Dr Ross McManus

Figure 1 Nuclear localisation of the NFkBIL1 protein which we have demonstrated is a regulatory protein with anti-inflammatory properties.

The research of the Genomics laboratory is concerned with investigating diseases with an inflammatory component. Our main focus is with diseases of the gastrointestinal tract, particularly coeliac disease and inflammatory bowel disease. We are also interested in other diseases which have inflammatory or immune mechanisms, such as sepsis and systemic inflammatory response syndrome, metabolic syndrome, and psoriasis among others. While this encompasses a broad group of diseases, they are thought to share mechanistic features. We use a broad approach to our investigations; principally using genomic technologies such as association mapping in large case control populations. In sepsis, we investigate inflammatory gene expression as an indicator of potential disease outcome.

Recent work in coeliac disease has led to the localisation of the region encoding the IL2/IL21 genes on chromosome 4q as contributing to the susceptibility to this common malady. This builds on earlier findings of genetic associations of the CTLA4/ICOS region and the TNF region emphasising the role of inflammatory cytokines and the regulation of T cell activity in this disease. We have also investigated the role of a candidate gene for coeliac disease and have demonstrated that it has wide ranging anti-inflammatory properties through the regulation of other proteins (Figure 1).

In inflammatory bowel disease (IBD) we have demonstrated an association in our population with the xenobiotic response system regulator, the pregnane X receptor (PXR/SXR). This is significant as it adds to the body of literature implicating other members of this functional class in IBD. We have shown single nucleotide polymorphisms. It is especially significant in that PXR has recently been shown to cross regulate NFkB particularly in the gut and that abberant regulation of PXR predisposes to gut inflammation (Figure 2).

Figure 2 This shows a comparison of the frequencies of haplotypes from the IBD population (black bars) compared to the control population (blue bars) for the PXR gene, indicating significantly different frequencies between the two groups.

In a collaborative study of sepsis, we have made significant findings including an important observation that patients expressing higher levels of TNFα and IFNδ fare much better than low expressers in response to devastating bacterial infections, as measured by RT-PCR of peripheral blood cells. Previously it was thought that high TNF levels were responsible for organ failure, however we no longer believe this to be a primary causative association.

We are also involved in a collaborative international study of metabolic syndrome (EU-funded LIPGENE project), investigating a patient subset derived from a French study of 13,000 individuals. This is an exciting prospect because a wealth of metabolic data is available on these patients. I collaborated in writing the workpackage description for this grant and in developing software to analyse this data (see www.hitagene.com).

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