february 2022

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

    february 2022