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

  • Junyu Long
    Affiliations
    Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
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  • Jin Bian
    Affiliations
    Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
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  • Haitao Zhao
    Correspondence
    Corresponding author. Address: Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Tel.: +86-010-69156042; Fax: +86-010-69156043.
    Affiliations
    Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
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Published:January 17, 2021DOI:https://doi.org/10.1016/j.jhep.2021.01.010

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      To the Editor:
      We were impressed by the promising results reported by Bianco and colleagues, who indicated that the polygenic risk score (PRS), which is based on PNPLA3-TM6SF2-GCKR-MBOAT7 variants, may be useful for predicting the risk of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) and dysmetabolism. In particular, positive PRS can be used to identify a subset of patients with dysmetabolism who are at high genetic risk of HCC.
      • Bianco C.
      • Jamialahmadi O.
      • Pelusi S.
      • Baselli G.
      • Dongiovanni P.
      • Zanoni I.
      • et al.
      Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.
      Considering that all the variants included in the PRS can be assessed easily and non-invasively, the novelty of this result and its significant implications for clinical practice should be emphasized. However, we still have a few concerns regarding this study.
      First, the AUC for HCC was 0.64 for hepatic fat PRS (PRS-HFC) and 0.65 for PRS-5 (PRS adjusted for HSD17B13) in the NAFLD cohort.
      • Bianco C.
      • Jamialahmadi O.
      • Pelusi S.
      • Baselli G.
      • Dongiovanni P.
      • Zanoni I.
      • et al.
      Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.
      The assessment of performance for PRS is important; however, these AUC values are not stellar. In general, the traditional thresholds for AUC are defined as follows: 0.5, no discrimination; 0.5-0.7, poor discrimination; ≥0.7, acceptable discrimination; ≥ 0.8, excellent discrimination; and ≥0.9, outstanding discrimination.
      • el Barzouhi A.
      • Vleggeert-Lankamp C.L.
      • Lycklama à Nijeholt G.J.
      • Van der Kallen B.F.
      • van den Hout W.B.
      • Koes B.W.
      • et al.
      Predictive value of MRI in decision making for disc surgery for sciatica.
      An important question to address in future studies would be to investigate whether inherited or de novo genetic factors such as copy number variants, methylation marks, and rare but highly penetrant polymorphisms not captured in this analysis of common variants or other non-invasive assessments, such as ultrasound elastography,
      • Lupsor-Platon M.
      • Serban T.
      • Silion A.I.
      • Tirpe A.
      • Florea M.
      Hepatocellular carcinoma and non-alcoholic fatty liver disease: a step forward for better evaluation using ultrasound elastography.
      can be integrated to generate a comprehensive risk score to enhance the predictive ability of PRS. In addition, this study used AUC to evaluate the predictive performance of PRS.
      • Bianco C.
      • Jamialahmadi O.
      • Pelusi S.
      • Baselli G.
      • Dongiovanni P.
      • Zanoni I.
      • et al.
      Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.
      Although AUC can be used to evaluate the ability of PRS to distinguish between patients with and without HCC, it cannot quantify the contribution of PRS to the burden of HCC on a population level. Thus, the population attributable fraction (PAF) may be used to estimate the extent to which risk factors, including PRS, age, sex, body mass index, and type 2 diabetes (T2D), mostly contribute to the burden of HCC on a population level.
      • Stockdale A.J.
      • Kreuels B.
      • Henrion M.Y.R.
      • Giorgi E.
      • Kyomuhangi I.
      • de Martel C.
      • et al.
      The global prevalence of hepatitis D virus infection: systematic review and meta-analysis.
      Hepatic fat content has a strong genetic background.
      • Anstee Q.M.
      • Darlay R.
      • Cockell S.
      • Meroni M.
      • Govaere O.
      • Tiniakos D.
      • et al.
      Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort.
      To date, a vast amount of genome-wide association studies (GWAS) have been performed in individuals of European descent.
      • Buniello A.
      • MacArthur J.A.L.
      • Cerezo M.
      • Harris L.W.
      • Hayhurst J.
      • Malangone C.
      • et al.
      The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019.
      However, genetic structure differs between populations with different ethnic components.
      • Guerrero R.
      • Vega G.L.
      • Grundy S.M.
      • Browning J.D.
      Ethnic differences in hepatic steatosis: an insulin resistance paradox?.
      Inter-ethnic differences in susceptibility to fatty liver disease have also been emphasized in multi-ethnic population studies, where for example, the susceptibility to fatty liver disease is shown to be lowest in individuals of African descent, intermediate in Europeans, and higher in Hispanics, independent of the confounders.
      • Guerrero R.
      • Vega G.L.
      • Grundy S.M.
      • Browning J.D.
      Ethnic differences in hepatic steatosis: an insulin resistance paradox?.
      Notably, since PRS is derived from GWAS and is mostly determined in individuals of European ethnicity, it may not be meaningful for individuals of other ethnicities. Failure to include populations from different ethnicities will hinder the application of genetic discoveries (such as PRS) to multi-ethnic individuals in clinical practice. The participants included in this study, which consisted of the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 individuals with HCC) and at-risk individuals (NAFLD cohort, n = 2,566; 226 individuals with HCC; and a replication cohort of 427 German patients with NAFLD), were of European descent.
      • Bianco C.
      • Jamialahmadi O.
      • Pelusi S.
      • Baselli G.
      • Dongiovanni P.
      • Zanoni I.
      • et al.
      Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.
      Therefore, the current PRS may not be generalizable to other populations, such as African Americans, Asians, and Hispanics. To address this important issue, quantitative genetic features of ethnicity should be included as covariates in the association tests, which could help adjust the ethnicity-specific effects in the primary PRS to a certain degree. Moreover, to improve the utility and generalizability of these results for all ethnicities, future PRS research should include analyses of genetic data from different ethnic backgrounds rather than only a Eurocentric pool.

      Financial support

      The authors received no financial support to prepare this manuscript.

      Authors' contributions

      All authors were involved in the writing of this commentary and reviewed it prior to submission.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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