Gene identified as a potential target for drugs to prevent liver disease

Date
April 8, 2020
Topics
  • The discovery of SLC39A8’s association with liver fibro-inflammatory disease could provide a new target for drug development for the prevention of liver disease in at-risk individuals.
  • Further validation for MRI-based metric cT1 as a marker for fibro-inflammatory disease

Identification of a gene associated with fibro-inflammatory liver disease could lead to the development of new drugs to prevent the disease in at-risk patients. With the worldwide emergence of obesity-related conditions such as type 2 diabetes and heavy alcohol consumption, non-alcoholic and alcoholic fatty liver diseases (NAFLD and AFLD) are increasingly common. This timely research is led by scientists at Perspectum, together with leading academics from University College London, the University of Westminster, and the University of Exeter.

The study, carried out in 14,440 Europeans from the UK Biobank, found that a genetic variation in a gene called SLC39A8 is linked to the risk of higher cT1 measures, an MRI-based proxy of fibro-inflammation in the liver. The same variation is also linked to elevated blood markers of liver cell injury and damage. This is the first evidence of the role of this gene in liver pathophysiology in humans. PNPLA3, a gene known to be associated with fatty liver and cirrhosis, was also associated with both increased cT1 and PDFF, an MRI measure of liver fat.

Although fatty liver diseases affect up to a third of the adult population globally, only a relatively small proportion will experience significant liver disease or liver-related death. Therefore, it is important to identify individuals at risk of developing the more severe and inflammatory version, steatohepatitis, which is considered to be the main driver of liver disease progression. In the United States, non-alcoholic steatohepatitis (NASH) has been estimated to affect approximately one in ten adults. Investigators in this study found genetic evidence that NAFLD and obesity cause higher cT1 measures. Since NAFLD is commonly seen in obese individuals and is the precursor of NASH, these associations provide supportive evidence for cT1 as a marker of fibro-inflammatory disease to help identify at-risk patients.

Understanding the underlying genetic susceptibility of steatohepatitis allows for new insights into the mechanisms behind chronic liver disease and helps to identify potential new drug targets. At present, there is still no approved drug for treating NASH. There is a race to market for NASH therapeutics currently, with 7 in Phase 3 trials. The global NASH market sales were estimated to be approximately $1.2 million in 2017 and are projected to reach $21.5 billion by 2025.

Professor Jimmy D Bell from the Research Centre for Optimal Health, University of Westminster commented, "This is an excellent example of the value of Big Data coupled to a novel non-invasive approach to assessing NASH. The identification of potential genetic markers for such a crucial condition, will no doubt open up new avenues of research and understanding leading to better monitoring and even treatment".

Read the full paper here.