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



Whitfield, John B, Schwantes-An, Tae-Hwi, Darlay, Rebecca, Aithal, Guruprasad P, Atkinson, Stephen R, Bataller, Ramon, Botwin, Greg, Chalasani, Naga P, Cordell, Heather J, Daly, Ann K
et al (show 31 more authors) (2022) A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers. JOURNAL OF HEPATOLOGY, 76 (2). pp. 275-282.

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Abstract

<h4>Background & aims</h4>Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk.<h4>Methods</h4>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).<h4>Results</h4>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.<h4>Conclusions</h4>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.<h4>Lay summary</h4>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.

Item Type: Article
Uncontrolled Keywords: Hepatocellular carcinoma, risk stratification, chronic alcohol use, genome-wide association, single nucleotide polymorphism, coffee
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 14 Apr 2022 13:36
Last Modified: 18 Jan 2023 21:05
DOI: 10.1016/j.jhep.2021.10.005
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3152778