John B Whitfield1, Tae-Hwi Schwantes-An2, Rebecca Darlay3, Guruprasad P Aithal4, Stephen R Atkinson5, Ramon Bataller6, Greg Botwin7, Naga P Chalasani8, Heather J Cordell3, Ann K Daly9, Christopher P Day10, Florian Eyer11, Tatiana Foroud2, Dermot Gleeson12, David Goldman13, Paul S Haber14, Jean-Marc Jacquet15, Tiebing Liang8, Suthat Liangpunsakul16, Steven Masson9, Philippe Mathurin17, Romain Moirand18, Andrew McQuillin19, Christophe Moreno20, Marsha Y Morgan21, Sebastian Mueller22, Beat Müllhaupt23, Laura E Nagy24, Pierre Nahon25, Bertrand Nalpas26, Sylvie Naveau27, Pascal Perney28, Munir Pirmohamed29, Helmut K Seitz22, Michael Soyka30, Felix Stickel23, Andrew Thompson31, Mark R Thursz5, Eric Trépo20, Timothy R Morgan32, Devanshi Seth33. 1. Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Queensland 4029, Australia. Electronic address: John.Whitfield@qimrberghofer.edu.au. 2. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis IN, USA. 3. Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom. 4. NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals and the University of Nottingham, Nottingham NG7 2UH, United Kingdom. 5. Department of Metabolism, Digestion & Reproduction, Imperial College London, UK. 6. Center for Liver Diseases, University of Pittsburgh Medical Center, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA. 7. Department of Veterans Affairs, VA Long Beach Healthcare System, 5901 East Seventh Street, Long Beach, CA 90822, USA; F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California CA 90048, USA. 8. Department of Medicine, Indiana University, Indianapolis, Indiana, IN 46202-5175, USA. 9. Faculty of Medical Sciences, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom. 10. Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom. 11. Division of Clinical Toxicology, Department of Internal Medicine 2, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany. 12. Liver Unit, Sheffield Teaching Hospitals, AO Floor Robert Hadfield Building, Northern General Hospital, Sheffied S5 7AU, UK. 13. Laboratory of Neurogenetics, NIAAA, Rockville, MD 20852, USA. 14. Drug Health Services, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; Faculty of Medicine and Health, the University of Sydney, Sydney, NSW 2006, Australia. 15. Service Addictologie, CHRU Caremeau, 30029 Nîmes, France. 16. Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University and Roudebush Veterans Administration Medical Center, Indianapolis, USA. 17. CHRU de Lille, Hôpital Claude Huriez, Rue M. Polonovski CS 70001, 59 037 Lille Cedex, France. 18. Univ Rennes, INRA, INSERM, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35000 Rennes, France. 19. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London WC1E 6DE, UK. 20. CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium. 21. UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, UK. 22. Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Zeppelinstraße 11-33, 69121 Heidelberg, Germany. 23. Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, CH-8901 Zurich, Switzerland. 24. Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio, OH 44195, USA. 25. Service d'Hépatologie, APHP Hôpital Avicenne et Université Paris 13, Bobigny, France; University Paris 13, Bobigny, France; Inserm U1162 Génomique fonctionnelle des tumeurs solides, Paris, France. 26. Service Addictologie, CHRU Caremeau, 30029 Nîmes, France; DISC, Inserm, 75013 Paris, France. 27. Hôpital Antoine-Béclère, 157 Rue de la Porte de Trivaux, 92140 Clamart, France. 28. Hôpital Universitaire Caremeau, Place du Pr. Robert Debre, 30029 Nîmes, France. 29. MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GL, UK. 30. Psychiatric Hospital University of Munich, Nussbaumsstr.7, 80336 Munich, Germany; Privatklinik Meiringen, Willigen, CH 3860 Meiringen, Switzerland. 31. MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GL, UK; Health Analytics, Lane Clark & Peacock LLP, London, UK. 32. Department of Veterans Affairs, VA Long Beach Healthcare System, 5901 East Seventh Street, Long Beach, CA 90822, USA; Department of Medicine, University of California, Irvine, USA. 33. Drug Health Services, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; Faculty of Medicine and Health, the University of Sydney, Sydney, NSW 2006, Australia; Centenary Institute of Cancer Medicine and Cell Biology, the University of Sydney, Sydney, NSW 2006, Australia. Electronic address: d.seth@sydney.edu.au.
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.
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.
Authors: Michael Roerecke; Afshin Vafaei; Omer S M Hasan; Bethany R Chrystoja; Marcus Cruz; Roy Lee; Manuela G Neuman; Jürgen Rehm Journal: Am J Gastroenterol Date: 2019-10 Impact factor: 10.864
Authors: Stephan Buch; Felix Stickel; Eric Trépo; Michael Way; Alexander Herrmann; Hans Dieter Nischalke; Mario Brosch; Jonas Rosendahl; Thomas Berg; Monika Ridinger; Marcella Rietschel; Andrew McQuillin; Josef Frank; Falk Kiefer; Stefan Schreiber; Wolfgang Lieb; Michael Soyka; Nasser Semmo; Elmar Aigner; Christian Datz; Renate Schmelz; Stefan Brückner; Sebastian Zeissig; Anna-Magdalena Stephan; Norbert Wodarz; Jacques Devière; Nicolas Clumeck; Christoph Sarrazin; Frank Lammert; Thierry Gustot; Pierre Deltenre; Henry Völzke; Markus M Lerch; Julia Mayerle; Florian Eyer; Clemens Schafmayer; Sven Cichon; Markus M Nöthen; Michael Nothnagel; David Ellinghaus; Klaus Huse; Andre Franke; Steffen Zopf; Claus Hellerbrand; Christophe Moreno; Denis Franchimont; Marsha Y Morgan; Jochen Hampe Journal: Nat Genet Date: 2015-10-19 Impact factor: 38.330
Authors: Nina Mars; Jukka T Koskela; Pietari Ripatti; Tuomo T J Kiiskinen; Aki S Havulinna; Joni V Lindbohm; Ari Ahola-Olli; Mitja Kurki; Juha Karjalainen; Priit Palta; Benjamin M Neale; Mark Daly; Veikko Salomaa; Aarno Palotie; Elisabeth Widén; Samuli Ripatti Journal: Nat Med Date: 2020-04-07 Impact factor: 53.440
Authors: Connor A Emdin; Mary E Haas; Amit V Khera; Krishna Aragam; Mark Chaffin; Derek Klarin; George Hindy; Lan Jiang; Wei-Qi Wei; Qiping Feng; Juha Karjalainen; Aki Havulinna; Tuomo Kiiskinen; Alexander Bick; Diego Ardissino; James G Wilson; Heribert Schunkert; Ruth McPherson; Hugh Watkins; Roberto Elosua; Matthew J Bown; Nilesh J Samani; Usman Baber; Jeanette Erdmann; Namrata Gupta; John Danesh; Danish Saleheen; Kyong-Mi Chang; Marijana Vujkovic; Ben Voight; Scott Damrauer; Julie Lynch; David Kaplan; Marina Serper; Philip Tsao; Josep Mercader; Craig Hanis; Mark Daly; Joshua Denny; Stacey Gabriel; Sekar Kathiresan Journal: PLoS Genet Date: 2020-04-13 Impact factor: 5.917