (N = 279 013/IHD = 71 698), the OR for IHD was 0.98 (0.96-1.00) per M-allele vs. I-allele. The OR for IHD per M-allele higher genetically determined liver fat content was 0.98 (0.94-1.03) vs. an observational estimate of 1.05 (1.02-1.09)(P for comparison = 0.02). Conclusion: Despite confirming the known observational association of liver fat content and NAFLD with IHD, lifelong, genetically high liver fat content was not causally associated with risk of IHD. These results suggest that the observational association is due to confounding or reverse causation.
Lauridsen et al. (2017) conducted a meta-analysis in ischaemic heart disease (n=279,013). Genetically high liver fat content (PNPLA3 I148M M-allele) vs. I-allele (lower liver fat content) was evaluated on ischaemic heart disease (OR 0.98, 95% CI 0.96-1.00). Lifelong, genetically high liver fat content was not causally associated with risk of ischaemic heart disease (OR 0.98; 95% CI 0.96-1.00 per M-allele vs I-allele).