Project ID CM-HD2024_43


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, Department of Medical & Molecular GeneticsWebsite

Co Supervisor 1B Faculty of Dentistry, Oral & Craniofacial Sciences, Centre for Host-Microbiome InteractionsWebsite

Additional Supervisor Michael Escudier

Investigating genetic and microbiome interactions in orofacial granulomatosis (oral Crohn’s disease)

Orofacial granulomatosis (OFG) is a rare inflammatory condition characterized by the presence of granulomas in the oral and facial regions and is often associated with intestinal Crohn’s disease (CD). Thanks to GWAS studies the genetics of CD is quite well defined but we know much less about the causes of OFG. Over recent years we have sought to understand this better and see if the overlap between the two conditions can be explained in part by similar genetic causes. We now have evidence suggesting this may indeed be the case for some key genes (e.g. NOD2) that we have shown are involved in both CD and OFG. We wish to explore this further to help understand the route to pathogenesis in OFG and develop tools to identify those patients who might be at high risk of developing CD.

The aim of this projects will be to investigate the genetic causes of OFG through whole exome sequencing, determine the genetic overlap with CD and explore the role of disease-causing variants that are identified particularly with a focus on NOD2 pathway and atopy. We will also measure the microbiome using biological markers in the blood and saliva of individuals in our study and apply modelling techniques to help us investigate their interactions with the microbes in the mouth and gut and correlate this with immune status and genetics.

Year 1: sample analysis and sequencing
Year 2: data acquisition, validation, microbiome analysis
Year 3: final analysis and modelling, functional studies

Representative Publications

A Sazonovs, CR Stevens, GR Venkataraman, K Yuan, B Avila, MT Abreu, et al. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility (2022). Nature Genetics 54 (9), 1275-1283. Goel, R. M., Prosdocimi, E. M., Amar, A., Omar, Y., Escudier, M. P., Sanderson, J. D., Wade, W. G. & Prescott, N. J. Streptococcus Salivarius: A Potential Salivary Biomarker for Orofacial Granulomatosis and Crohn’s Disease? (Feb 2019) Inflammatory Bowel Diseases. Mentzer, A., Nayee, S., Omar, Y., Hullah, E., Taylor, K., Goel, R., Bye, H., Shembesh, T., Elliott, T.R., Campbell, H., Patel, P., Nolan, A., Mansfield, J., Challacombe, S., Escudier, M., Mathew, C.G., Sanderson, J.D., Prescott N.J. Genetic Association Analysis Reveals Differences in the Contribution of NOD2 Variants to the Clinical Phenotypes of Orofacial Granulomatosis (2016) Inflammatory Bowel Diseases, 22 (7), pp. 1552-1558.
• Genome-scale metabolic modelling of the human gut microbiome reveals changes in the glyoxylate and dicarboxylate metabolism in metabolic disorders. Proffitt, C., Bidkhori, G., Lee, S., Tebani, A., Mardinoglu, A., Uhlen, M., Moyes, D. L. & Shoaie, S., 15 Jul 2022, In: iScience. 25, 7, 104513. 10.1016/j.isci.2022.104513 • Host-Mycobiome Metabolic Interactions in Health and Disease. Begum, N., Harzandi, A., Lee, S., Uhlen, M., Moyes, D. & Shoaie, S., 2022, (Accepted/In press) In: Gut Microbes. DOI: 10.1080/19490976.2022.2121576