New genetic variants associated with an increased risk for heavy drinkers to develop cirrhosis, or scarring of the liver, are reported in a study published online this week in Nature Genetics. The study finds that alcohol-related cirrhosis and fatty liver disease not caused by alcohol share genetic risk factors.
A build-up of fat in the liver occurs in most heavy drinkers, but cirrhosis develops in only 10-15% of alcohol misusers. Previous studies have found that genetics has a role in the risk of developing cirrhosis from alcohol misuse, but only one genetic risk variant, in the gene PNPLA3, has been identified so far.
Felix Stickel and colleagues performed a genome-wide association study in individuals of European descent (from Germany, UK and Belgium), comparing genetic variation between 712 long-term heavy drinkers with cirrhosis and 1,426 long-term heavy drinkers without any evidence of liver damage, with replication of their results in a further 1,148 individuals with cirrhosis and 922 without. They confirm that variants in PNPLA3 confer an increased risk of developing cirrhosis and identify risk variants in two new genes: MBOAT7 and TM6SF2. All three genes are involved in the processing of fats, suggesting that this pathway is important in the development of alcohol-related cirrhosis.
Although the susceptibility genes found in this study are not directly related to genes involved in alcohol dependence, they do overlap with susceptibility genes for non-alcoholic fatty liver disease. The authors suggest that the risk-associated genes may be therapeutic targets in both disorders and could also be used to identify high-risk populations for targeted intervention.