A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers

BACKGROUND & AIMS: Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk.

METHODS: Three cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (>/=80 g/day (men), >/=50 g/day (women), for >/=10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC).

RESULTS: A combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 +/- 0.06 vs. 0.61 +/- 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption.

CONCLUSIONS: A risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions.

LAY SUMMARY: Excessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients.

Additional Info

  • Authors:

    Whitfield, J. B.;Schwantes-An, T. H.;Darlay, R.;Aithal, G. P.;Atkinson, S. R.;Bataller, R.;Botwin, G.;Chalasani, N. P.;Cordell, H. J.;Daly, A. K.;Day, C. P.;Eyer, F.;Foroud, T.;Gleeson, D.;Goldman, D.;Haber, P. S.;Jacquet, J. M.;Liang, T.;Liangpunsakul, S.;Masson, S.;Mathurin, P.;Moirand, R.;McQuillin, A.;Moreno, C.;Morgan, M. Y.;Mueller, S.;Mullhaupt, B.;Nagy, L. E.;Nahon, P.;Nalpas, B.;Naveau, S.;Perney, P.;Pirmohamed, M.;Seitz, H. K.;Soyka, M.;Stickel, F.;Thompson, A.;Thursz, M. R.;Trepo, E.;Morgan, T. R.;Seth, D.;Genom, A. L. C. Consortium

  • Issue: J Hepatol . 2022 Feb;76(2):275-282. doi: 10.1016/j.jhep.2021.10.005
  • Published Date: 2022 Feb
  • More Information:

    For more information about this abstract, please contact
    This email address is being protected from spambots. You need JavaScript enabled to view it. at the Deutsche Weinakademie GmbH

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