Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Feb;76(2):275-282.
doi: 10.1016/j.jhep.2021.10.005. Epub 2021 Oct 14.

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

John B Whitfield  1 , Tae-Hwi Schwantes-An  2 , Rebecca Darlay  3 , Guruprasad P Aithal  4 , Stephen R Atkinson  5 , Ramon Bataller  6 , Greg Botwin  7 , Naga P Chalasani  8 , Heather J Cordell  3 , Ann K Daly  9 , Christopher P Day  10 , Florian Eyer  11 , Tatiana Foroud  2 , Dermot Gleeson  12 , David Goldman  13 , Paul S Haber  14 , Jean-Marc Jacquet  15 , Tiebing Liang  8 , Suthat Liangpunsakul  16 , Steven Masson  9 , Philippe Mathurin  17 , Romain Moirand  18 , Andrew McQuillin  19 , Christophe Moreno  20 , Marsha Y Morgan  21 , Sebastian Mueller  22 , Beat Müllhaupt  23 , Laura E Nagy  24 , Pierre Nahon  25 , Bertrand Nalpas  26 , Sylvie Naveau  27 , Pascal Perney  28 , Munir Pirmohamed  29 , Helmut K Seitz  22 , Michael Soyka  30 , Felix Stickel  23 , Andrew Thompson  31 , Mark R Thursz  5 , Eric Trépo  20 , Timothy R Morgan  32 , Devanshi Seth  33 ; GenomALC Consortium
Affiliations

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

John B Whitfield et al. J Hepatol. 2022 Feb.

Erratum in

  • Corrigendum to: 'A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers' [J Hepatol 2022 (76) 275-282].
    Whitfield JB, Schwantes-An TH, Darlay R, Aithal GP, Atkinson SR, Bataller R, Botwin G, Chalasani NP, Cordell HJ, Daly AK, Day CP, Eyer F, Foroud T, Gleeson D, Goldman D, Haber PS, Jacquet JM, Liang T, Liangpunsakul S, Masson S, Mathurin P, Moirand R, McQuillin A, Moreno C, Morgan MY, Mueller S, Müllhaupt B, Nagy LE, Nahon P, Nalpas B, Naveau S, Perney P, Pirmohamed M, Seitz HK, Soyka M, Stickel F, Thompson A, Thursz MR, Trépo E, Morgan TR, Seth D; GenomALC Consortium. Whitfield JB, et al. J Hepatol. 2022 May;76(5):1244-1245. doi: 10.1016/j.jhep.2022.02.011. Epub 2022 Mar 11. J Hepatol. 2022. PMID: 35287983 No abstract available.

Abstract

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.

Keywords: Hepatocellular carcinoma; chronic alcohol use; coffee; genome-wide association; risk stratification; single nucleotide polymorphism.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest NPC has a number of consulting agreements with and research grants from the pharmaceutical industry but they are not significantly or directly related to this paper. MP receives research funding from various organisations including the MRC and NIHR. He has also received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (co-funded by MRC and Roche, UCB, Eli Lilly and Novartis); a PhD studentship jointly funded by EPSRC and Astra Zeneca; and grant funding from Vistagen Therapeutics. He has also unrestricted educational grant support for the UK Pharmacogenetics and Stratified Medicine Network from Bristol-Myers Squibb and UCB. He has developed an HLA genotyping panel with MC Diagnostics, but does not benefit financially from this. He is part of the IMI Consortium ARDAT (www.ardat.org). None of these funding sources were deployed in the undertaking of this study. 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.

Figures

Figure 1.
Figure 1.
Distribution of 3-SNP scores in cases and controls from the GenomALC-1 data, showing the boundaries of the lowest (Q1) and highest (Q5) quintiles at 0.033 and 0.964, respectively (dotted lines).
Figure 2.
Figure 2.
Odds ratios, by country and overall, for the risk of alcohol-related cirrhosis in the GenomALC-1 cohort when results for the 3-SNP score are divided into low (<0), intermediate (0 to 0.7) and high (>0.7) categories. Error bars show 95% confidence intervals.
See this image and copyright information in PMC

Comment in

References

    1. Askgaard G, Leon DA, Kjaer MS, Deleuran T, Gerds TA, Tolstrup JS: Risk for alcoholic liver cirrhosis after an initial hospital contact with alcohol problems: A nationwide prospective cohort study. Hepatology 2017, 65:929–37. 10.1002/hep.28943. - DOI - PubMed
    1. Askgaard G, Kjaer MS, Tolstrup JS: Opportunities to Prevent Alcoholic Liver Cirrhosis in High-Risk Populations: A Systematic Review With Meta-Analysis. Am J Gastroenterol 2019, 114:221–32. 10.1038/s41395-018-0282-6. - DOI - PubMed
    1. Hasin DS, Stinson FS, Ogburn E, Grant BF: Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry 2007, 64:830–42. 10.1001/archpsyc.64.7.830. - DOI - PubMed
    1. Wong T, Dang K, Ladhani S, Singal AK, Wong RJ: Prevalence of Alcoholic Fatty Liver Disease Among Adults in the United States, 2001–2016. JAMA 2019, 321:1723–5. 10.1001/jama.2019.2276. - DOI - PMC - PubMed
    1. Pequignot G, Tuyns AJ, Berta JL: Ascitic cirrhosis in relation to alcohol consumption. IntJEpidemiol 1978, 7:113–20. - PubMed

Publication types

MeSH terms