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Reply to: “External validation of a genetic risk score that predicts development of alcohol-related cirrhosis”

  • John B. Whitfield
    Affiliations
    Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Queensland 4029, Australia
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  • Timothy R. Morgan
    Affiliations
    Department of Medicine, University of California, Irvine, USA

    Department of Veterans Affairs, VA Long Beach Healthcare System, 5901 East Seventh Street, Long Beach, CA 90822, USA
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  • Devanshi Seth
    Correspondence
    Corresponding author. Address: Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW 2006, Australia; Tel.: +61 95656268, fax: +61 95656101.
    Affiliations
    Edith Collins Centre (Translational Research in Alcohol Drugs and Toxicology), Sydney Local Health District, Missenden Road, Camperdown, NSW 2050, Australia

    Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia

    Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW 2006, Australia
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Published:August 30, 2022DOI:https://doi.org/10.1016/j.jhep.2022.08.024

      Linked Article

      To the Editor:
      Thank you for the opportunity to respond to the letter from Johansen et al.,
      • Johansen S.
      • Thiele M.
      • Juel H.B.
      • Hansen T.
      • Krag A.
      External validation of a genetic risk score that predicts development of alcohol-related cirrhosis.
      extending our earlier findings reported in the Journal.
      • Whitfield J.B.
      • Schwantes-An T.H.
      • Darlay R.
      • Aithal G.P.
      • Atkinson S.R.
      • Bataller R.
      • et al.
      A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.
      By applying our 3-SNP (single nucleotide polymorphism) score, Johansen et al. were able to stratify alcohol-related liver disease risk in a cohort with less extreme (but still elevated-risk) alcohol intake. The AUCs and odds ratios in this Danish cohort were very similar to those which we reported.
      Johansen et al. comment that ‘… the closer the patients come to clinical disease, the less powerful a genetic score is compared to other non-invasive tests.’ This is true, and important, and applies to all risk stratification protocols – not only genetic risk scores. A patient with clinical symptoms needs tests which evaluate their current situation. It is patients who are at high risk of conditions which have not yet occurred, or in some cases people from the general population, who may benefit from risk stratification through genetic scores. Specifically, patients with normal results for “… non-invasive tests for advanced fibrosis like ELF (enhanced liver fibrosis) test and FIB-4 (fibrosis-4) index …” may still develop significant fibrosis, cirrhosis and hepatocellular carcinoma in the future. Genetic tests can give a predictive measure of their underlying risk, as opposed to tests for already existing liver fibrosis (e.g. FIB-4 and ELF) that are intermediate tests diagnosing ‘early disease’ usually without symptoms.
      The distinction between ‘trait’ and ‘state’ markers has been explored for a number of psychiatric conditions, including alcohol dependence and alcohol-related disease. For a long time no trait markers (able to assess future risk of disease) could be confirmed but genetic risk scores now offer this possibility for many conditions. The effectiveness of such scores in improving outcomes, and the ways to integrate them with current patterns of investigation, are being explored
      • Khera A.V.
      • Chaffin M.
      • Aragam K.G.
      • Haas M.E.
      • Roselli C.
      • Choi S.H.
      • et al.
      Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations.
      • Mars N.
      • Koskela J.T.
      • Ripatti P.
      • Kiiskinen T.T.J.
      • Havulinna A.S.
      • Lindbohm J.V.
      • et al.
      Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers.
      • Hao L.
      • Kraft P.
      • Berriz G.F.
      • Hynes E.D.
      • Koch C.
      • Korategere V.K.P.
      • et al.
      Development of a clinical polygenic risk score assay and reporting workflow.
      and although the predictive value of a genetic score will always depend on the heritability of the condition, results so far are promising.

      Financial support

      This letter did not require financial support. The original study was funded by NIH / NIAAA UO1AA018389 and RO1AA018389 .

      Authors' contributions

      JBW drafted the response and DS and TRM edited. All authors read, critically reviewed and approved the final version.

      Conflict of interest

      JBW and DS have no conflict of interests. TRM has conducted clinical research with AbbVie, Genfit, Gilead, and Merck but none of these are related to this manuscript.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

      References

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        • Thiele M.
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        • Krag A.
        External validation of a genetic risk score that predicts development of alcohol-related cirrhosis.
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        A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.
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