Combined Effect of PNPLA3, TM6SF2, and HSD17B13 Variants on Risk of Cirrhosis and Hepatocellular Carcinoma in 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 [TM6...

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Vydané v:	Hepatology (Baltimore, Md.) Ročník 72; číslo 3; s. 845 - 856
Hlavní autori:	Gellert‐Kristensen, Helene, Richardson, Tom G., Davey Smith, George, Nordestgaard, Børge G., Tybjærg‐Hansen, Anne, Stender, Stefan
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Wolters Kluwer Health, Inc 01.09.2020
Predmet:	17-Hydroxysteroid Dehydrogenases - genetics Alanine Alanine transaminase Alanine Transaminase - blood Biobanks Carcinoma, Hepatocellular - blood Carcinoma, Hepatocellular - epidemiology Carcinoma, Hepatocellular - genetics Cirrhosis Denmark - epidemiology Fatty liver Female Genetic diversity Genetic Predisposition to Disease Health risk assessment Hepatocellular carcinoma Hepatology Humans Lipase - genetics Liver cancer Liver cirrhosis Liver Cirrhosis - blood Liver Cirrhosis - epidemiology Liver Cirrhosis - genetics Liver diseases Liver Neoplasms - blood Liver Neoplasms - epidemiology Liver Neoplasms - genetics Male Membrane Proteins - genetics Middle Aged Non-alcoholic Fatty Liver Disease - blood Non-alcoholic Fatty Liver Disease - diagnosis Non-alcoholic Fatty Liver Disease - epidemiology Phospholipase Polymorphism, Single Nucleotide Risk Factors United Kingdom - epidemiology Denmark United Kingdom United Kingdom > UK
ISSN:	0270-9139, 1527-3350, 1527-3350
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0270-9139 1527-3350 1527-3350
DOI:	10.1002/hep.31238