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

Published:October 13, 2021DOI:https://doi.org/10.1016/j.jhep.2021.10.005

      Highlights

      • Genetic factors (SNPs) are known to be associated with the risk of alcohol-related cirrhosis.
      • Our 3-SNP GRS stratified alcohol users at low-/high-risk of alcohol-related cirrhosis.
      • High GRS increased the relative risk of cirrhosis more than 3-fold in alcohol users.
      • Presence of diabetes with high GRS further increased the risk more than 10-fold.

      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.

      Graphical abstract

      Keywords

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