Genetic Variant Drives Development of Inflammatory Bowel Disease

A genetic variant responsible for driving the development of inflammatory bowel disease (IBD) is associated with a genetic pathway that is involved in other immune disorders, indicating that this variant could serve as a critical therapeutic target.

That’s the key finding of a study recently published in the Journal of Crohn’s and Colitis.

Crohn’s disease and ulcerative colitis, the two main forms of IBD, have an important genetic component. Researchers have identified more than 240 genetic regions that associate with IBD, more than any pathological condition that’s been studied. But because each genetic region has multiple markers, it’s essential to identify those that are causally involved.

Researchers from Children’s Hospital of Philadelphia (CHOP) set out to characterize the single nucleotide polymorphism (SNP) rs1887428, located on the promoter region of the JAK2 gene. The protein coded by this gene is responsible for controlling the production of blood cells, and mutations of JAK2 have been linked to multiple blood cancers.

Investigators have developed multiple drugs to target the JAK pathway to treat autoimmune disorders and malignancies, but genetic and biological markers are needed to determine whether patients will respond to them.

"We chose this SNP for in-depth study because of its high probability for modifying JAK2 expression," said Christopher Cardinale, MD, PhD, a scientist in the Center for Applied Genomics at CHOP and first author of the study. "The model we established in this study may help us learn more about other causal SNPs associated with other autoimmune diseases."

The study identified proteins known as transcription factors, which regulate gene expression, that were associated with this particular SNP. In particular, two transcription factors – RBPJ and CUX1 – can recognize the DNA sequence altered by the rs1887428 SNP. Researchers also found that although the SNP has a very modest influence on JAK2 expression, the effect was heightened by other proteins in the JAK2 pathway.

The study has promising implications for IBD precision medicine, researchers noted.

"Using this method, we believe we have added an important tool to our arsenal of SNP-to-gene assignment methods, allowing us to pinpoint disease-driving genetic mutations that have previously been difficult to properly assign risk," said Hakon Hakonarson, MD, PhD, Director of the Center for Applied Genomics at CHOP and senior author of the paper.

"This study in particular also provides evidence that drugs targeting JAK2 may provide some benefit for those patients suffering from IBD who carry mutations that upregulate the JAK2 pathway, though such precision-based approaches would need to be validated in clinical studies."

This study adds to recent research about IBD. Mount Sinai recently published a series of four studies describing new predictive analytics tools and environmental risk factors that could lead to a new understanding of what triggers Crohn’s disease.

The studies offer new ways to identify individuals who may be at high risk of developing the disease, leading to more informed prevention efforts.

“Early identification of individuals at high risk for disease development could allow for close monitoring and interventions to delay, attenuate, or even halt disease initiation,” said Jean-Frederic Colombel, MD, Professor of Medicine (Gastroenterology) at the Icahn School of Medicine at Mount Sinai and Co-Director of Mount Sinai’s Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center.

“This is highly relevant as we seek to predict and prevent IBD, which continues to sharply increase in numbers across the globe. In the absence of a cure, our clinical strategy will center on aggressive and innovative mechanisms to predict and prevent the disease.”