Alcoholic liver cirrhosis (ALC) remains a major cause of morbidity and mortality and is the most common cause of liver disease In the developed world. It is unknown why only a minority of heavy and prolonged alcohol mis-users develop ALC. There is a weak relationship between the amount of alcohol consumed and development of ALC such that some develop severe liver disease with moderate levels of alcohol use although others with very high levels of consumption only progress to mild liver Injury. Apart from a greater vulnerability in women than men, few contributory factors have been identified for the development of ALC. To date, only one genetic polymorphism (in PNPLA3) has shown replicable positive result as a risk factor for ALC, although evidence from twin studies and Inter-ethnic variability in ALC mortality rates, supports a genetic component in ALC. Candidate gene studies have been inconclusive but these have generally been too small to yield definitive re-sults. Risk identification is likely to provide Insights into the pathogenic process and may suggest strategies for hami reduction. High-throughput genome-wide search for genetic changes called single nucleotide polymor-phlsms (SNPs) provides an ideal opportunity to Identify genes responsible for this polygenic disorder and is now technically feasible. We have gathered an experienced multidisciplinary team from the USA, Australia, France, Germany, Switzerland and UK with a proven track record in clinical alcoholic liver disease and in genetics. We propose to prospectively collect clinical data and DNA from 1250 heavy drinkers without known liver disease (Controls) and 1250 heavy drinkers with ALC (Cases). To these 2500 specimens we will add clinical data/DNAfrom more than 2700 heavy drinkers (~1100 with ALC) from existing databases/biorepositories in the possession of several study co-PIs. Cases and controls will be matched for age, gender, race/ethnicity and country of origin. DNA will be genotyped with the lllumina Human660-Quad SNP an-ay at CIDR to generate SNP profiles in the Cases and Controls. Data will be analysed to identify genetic variants that predispose some heavy drinkers to ALC in order to answer the question 'Why do only a minority of alcoholics develop liver cirrhosis?

Public Health Relevance

Identification of genetic risk factors that predispose some heavy drinkers to develop ALC will likely illuminate new biological pathways and generate new hypothesis on how alcohol damages the liver. This will lead to strategies to prevent liver disease and development of new treatment modalities.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Neuroscience Review Subcommittee (AA)
Program Officer
Gao, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Southern California Institute for Research/Education
Long Beach
United States
Zip Code
Khanova, Elena; Wu, Raymond; Wang, Wen et al. (2018) Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology 67:1737-1753
Whitfield, John B; Masson, Steven; Liangpunsakul, Suthat et al. (2018) Evaluation of laboratory tests for cirrhosis and for alcohol use, in the context of alcoholic cirrhosis. Alcohol 66:1-7
Hollister, Kristin; Kusumanchi, Praveen; Ross, Ruth Ann et al. (2018) Levels of circulating follicular helper T cells, T helper 1 cells, and the prognostic significance of soluble form of CD40 ligand on survival in patients with alcoholic cirrhosis. Liver Res 2:52-59
Chang, Binxia; Hao, Shuli; Zhang, Longyu et al. (2018) Association Between Aldehyde Dehydrogenase 2 Glu504Lys Polymorphism and Alcoholic Liver Disease. Am J Med Sci 356:10-14
Walline, Crystal C; Blum, Janice S; Linton, Tobyn et al. (2018) Early activation of peripheral monocytes with hallmarks of M1 and M2 monocytic cells in excessive alcohol drinkers: a pilot study. J Investig Med 66:1-4
Jinjuvadia, Raxitkumar; Antaki, Fadi; Lohia, Prateek et al. (2017) The Association Between Nonalcoholic Fatty Liver Disease and Metabolic Abnormalities in The United States Population. J Clin Gastroenterol 51:160-166
Patel, Suhag; Jinjuvadia, Raxitkumar; Patel, Ravi et al. (2016) Insulin Resistance is Associated With Significant Liver Fibrosis in Chronic Hepatitis C Patients: A Systemic Review and Meta-Analysis. J Clin Gastroenterol 50:80-4
Liangpunsakul, Suthat; Haber, Paul; McCaughan, Geoffrey W (2016) Alcoholic Liver Disease in Asia, Europe, and North America. Gastroenterology 150:1786-97
Thursz, Mark; Morgan, Timothy R (2016) Treatment of Severe Alcoholic Hepatitis. Gastroenterology 150:1823-34
Ju, Cynthia; Liangpunsakul, Suthat (2016) Role of hepatic macrophages in alcoholic liver disease. J Investig Med 64:1075-7

Showing the most recent 10 out of 18 publications