Ryan Hlady, PhD

Pilot Research Award
$50,000 over one year

Mayo Clinic Rochester

Discovery of non-invasive epigenetic biomarkers for AATD liver disease

Alpha-1 Antitrypsin Deficiency (or AATD) can cause liver and lung disease. Patients with AATD produce large amounts of abnormal alpha-1 antitrypsin protein (AAT) in their liver where it gets 'stuck'. Liver cells are unable to break down all the AAT, which gradually damages and scars the liver. This eventually results in loss of liver function requiring a liver transplant or leads to liver cancer. The underlying cause of AATD is a mutation in the alpha-1 gene inherited from both parents. The alpha-1 gene DNA is a blueprint telling the liver how to make alpha-1 antitrypsin protein. All genes needed to make the cells in our body are called the genome. 'On top' of the genome is a second layer of information known as the epigenome. The epigenome acts as an interface between our environment and our genome. Since not everyone with an alpha-1 mutation gets liver disease, other things must contribute. Variation within our epigenome holds significant promise as the 'missing piece' explaining variation in AATD. Interestingly, dying cells shed their DNA into the bloodstream, which is termed cell-free DNA (cfDNA). CfDNA contains mutations that might drive disease, but also epigenetic information (called DNA methylation). DNA methylation reflects the disease process and provides information on where in the body that DNA originated from. The only other reliable way of diagnosing liver disease, unfortunately, relies on a biopsy, which can be painful and has some risk of complications. Thus, by defining the cfDNA methylation signature of AATD and its relationships to altered methylation in diseased liver tissue, we expect to develop a new non-invasive way to identify and monitor AATD, or response of patients to emerging therapies that target the abnormal alpha-1 protein.