People with the PNPLA3 genetic variant may be at increased risk for developing severe alcohol-related liver disease, and those with the SLC38A4 variant may be at risk for developing alcoholic hepatitis, according to data presented recently at the 2016 International Liver Congress in Barcelona, Spain.
Stephen Atkinson, from Imperial College in London, and colleagues evaluated genetic variations in patients with alcohol-related liver disease and alcoholic hepatitis. He noted that alcohol misuse is the leading cause of cirrhosis in the Western world, and approximately half of all deaths related to cirrhosis are attributable to alcohol.
“One of the issues with alcohol-related liver disease is that it comprises a spectrum of clinical presentations. For the same amount of alcohol, not all people develop severe liver disease with significant variability in disease progression,” he stated during the conference.
The researchers used data from the Genome-Wide Association Study (GWAS), which sought to compare genetic differences between individuals who do have disease and those who do not in order to understand what genetic characteristics might contribute to the risk of developing diseases.
They analyzed more than 500 000 genetic variables focused on common variations that would typically be seen in approximately 5% of the population. They compared the frequencies of risk alleles to identify disease associations, focusing on variations that could contribute to alcoholic hepatitis.
The study was divided into an exploratory stage (n=650) and a replication stage (n=1401). For each stage, the researchers compared cases of alcohol-related liver disease with a control group. Researchers examined multiple genes in the exploratory stage, and took the genes that were most likely to be strongly associated with alcoholic hepatitis and examined these genes in a second group of patients in the replication stage. From the replication stage, researchers reported the genes that formed independent associations with the development of alcoholic hepatitis.
Within the replication population, PNPLA3 was a risk factor for alcohol-related liver disease (P=7.00E-08) and SLC38A4 was independently associated with the risk of developing disease (P=.023). Dr Atkinson notes that approximately 25% of the general population has the PNPLA3 variant, and about half share the variant in SLC38A4.
He also explained that GWAS data did not identify an association between SLC38A4 and alcoholic cirrhosis, suggesting that this variation is specific to alcoholic hepatitis. The gene is responsible for transporting amino acids into the liver, which are then used as a substrate to generate glucose.
“This gene is implicated in processes that are relevant to the development of alcoholic hepatitis,” Dr Atkinson concluded. “And this may be a step forward in allowing us to work towards building an idea of which patients who drink alcohol to excess are at increased risk of developing severe forms of alcoholic hepatitis.”
1. Atkinson S. Abstract GS03. A genome-wide association study identifies PNPLA3 and SLC38A4 as risk loci for alcoholic hepatitis. Presented at the International Liver Congress; April 13-17, 2016; Barcelona, Spain