Dataset Information

HSD17B13 truncated variant is associated with a mild hepatic phenotype in Wilson's Disease.

ABSTRACT: HSD17B13 encodes hydroxysteroid 17-? dehydrogenase 13, a novel liver lipid-droplet associated protein that is involved in the regulation of lipid biosynthetic processes. A protein-truncating HSD17B13 variant (rs72613567) was shown to protect individuals from alcoholic and non-alcoholic liver disease. Since steatosis is a common feature in Wilson's disease (WD), we aimed to assess whether the HSD17B13 variant modulates the phenotypic presentation and progression of WD. Methods:The HSD17B13:TA (rs72613567) variant was determined by allelic discrimination real-time PCR in 586 patients. The HSD17B13 genotype was correlated with the phenotypic presentation. The age of onset and the type of symptoms at presentation were used as markers of the WD phenotype. Results:The overall HSD17B13:TA allele frequency in patients with WD was 23.3% (273/1,172), not significantly different from the reported minor allele frequency. There was a significantly lower HSD17B13:TA allele frequency in patients with fulminant WD compared to all other phenotypic WD groups (11.0% vs. 24.0%, p < 0.01). Among the patients with fulminant WD there was a trend for a gender effect; none of the male patients carried the HSD17B13:TA allele. HSD17B13:TA allele frequency was more common in patients with minimal or no fibrosis (49 [31.1%] had simple steatosis and 20 minimal changes at biopsy) than in patients with cirrhosis or advanced fibrosis (22.3%, p = 0.025). Conclusions:The HSD17B13:TA allele modulates the phenotype and outcome of WD. This allele likely ameliorates hepatic fibrosis and reduces the transition from copper induced hemolysis to fulminant disease in patients with WD. Lay summary:Wilson's disease is a hereditary disease caused by accumulation of copper in the liver and other tissues. It presents with a variety of clinical symptoms. In this study we explored the role of a recently described gene mutation (HSD17B13:TA) which apparently protects the liver against toxins like alcohol. The results indicate that this mutation plays a role in the evolution of liver disease. Patients with Wilson's disease who carry this mutation are more likely to have mild disease, while the absence of the mutation is associated with the most severe form - fulminant Wilson's disease.

SUBMITTER: Ferenci P

PROVIDER: S-EPMC7001574 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

HSD17B13 truncated variant is associated with a mild hepatic phenotype in Wilson's Disease.

Ferenci Peter P Pfeiffenberger Jan J Stättermayer Albert Friedrich AF Stauber Rudolf E RE Willheim Claudia C Weiss Karl H KH Munda-Steindl Petra P Trauner Michael M Schilsky Michael M Zoller Heinz H

JHEP reports : innovation in hepatology 20190319 1

<i>HSD17B13</i> encodes hydroxysteroid 17-β dehydrogenase 13, a novel liver lipid-droplet associated protein that is involved in the regulation of lipid biosynthetic processes. A protein-truncating <i>HSD17B13</i> variant (rs72613567) was shown to protect individuals from alcoholic and non-alcoholic liver disease. Since steatosis is a common feature in Wilson's disease (WD), we aimed to assess whether the HSD17B13 variant modulates the phenotypic presentation and progression of WD.<h4>Methods</h ...[more]

PMID: 32039348

Similar Datasets

Project description:BACKGROUND:Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS:We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS:A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10-12) and AST (P=6.2×10-10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS:A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.).

Project description:BackgroundMacrophages play a significant role in liver disease development and progression. The macrophage activation marker soluble (s)CD163 is associated with severity and prognosis in a number of different acute and chronic liver diseases but has been only sparsely examined in Wilson's disease (WD). We investigated sCD163 levels in patients with acute and chronic WD and hypothesized associations with liver disease phenotype and biochemical markers of liver injury.MethodsWe investigated sCD163 in two independent cohorts of WD patients: 28 patients with fulminant WD from the US Acute Liver Failure (ALF) Study Group registry and 147 patients with chronic disease from a German WD registry. We included a control group of 19 healthy individuals. Serum sCD163 levels were measured by ELISA. Liver CD163 expression was determined by immunohistochemistry.ResultsIn the ALF cohort, median sCD163 was 10-fold higher than in healthy controls (14.6(2.5-30.9) vs. 1.5(1.0-2.7) mg/L, p < 0.001). In the chronic cohort, median sCD163 was 2.6(0.9-24.9) mg/L. There was no difference in sCD163 according to subgroups based on initial clinical presentation, i.e. asymptomatic, neurologic, hepatic, or mixed. Patients with cirrhosis at the time of diagnosis had higher sCD163 compared with those without cirrhosis (3.0(1.2-24.9) vs. 2.3(0.9-8.0) mg/L, p < 0.001); and both cohorts significantly lower than the ALF patients. Further, sCD163 correlated positively with ALT, AST, GGT and INR (rho = 0.27-0.53); and negatively with albumin (rho = - 0.37), (p ≤ 0.001, all). We observed immunohistochemical CD163 expression in liver tissue from ALF patients.ConclusionsAlthough sCD163 is not specific for WD, it was elevated in WD patients, especially in those with ALF. Further, sCD163 was higher in patients with cirrhosis compared to patients without cirrhosis and associated with biochemical markers of liver injury and hepatocellular function. Thus, macrophage activation is evident in WD and associates with liver disease phenotype and biochemical parameters of liver disease. Our findings suggest that sCD163 may be used as a marker of liver disease severity in WD patients.

Dataset Information

HSD17B13 truncated variant is associated with a mild hepatic phenotype in Wilson's Disease.

Publications

HSD17B13 truncated variant is associated with a mild hepatic phenotype in Wilson's Disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets