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Genetic Variation of SAMM50 Is Not an Independent Risk Factor for Alcoholic Hepatocellular Carcinoma in Caucasian Patients.

ABSTRACT: 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.

SUBMITTER: Nischalke HD

PROVIDER: S-EPMC9740343 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Genetic Variation of <i>SAMM50</i> Is Not an Independent Risk Factor for Alcoholic Hepatocellular Carcinoma in Caucasian Patients.

Nischalke Hans Dieter HD Schmalz Franziska F Buch Stephan S Fischer Janett J Möller Christine C Matz-Soja Madlen M Krämer Benjamin B Langhans Bettina B Klüners Alexandra A Soyka Michael M Stickel Felix F Nattermann Jacob J Berg Thomas T Strassburg Christian P CP Lutz Philipp P

International journal of molecular sciences 20221205 23

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 v ...[more]

PMID: 36499681

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Project description:AimTo uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma (HCC) susceptibility in Caucasians.MethodsThe present retrospective case-control study compared genotype frequencies between a cohort of HCC cases and two, independent, HCC-free, age/sex-matched control groups. The HCC cohort comprised 192 homogeneous patients that had undergone orthotopic liver transplantation. The first control group comprised 167 patients that were matched to the HCC cohort for the percentage of hepatitis B (HBV) and/or hepatitis C (HCV) infections. A second control group included 192 virus-free, healthy individuals that were used to evaluate the generalizability of the identified predictive markers. All cases and controls were Caucasian. The three study populations were characterized with a panel of 31 markers derived from 21 genes that encoded key proteins involved in hepatocarcinogenesis-related pathways. The study end-point was to assess the association between genetic variants and HCC onset.ResultsFive genetic markers were identified as risk factors for HCC in high-risk patients infected with HBV/HCV. According to a dominant model, reduced HCC risk was associated with three polymorphisms: ERCC1 rs3212986 (OR = 0.46, 95%CI: 0.30-0.71, P = 0.0005), GST-P1 rs1138272 (OR = 0.41, 95%CI: 0.21-0.81, P = 0.0097), and CYP17A1 rs743572 (OR = 0.50, 95%CI: 0.31-0.79, P = 0.0032). Conversely, according to a recessive model, increased HCC risk was associated with two polymorphisms: XRCC3 rs1799794 (OR = 3.70, 95%CI: 1.02-13.39, P = 0.0461) and ABCB1 rs1128503 (OR = 2.06, 95%CI: 1.18-3.61, P = 0.0111). These associations remained significant in a subgroup analysis, where patients were stratified according to viral status (HBV- or HCV-positive serology). Two variants exhibited a serology-specific effect: ABCB1 rs1128503 (OR = 4.18, 95%CI: 1.55-11.29, P = 0.0048) showed an effect in the HBV-positive subgroup; and ERCC1 rs3212986 (OR = 0.33, 95%CI: 0.18-0.60, P = 0.0003) showed an effect in the HCV-positive subgroup. Among the five markers identified, ERCC1 rs3212986 (OR = 0.43, P < 0.0001) and CYP17A1 rs743572 (OR = 0.73, P = 0.0310) had a different distribution in patients with HCC compared to healthy individuals. With a recursive partitioning approach, we also demonstrated that significant gene-gene interactions between ERCC1 rs3212986, CYP17A1 rs743572, GST-P1 rs1138272, and the previously described UGT1A7*3 predictive marker, played a role in the complex trait of HCC susceptibility.ConclusionWe identified five polymorphisms and interactions that contributed crucially to predicting HCC risk. These findings represented an important step towards improving HCC diagnosis and management.

Project description:Background & aimsHepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification.MethodsWe examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5).ResultsIn the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10-13). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10-7). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10-5) and without cirrhosis (p <0.05).ConclusionsOur results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings.Lay summaryBy analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population.

Dataset Information

Genetic Variation of SAMM50 Is Not an Independent Risk Factor for Alcoholic Hepatocellular Carcinoma in Caucasian Patients.

Publications

Genetic Variation of <i>SAMM50</i> Is Not an Independent Risk Factor for Alcoholic Hepatocellular Carcinoma in Caucasian Patients.

Similar Datasets

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