Genetic risk of fatty liver disease and mortality in the general population: A Mendelian randomization study
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Genetic risk of fatty liver disease and mortality in the general population : A Mendelian randomization study. / Gellert-Kristensen, Helene; Tybjærg-Hansen, Anne; Nordestgaard, Børge G.; Ghouse, Jonas; Fuchs, Andreas; Kühl, Jørgen T.; Sigvardsen, Per E.; Kofoed, Klaus F.; Stender, Stefan.
I: Liver International, Bind 43, Nr. 9, 2023, s. 1955-1965.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Genetic risk of fatty liver disease and mortality in the general population
T2 - A Mendelian randomization study
AU - Gellert-Kristensen, Helene
AU - Tybjærg-Hansen, Anne
AU - Nordestgaard, Børge G.
AU - Ghouse, Jonas
AU - Fuchs, Andreas
AU - Kühl, Jørgen T.
AU - Sigvardsen, Per E.
AU - Kofoed, Klaus F.
AU - Stender, Stefan
N1 - Publisher Copyright: © 2023 The Authors. Liver International published by John Wiley & Sons Ltd.
PY - 2023
Y1 - 2023
N2 - Background & Aims: Fatty 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. Methods: We 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. Results: During 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. Conclusions: Human genetic data support that fatty liver disease is a causal driver of liver-related mortality.
AB - Background & Aims: Fatty 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. Methods: We 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. Results: During 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. Conclusions: Human genetic data support that fatty liver disease is a causal driver of liver-related mortality.
KW - epidemiology
KW - fatty liver
KW - genetics
KW - liver cirrhosis
KW - Mendelian randomization analysis
U2 - 10.1111/liv.15629
DO - 10.1111/liv.15629
M3 - Journal article
C2 - 37269170
AN - SCOPUS:85161396187
VL - 43
SP - 1955
EP - 1965
JO - Liver International
JF - Liver International
SN - 1478-3223
IS - 9
ER -
ID: 366305839