Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 23, Pages -Publisher
MDPI
DOI: 10.3390/ijms232315353
Keywords
cirrhosis; alcohol-associated liver disease; HCC; SAMM50
Funding
- Deutsche Krebshilfe [70114349]
- Swiss National Fund [SNF 310030_169196]
- German Research Foundation [DFG SFB/TRR 57, SPP1937]
- Hector foundation [M88]
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Hepatocellular carcinoma (HCC) is a severe complication of advanced alcoholic liver disease. This study found an association between genetic variation in SAMM50 and HCC in patients with alcoholic liver disease. Although minor variants of SAMM50 were strongly associated with alcoholic HCC, this association was found to be dependent on the presence of the well-known risk variant PNPLA3 148M.
Hepatocellular carcinoma (HCC) is a severe complication of advanced alcoholic liver disease, which is modulated by genetic predisposition. Identifying new genetic loci might improve screening. Genetic variation of SAMM50 was linked to HCC. We aimed to validate this finding in a large cohort of patients with advanced alcoholic liver disease (ALD). A large, well-characterised cohort of patients with alcoholic cirrhosis without (n = 674) and with (n = 386) HCC, as well as controls with HCC due to viral hepatitis (n = 134), controls with heavy alcohol abuse without liver disease (n = 266) and healthy subjects (n = 237), were genotyped for SAMM50 rs3827385 and rs3761472 and for PNPLA3 rs738409. Genotype frequencies were compared between patients with alcohol-associated cirrhosis with and without HCC by uni- and multivariate analysis. Minor variants in both SAMM50 rs3827385 and rs3761472 were significantly more frequent in patients with alcoholic HCC versus alcoholic cirrhosis and versus the control cohorts. An even stronger association was noted for PNPLA3 rs738409. The univariate analysis resulted in an odds ratio (OR) of 1.8 for carriers of at least one minor variant of SAMM50 rs3827385 and rs3761472 (each p < 0.001), but this association was lost in multivariate analysis with age (OR 1.1/year), male sex (OR 3.2), diabetes (OR 1.9) and carriage of PNPLA3 148M (OR 2.1) remaining in the final model. Although minor variants of both SAMM50 loci are strongly associated with alcoholic HCC, this association is not independent of carriage of the well-known risk variant PNPLA3 148M.
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