Combined effect of PNPLA3, TM6SF2, and HSD17B13 variants on risk of cirrhosis and hepatocellular carcinoma in the general population

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 risk‐increasing alleles. We examined 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 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) 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 to those with score 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 12‐fold higher risk of cirrhosis and up to 29‐fold higher risk of HCC in individuals from the general population.