Supervisor View Full Details 2nd

• genetics, genomics and molecular biology

• Medicine

• Rheumatology

My research is centred on understanding genetic and epigenetic influences on the severity of tissue damage in rheumatoid arthritis (RA). These studies have involved using well characterised RA populations from around Europe that have both radiological damage scores (Larsen or SHS) and genome-wide genetic data. We also undertake functional studies using synovial and leucocyte cells from patients, and the CIA model.

Ongoing studies:
• Identification of genetic variants associated with severity of radiological damage
• Biological roles of C5orf30 - a novel regulator of tissue damage and inflammation
• Epigenome-wide association studies of response to anti-TNF and Methotrexate
• Exome sequencing to determine genetic basis of monogenic and polygenic rheumatic diseases

Key recent references:
JAMA. 2015;313:1645-56, Proc Natl Acad Sci U S A. 2015;112:11618-23, Arthritis Rheum 2016;68:1353-1360, Ann Rheum Dis 2017;76:208-213, J Immunol 2019:202:1069-1078.

Role of C5orf30 in inflammation:
The importance of this locus in RA was identified by my group using genetic methods. We subsequently characterized an anti-inflammatory and anti-catabolic role in RA synovial fibroblasts and the CIA model. Current and future studies will determine its role in neutrophil, dendritic cell and monocyte/macrophage biology and determine the molecular mechanisms linking the variant rs26232 with RA.

Potential role of epigenetics in methotrexate therapy:
The exact mechanisms of action of methotrexate in RA are poorly understood but may involve altered intracellular methyl donor status with consequent changes in DNA methylation. Synovial cells will be exposed to methotrexate and assays of biological function (invasion, proliferation, migration, cytokine production) will be assessed. Effects on DNA methylation will be assessed using genome-wide methylation arrays and transcriptomic changes by high throughput sequencing.

Identification of novel genetic basis for rheumatic diseases:
The advent of low cost DNA sequencing has resulted in the ability to discover the genetic basis for a range of previous uncharactised or uncommon conditions. This knowledge will led to a better understanding of disease mechanisms and improved (personalized) therapies. A national biobank of such conditions is being developed (http://www.molecularmedicineireland.ie/research/arthritis-research-coalition/) and initial studies have resulted in discovery of novel mutations in key inflammatory genes in individuals and families. Exome screen of an autoinflammatory bone condition (chronic recurrent multifocal osteomyelitis) is ongoing. The project will involve understanding the genotype-phenotype associations of disease-related mutations using molecular and cellular approaches in human tissue and animal models.

The fellow will work within a team of clinical and laboratory scientists and gain extensive experience in molecular and cellular biology, statistical analysis and joint arthroscopy. The data will be presented at national and international rheumatology and immunology conferences and result in publications in high impact factor journals.