Polygenic risk score: A promising predictor for hepatocellular carcinoma in the population with non-alcoholic fatty liver disease

Long, Junyu; Bian, Jin; Zhao, Hong

doi:10.1016/j.jhep.2021.01.010

Cited by 3 publications

(1 citation statement)

References 7 publications

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“…The utility of PRS is higher early in life and at early disease stages; being the genetic risk triggered by environmental factors, it could be diminished by changes in lifestyle. A positive PRS test may identify a subset of individuals with dysmetabolism at high genetic risk of HCC, who could benefit from a surveillance programme 4,19,20 . Of note, one patient who developed HCC during the follow‐up had a PRS value over the positive threshold, thus supporting the usefulness of PRS for HCC risk stratification purposes.…”

Section: Discussionmentioning

confidence: 83%

Clinical exome sequencing for diagnosing severe cryptogenic liver disease in adults: A case series

Pelusi

Ronzoni

Malvestiti

et al. 2022

Liver International

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Liver diseases remain unexplained in up to 30% of adult patients; genetic analysis could help establish the correct diagnosis. In six adult patients with cryptogenic liver disease, we performed whole‐exome sequencing (WES) and evaluated the individual predisposition to progressive fatty liver disease by polygenic risk scores (PRS). In one patient, WES was allowed to diagnose the Hermansky–Pudlak syndrome. In the other two patients, genetic variants in LDLRAP1/MSH6 and ALDOB genes were identified, contributing to explaining the clinical presentation and disease pathogenesis (50% diagnostic uptake). In the other three patients, rare variants with a high likelihood of disrupting protein function in APOB, ATP7B, ABCB4 and ATP8B1 were identified. One patient who developed hepatocellular carcinoma during the follow‐up had a high PRS value. The study supports the role of WES, combined with risk stratification by PRS and accurate clinical assessment in improving the diagnosis and informed management in patients with cryptogenic liver disease, a positive family history or severe fatty liver not fully accounted for by environmental triggers.

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Section: Discussionmentioning

confidence: 83%

Clinical exome sequencing for diagnosing severe cryptogenic liver disease in adults: A case series

Pelusi

Ronzoni

Malvestiti

et al. 2022

Liver International

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Genetic Markers Predisposing to Nonalcoholic Steatohepatitis

Sohal

Chaudhry

Kowdley

2023

Clinics in Liver Disease

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Reply to: “Polygenic risk score: A promising predictor for hepatocellular carcinoma in the population with non-alcoholic fatty liver disease”

Jamialahmadi

Bianco

Pelusi

et al. 2021

Journal of Hepatology

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To the Editor: We thank Long et al. for their positive comments on the novelty and the potential clinical impact of our recent study on the use of polygenic risk scores (PRSs) to infer causality between hepatic fat and carcinogenesis, and to predict hepatocellular carcinoma (HCC) development in individuals with dysmetabolism and nonalcoholic fatty liver disease (NAFLD). 1,2 As highlighted by Long et al., 2 the PRS prediction for HCC in a large European NAFLD cohort was largely superior to that of the single genetic risk variants. However, the AUC was relatively low (<0.7) and, in fact, we refrained from proposing the clinical use of PRS as a standalone diagnostic test. Additionally, in our study, PRS and classical risk factors were independently associated with HCC and together conferred a significant improvement in diagnostic accuracy compared to each of them alone. 1 We observed a non-linear relationship between PRS and HCC risk, and in line with previous data, a synergistic effect between PRS and severity of insulin resistance in determining liver disease. 1,3,4 Therefore, we identified the optimal thresholds to discriminate HCC risk and validated these thresholds in participants with obesity and type 2 diabetes from the UK Biobank cohort. In this population-based study, PRS alone had and AUROC of 0.70 for detecting HCC. A positive PRS test was observed in approximately 1 in 10 individuals and it was able to predict HCC with 90% specificity. We reasoned that, as part of the ability of a PRS to predict HCC is mediated by the life-long burden of genetic variants on liver damage, 1 the PRS may be optimal to identify young at-risk individuals for whom preventive measures and surveillance programs can be implemented long before cirrhosis development. 1 As Long et al. suggested, we now report the fraction of HCC variability explained by genetic predisposition to NAFLD in order to assess the relative burden compared to classical risk factors. The population attributable fraction (PAF) of cirrhosis and HCC accounted for by PRS compared to the single genetic variants in the UK Biobank population-based cohort is shown in Table 1. 5 Remarkably, genetic predisposition to NAFLD jointly accounted for 30.39% and 60.95% of cirrhosis and HCC variability, respectively (17.28 and 57.49% for the PRS). Considering HCC, this compares to 58.57% accounted for by male sex, and 33.35% and 41.78% by obesity and type 2 diabetes, respectively. It is important to bear in mind that sex, a major determinant of HCC risk, is also genetically determined, and that adiposity and type 2 diabetes also share a large inherited fraction predisposing to liver disease. 3 In our paper, the PRS was based on PNPLA3-TM6SF2-

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Polygenic risk score: A promising predictor for hepatocellular carcinoma in the population with non-alcoholic fatty liver disease

Cited by 3 publications

References 7 publications

Clinical exome sequencing for diagnosing severe cryptogenic liver disease in adults: A case series

Clinical exome sequencing for diagnosing severe cryptogenic liver disease in adults: A case series

Genetic Markers Predisposing to Nonalcoholic Steatohepatitis

Reply to: “Polygenic risk score: A promising predictor for hepatocellular carcinoma in the population with non-alcoholic fatty liver disease”

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