Dr Rebecca Jeyaraj

F1/F2 Research Awards Winner

“Variation in genes involved in bile acid homeostasis and their contribution to paediatric non-alcoholic fatty liver disease.”

Although some studies suggest a significant heritability factor in the development of NAFLD, less than 5% of the overall genetic risk of NAFLD has been accounted for and identified. This may be partly because genome-wide association studies use only common variants, whilst rare or low frequency genetic variants with significant effects are not studied. We believed that a
candidate gene approach could help address this problem of “missing heritability” by identifying rare but important risk variants in selected genes. Recently, growing attention is being paid to the role of bile acids in the pathophysiology of NAFLD. Bile acids regulate glucose and lipid metabolism by acting as signalling molecules through receptors such as the farnesoid X
receptor. Variation in genes involved in bile acid homeostasis may therefore affect glucose and lipid homeostasis, which could in turn affect predisposition to NAFLD.

To test this hypothesis, this project aims to analyse sequence data of selected genes involved in bile acid homeostasis from 100 children with biopsy-proven NAFLD. In silico prediction will be used to explore the likely effect of genetic variants on protein function and wider cellular processes.

Dr Jeyaraj and the team will also seek to identify distinct subgroups of patients, and test for whether the identified genetic variants in these young people relate to the
pattern or severity of their liver disease.

The findings from this project could help clarify which children are at risk of developing severe NAFLD, as well as identify new ways of treating the condition before it progresses to liver inflammation and scarring. They hope this project will contribute to wider efforts to improve liver health, both in childhood and in later adult life.

Why did you choose this project?

‘Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases of childhood. It affects around one-third of children and adolescents with obesity, leaving them at risk of developing liver inflammation and scarring over the course of their lives. I was particularly interested in the question of why some children go on to develop severe NAFLD. I really enjoy working with children and their families and hope to specialise in caring for children with liver disease in the future, therefore this project was a natural choice for me as it allows me to develop my skills in bioinformatic analysis while seeking to answer an important and challenging question in the field of hepatology.’