Helene Gellert-Kristensen1,2, Tom G Richardson3, George Davey Smith3, Børge G Nordestgaard2,4,5,6, Anne Tybjaerg-Hansen1,2,5,6, Stefan Stender1,2,7. 1. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark. 2. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 3. Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom. 4. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev, Denmark. 5. The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark. 6. The Copenhagen City Heart Study, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark. 7. Department of Clinical Biochemistry, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
Abstract
BACKGROUND AND AIMS: We hypothesized that a genetic risk score (GRS) for fatty liver disease influences the risk of cirrhosis and hepatocellular carcinoma (HCC). Three genetic variants (patatin-like phospholipase domain-containing protein 3 [PNPLA3] p.I148M; transmembrane 6, superfamily member 2 [TM6SF2] p.E167K; and hydroxysteroid 17-beta dehydrogenase 13 [HSD17B13] rs72613567) were combined into a risk score, ranging from 0 to 6 for risk-increasing alleles. APPROACH AND RESULTS: We examined the association of the risk score with plasma markers of liver disease and with cirrhosis and HCC in 110,761 individuals from Copenhagen, Denmark, and 334,691 individuals from the UK Biobank. The frequencies of risk scores of 0, 1, 2, 3, 4, and 5 or 6 were 5%, 25%, 41%, 23%, 5.5%, and 0.5%, respectively. A higher GRS was associated with an increase in plasma alanine aminotransferase (ALT) level of 26% in those with score 5 or 6 versus 0. In meta-analysis of the Copenhagen studies and the UK Biobank, individuals with scores 1, 2, 3, 4, and 5 or 6 had odds ratios (ORs) for cirrhosis of 1.6 (95% confidence interval [CI], 1.3, 1.9), 2.0 (95% CI, 1.8, 2.2), 3.1 (95% CI, 2.7, 3.5), 5.2 (95% CI, 4.2, 6.4), and 12 (95% CI, 7.7, 19), respectively, as compared with those with a score of 0. The corresponding ORs for HCC were 1.2 (95% CI, 0.9, 1.7), 1.0 (95% CI, 0.7, 1.3), 2.4 (95% CI, 1.9, 3.0), 3.3 (95% CI, 2.2, 5.0), and 29 (95% CI, 17, 51). CONCLUSION: A GRS for fatty liver disease confers up to a 12-fold higher risk of cirrhosis and up to a 29-fold higher risk of HCC in individuals from the general population.
BACKGROUND AND AIMS: We hypothesized that a genetic risk score (GRS) for fatty liver disease influences the risk of cirrhosis and hepatocellular carcinoma (HCC). Three genetic variants (patatin-like phospholipase domain-containing protein 3 [PNPLA3] p.I148M; transmembrane 6, superfamily member 2 [TM6SF2] p.E167K; and hydroxysteroid 17-beta dehydrogenase 13 [HSD17B13] rs72613567) were combined into a risk score, ranging from 0 to 6 for risk-increasing alleles. APPROACH AND RESULTS: We examined the association of the risk score with plasma markers of liver disease and with cirrhosis and HCC in 110,761 individuals from Copenhagen, Denmark, and 334,691 individuals from the UK Biobank. The frequencies of risk scores of 0, 1, 2, 3, 4, and 5 or 6 were 5%, 25%, 41%, 23%, 5.5%, and 0.5%, respectively. A higher GRS was associated with an increase in plasma alanine aminotransferase (ALT) level of 26% in those with score 5 or 6 versus 0. In meta-analysis of the Copenhagen studies and the UK Biobank, individuals with scores 1, 2, 3, 4, and 5 or 6 had odds ratios (ORs) for cirrhosis of 1.6 (95% confidence interval [CI], 1.3, 1.9), 2.0 (95% CI, 1.8, 2.2), 3.1 (95% CI, 2.7, 3.5), 5.2 (95% CI, 4.2, 6.4), and 12 (95% CI, 7.7, 19), respectively, as compared with those with a score of 0. The corresponding ORs for HCC were 1.2 (95% CI, 0.9, 1.7), 1.0 (95% CI, 0.7, 1.3), 2.4 (95% CI, 1.9, 3.0), 3.3 (95% CI, 2.2, 5.0), and 29 (95% CI, 17, 51). CONCLUSION: A GRS for fatty liver disease confers up to a 12-fold higher risk of cirrhosis and up to a 29-fold higher risk of HCC in individuals from the general population.
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