Affiliation:
1. Department of Clinical Biochemistry Copenhagen University Hospital – Rigshospitalet Copenhagen Denmark
2. The Copenhagen General Population Study Copenhagen University Hospital – Herlev Gentofte Herlev Denmark
3. The Copenhagen City Heart Study Copenhagen University Hospital – Bispebjerg Frederiksberg Frederiksberg Denmark
4. Department of Clinical Medicine, Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
5. Department of Clinical Biochemistry Copenhagen University Hospital – Herlev Gentofte Herlev Denmark
6. Department of Cardiology Copenhagen University Hospital – Rigshospitalet Copenhagen Denmark
7. Department of Radiology Copenhagen University Hospital – Rigshospitalet Copenhagen Denmark
Abstract
AbstractBackground & AimsFatty liver disease has been associated with higher all‐cause as well as liver‐related, ischemic heart disease (IHD)‐related and extrahepatic cancer‐related mortality in observational epidemiological studies. We tested the hypothesis that fatty liver disease is a causal risk factor for higher mortality.MethodsWe genotyped seven genetic variants known to be associated with fatty liver disease (in PNPLA3, TM6SF2, HSD17B13, MTARC1, MBOAT7, GCKR, and GPAM) in 110 913 individuals from the Danish general population. Hepatic steatosis was measured by hepatic computed tomography in n = 6965. Using a Mendelian randomization framework, we tested whether genetically proxied hepatic steatosis and/or elevated plasma alanine transaminase (ALT) was associated with liver‐related mortality.ResultsDuring a median follow‐up of 9.5 years, 16 119 individuals died. In observational analyses, baseline elevated plasma ALT was associated with higher all‐cause (1.26‐fold), liver‐related (9‐fold), and extrahepatic cancer‐related (1.25‐fold) mortality. In genetic analyses, the risk alleles in PNPLA3, TM6SF2, and HSD17B13 were individually associated with higher liver‐related mortality. The largest effects were seen for the PNPLA3 and TM6SF2 risk alleles, for which homozygous carriers had 3‐fold and 6‐fold, respectively, higher liver‐related mortality than non‐carriers. None of the risk alleles, individually or combined into risk scores, were robustly associated with all‐cause, IHD‐related, or extrahepatic cancer‐related mortality. In instrumental variable analyses, genetically proxied hepatic steatosis and higher plasma ALT were associated with liver‐related mortality.ConclusionsHuman genetic data support that fatty liver disease is a causal driver of liver‐related mortality.
Funder
Independent Research Fund Denmark
Cited by
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