Gene Variant Linked to Cirrhosis in Alcoholic Caucasians

Abstract

A study from Germany found that a variation in the PNPLA3 (adiponutrin) gene was associated with cirrhosis of the liver and elevated transaminase levels in alcoholic Caucasians. A report of the findings appeared online December 7, 2010 in Hepatology (available: http://onlinelibrary.wiley.com/doi/10.1002/hep.24017/pdf) and was published in the January 2011 issue of the journal. The risk of cirrhosis in alcoholics in the genetic high risk group may be >25%. Studies have shown that, although most heavy drinkers display signs of hepatitis steatosis, only 10%–35% of alcoholics develop hepatic inflammation, with up to 20% progressing to cirrhosis. Further medical evidence suggests a link between PNPLA3 gene variation and liver fat content; specifically, the single nucleotide polymorphism rs738409 was reported previously to be associated with advanced alcoholic liver disease in alcohol-dependent individuals of European and Native American descent. The research team led by Jochen Hampe, MD, from Christian-Albrechts-Universität in Kiel determined the genotype and allele frequencies of PNPLA3 rs738409 in 1043 alcoholics with or without alcoholic liver injury and in 376 at-risk drinkers from a population-based cohort. Cirrhosis and steatosis were determined by standard diagnostic testing and liver biopsy. Alanine aminotransferase and aspartate aminotransferase levels were established using routine clinical chemistry testing. Study participants were categorized as alcoholic liver cirrhosis; alcoholics with liver steatosis on ultrasound and elevation of Alanine aminotransferase as alcoholic liver damage; alcoholic liver steatosis and normal liver enzyme levels as alcoholic fatty liver; and alcoholics with normal appearance of the liver on ultrasound and normal liver enzyme levels as alcoholic controls. The researchers discovered that the single nucleotide polymorphism rs738409 was strongly over-represented in patients with alcoholic liver cirrhosis (n = 210; odds ratio [OR], 2.79) and alcoholic liver damage (n = 219; OR, 2.33) compared with alcoholics without liver damage. Additionally, the frequency of allele PNPLA3 rs738409 in alcoholic fatty liver participants was lower than in alcoholics without steatosis and normal liver enzymes. The report concludes that PNPLA3 rs738409(G/G) carriers represent a genetically defined subpopulation of high-risk individuals susceptible to progression from clinically silent alcoholic liver disease to obvious cirrhosis. “In total, 26.6% of the population attributable risk for the progression of early to advanced alcoholic liver disease are conferred by the presence of this risk allele,” the authors state. “Homozygous carriers of genotype PNPLA3 rs738409(G/G) should thus be considered a target group for future rigorous pharmacological and nonpharmacological interventions.”