Thank you for the opportunity to respond to the letter from Johansen et al.,
[1]
extending our earlier findings reported in the Journal.[2]
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
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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:
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References
- External validation of a genetic risk score that predicts development of alcohol-related cirrhosis.J Hepatol. 2022; 77: 1720-1721https://doi.org/10.1016/j.jhep.2022.06.006
- A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.J Hepatol. 2022; 76: 275-282
- Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations.Nat Genet. 2018; 50: 1219-1224
- Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers.Nat Med. 2020; 26: 549-557
- Development of a clinical polygenic risk score assay and reporting workflow.Nat Med. 2022; 28: 1006-1013
Article info
Publication history
Published online: August 30, 2022
Accepted:
August 11,
2022
Received:
July 31,
2022
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.