There are two main forms of inflammatory bowel disease (IBD): Crohn’s Disease (CD) and Ulcerative Colitis (UC), which are distinguished by location within the body and severity. CD is much more severe, with patients showing deep inflammation of the terminal ileum and colon, while UC is characterised by superficial inflammation within the colon. Current treatments, mostly based on monoclonal antibodies, are used for both CD and UC despite their differences. Only a small percentage of patients are entering deep remission after being treated. This low treatment success has prompted a more in-depth genetic analysis of CD in order to determine a more effective solution.
According to a paper published in nature in 2012 headed by researchers at the Sanger Institute, Over 200 loci associated with IBD have been identified by genome-wide association studies (GWAS) – this is done by comparing DNA markers across the genomes of individuals with IBD. Many of the 200 loci already identified are known to be involved in the pro-inflammatory interleukin-23 pathway. However, with this method, rare genetic forms of the disease with potentially higher functional symptoms are often missed that play a key role in genetic predisposition to CD. Dr Inga Peter and her colleagues at the Icahn School of Medicine have identified the need to sequence rare variants in order to refine “the pathways associated with disease pathogenesis and design new therapies”.
The group’s research focused on the Ashkenazi Jews due to the high prevalence of IBD in their population. Amongst them, there are approximately 3 times more cases in comparison to Europeans without Jewish ancestry. This is largely due to the insular nature of the community making mutation frequencies high. The group was studied in order to identify alleles of the LRRK2 gene which had a high association with CD. The LRRK2 gene also has the largest genetic effect reported in Parkinson’s Disease (PD). The normal function of the LRRK2 gene is expressed in macrophages and stem cells within the small intestine and encodes for a protein that destroys debris within cells.
Interestingly identified the team found that certain genetic variants that were associated with protection against CD and others with risk. This was true not only for those suffering from CD but also in PD patients. The trend was seen in both Jewish and non-Jewish populations. Despite this linked effect, the risk variant was seen more frequently in CD cases than PD. After further analysis into the link between the two diseases they established that there are certain genetic mutations which are present in both conditions – the team have identified that one gene’s variants are responsible for the two seemingly unrelated phenotypes. This is an important conclusion as it allows health professionals to identify a subset of CD patients who are at greater risk to PD onset. Not only can the variant increase risk of developing PD but if two copies of the allele are present this can lead to a 6-year earlier age of onset.
The identification of alleles that increase a patient’s protection is important as it highlights the desired functional effect that could be used in new CD and PD treatments – it gives researchers a clear signposted goal which previously has been more ambiguous. For example, the R1398H variant is a loss of function allele that blocks the pro-inflammatory interleukin-23 pathway, protecting the patient from severe cases of CD. Being able to recreate this effect would be a successful treatment option. It has already been shown that mice deficient in receptors of this pathway develop less severe symptoms of IBD.
The team highlighted that despite their study failing to explicitly screen CD patients for PD, the genetic link found between the two diseases cannot be disregarded. This is especially true since PD is found is >1% of the population. Interest in the LRRK2 gene is now coming to fruition through many recent studies looking at its effects on CD and PD but also on risks associated with some cancers. As the understanding of LRRK2 and its variants’ effects increase so does the opportunity for more specific and effective treatments to arise.