Scientists at deCODE genetics in Iceland have discovered rare and protective loss-of-function variants that point to potential drug targets for non-alcoholic fatty liver disease (NAFLD).

REYKJAVIK, Iceland, Oct. 24, 2022 /PRNewswire/ -- Scientists from deCODE genetics, an Amgen subsidiary, publish a large genome-wide association study on non-alcoholic fatty liver disease (NAFLD) today in Nature Genetics.

Sequence variants associated with NAFLD were identified, including rare and protective loss-of-function variants that point to potential drug targets. Plasma proteomic analyzes provided further information on the pathogenesis of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem and is estimated to affect up to 25% of the world's population. Non-alcoholic fatty liver disease (NAFLD), when more than 5% of the liver is fatty without identifiable causes such as excessive alcohol consumption, is the first stage of NAFLD disease. NAFLD can progress to non-alcoholic steatohepatitis (NASH), which in turn can progress to liver cirrhosis and hepatocellular carcinoma (HCC). NAFLD disease can be difficult to diagnose and control, and no treatment is currently available. Therefore, the identification of possible pharmacological targets and biomarkers is of great importance.

An extensive genome-wide association study of NAFLD, liver cirrhosis, and HCC was performed, and the results were integrated with expression and proteomic data. For NAFLD, 9,491 clinical cases from Iceland, the United Kingdom, the United States, and Finland were used, in addition to the proton density fat fraction (PDFF) extracted from 36,116 liver MRIs. Among the sequence variants the scientists found, in the Icelandic population, there were rare, protective, and predicted loss-of-function variants in MTARC1 and GPAM, suggesting that inhibition of MTARC1 or GPAM could be therapeutic for NAFLD or NASH.

The levels of thousands of proteins measured in plasma were analyzed, identifying possible biomarkers of the disease, of its progression or of its commitment to the target, and models that can discriminate between NAFLD and cirrhosis were built using the data from the proteomics. The results therefore provide an avenue for the development of non-invasive tools to assess and diagnose non-alcoholic fatty liver disease.

Additionally, the pleiotropic effects of the identified variants were explored by looking at associations with 52 other phenotypes and traits. BMI is one of the most common risk factors for NAFLD and longitudinal measures of PDFF suggested that carriers of p.Ile148Met, the well-known NAFLD risk variant, in PNPLA3 are more likely to change BMI than non-carriers.

To date, this study is one of the largest to shed light on the genetic basis of non-alcoholic fatty liver disease and it is hoped that the results will contribute to the development of diagnostic tools or therapies that can help patients who they suffer from it

CONTACTO:Thora Kristin Asgeirsdottir,thoraa@decode.is 354 894 1909deCODE genetics

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