Format

Send to

Choose Destination
Eur Heart J. 2018 Feb 1;39(5):385-393. doi: 10.1093/eurheartj/ehx662.

Liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease: Mendelian randomization and meta-analysis of 279 013 individuals.

Author information

1
Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
2
Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
3
Department of Radiology, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
4
Department of Cardiology, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
5
The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev Ringvej 75, 2730 Herlev, Denmark.
6
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev Ringvej 75, 2730 Herlev, Denmark.
7
The Copenhagen City Heart Study, Frederiksberg Hospital, Nordre Fasanvej 57, 2000 Frederiksberg, Denmark.

Abstract

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.

KEYWORDS:

Cardiovascular disease; Causality; Epidemiology; Genetics; Liver disease

PMID:
29228164
DOI:
10.1093/eurheartj/ehx662

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center