Dr Elizabeth Goode - T cell gene-expression
Deriving T cell gene-expression signatures of primary sclerosing cholangitis
Awarded to Norfolk and Norwich University Hospital
Dr Elizabeth Goode, Wellcome Trust Clinical Research Fellow
The total grant awarded is £24,480
Duration of award: 08 January 2018 to 08 January 2019
Award details: Deriving T cell gene-expression signatures of primary sclerosing cholangitis
One in 10,000 people in the Western world lives with primary sclerosing cholangitis (PSC), an immune-mediated, inflammatory disease of the bile ducts. Most also have inflammatory bowel disease (IBD). People with PSC also have an increased risk of cancers and serious liver damage. There is no medical treatment for PSC and the only life-saving option for those with severe disease is a liver transplant. The lack of an effective treatment for PSC reflects our current limited understanding of how the disease develops.
People with PSC are thought to have a genetic predisposition for developing PSC. Our DNA, laid down at conception, gives us an unrivalled opportunity to understand the underlying causal biology of the disease. This is because the genetic variants associated with the predisposition to develop a disease affect genes and biological pathways that contribute to the development of the disease. Twenty-three regions of the genome (called genetic loci) have been associated with PSC risk. These genetic loci offer the potential for huge insight into the causal biology of PSC, if only we can robustly identify the true causal variants driving these loci and the genes they affect. However, this is complicated by the fact that the majority of disease-associated risk loci occur within regions of the genome that do not code for genes (i.e. are non-coding risk loci).
In this study we aimed to identify the true genes underlying each of the twenty-three known loci associated with risk of developing PSC. We know that many non-coding risk variants associated with other complex diseases exert an effect upon the quantity of gene expression, also called expression quantitative trait loci (eQTLs).
Colocalisation is a statistical method to assess the evidence that a single shared causal variant is responsible for driving PSC risk and expression of a particular gene via an eQTL. In order to identify which genes are dysregulated by PSC risk loci, we performed colocalisation with eQTLs mapped in multiple cell types and tissues mechanistically relevant to PSC. Because PSC is rare, eQTLs have not previously been mapped in all cell-types most relevant to this disease. With the aid of PSC Support funding, we therefore, mapped eQTLs in six peripheral blood T-cell subsets (including the rare CCR9+ gut-homing T-cells that have been previously mechanistically associated with PSC) from 80 patients with PSC and IBD. With colocalisation, we assigned causal genes to five PSC risk loci. Three of these genes, PRKD2, ETS2 and UBASH3A, are of particular interest as they are genes that are currently the target of existing or experimental therapeutic agents.
Firstly, reduced expression of the PRKD2 gene causes excessive development of immune cells called T follicular helper and activation of B-cells, and is associated with increased risk of PSC. Several studies are investigating the therapeutic effects of increasing the activity of PRKD2.
The ETS2 gene is involved in the production of pro-inflammatory mediators and ETS2 inhibitors are currently the subject of early therapeutic trials.
Finally, the UBASH3A gene dampens the NF-kB/I-KKb pathway, an inflammatory pathway that is already targeted by drugs called proteasome inhibitors and acetylsalicylic acid, both of which could be potentially therapeutic in PSC.
PSC is a debilitating disease with serious complications, for which new therapeutic options are urgently needed. In this study, supported by PSC Support, we identified multiple genes with a causal role in the way PSC develops, several of which are potential candidates for future therapeutic targets.
Updated 09 September 2022