A study published in the European Heart Journal evaluated the hypothesis that a high liver fat content or a diagnosis of non-alcoholic fatty liver disease (NAFLD) is a causal risk factor for ischemic heart disease (IHD). The findings of this study confirmed the association of liver fat content and NAFLD with IHD, however, lifelong, genetically high liver fat content was not causally linked with the risk of IHD.

The study cohort comprised the Danish general population (n = 94,708/IHD = 10,897). The researchers investigated whether a high liver fat content or a diagnosis of NAFLD was related observationally with IHD. Following this, they used Mendelian randomization to determine 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. The results showed that the risk of IHD escalated stepwise with an increase in liver fat content up to an odds ratio (OR) of 2.41. The corresponding OR for IHD in people with and those without NAFLD was 1.65. Moreover, PNPLA3 I148M was associated with a stepwise increase in liver fat content of up to 28% in MM versus II-homozygotes and with ORs of 2.03 for NAFLD, 3.28 for cirrhosis, and 0.95 for IHD. In meta-analysis (N = 2,79,013/IHD = 71,698), the OR for IHD was 0.98 per M-allele versus I-allele. Moreover, the OR for IHD per M-allele higher genetically determined liver fat content was 0.98 in contrast to an observational estimate of 1.05.