Scientists have discovered a genetic variation in the janus kinase 2 (JAK2) gene — a gene involved in a signaling pathway implicated in other autoimmune diseases — that can lead to the onset of inflammatory bowel disease (IBD).
The findings were reported in the study “Regulation of Janus Kinase 2 by an Inflammatory Bowel Disease Causal Non-coding Single Nucleotide Polymorphism,” which was published in the Journal of Crohn’s and Colitis.
IBD comprises a group of autoimmune disorders that cause inflammation and disrupt the function of the gastrointestinal tract. To date, more than 240 genetic regions have been associated with the development of IBD. A small subset of these regions are located in DNA sequences that do not encode proteins — called non-coding regions.
The single nucleotide polymorphism (SNP) rs1887428, which is found in the promoter region of the JAK2 gene, is one of the genetic variants located in a non-coding region of the genome that is thought to increase the risk of IBD.
SNPs, pronounced “snips,” are variations in a single nucleotide — the building blocks of DNA — in the DNA sequence of a gene. A promoter is a non-coding region of a gene that is responsible for controlling its activity, and the genome refers to all of the genes present in our DNA.
The rs1887428 SNP was the target of the new study led by researchers at Children’s Hospital of Philadelphia (CHOP), who focus on investigating the genetic factors contributing to the development of IBD.
“We chose this SNP for in-depth study because of its high probability for modifying JAK2 expression [activity],” Christopher Cardinale, MD, PhD, a scientist at the Center for Applied Genomics at CHOP and first author of the study, said in a press release.
JAK2 provides instructions to make a protein that is known to control cell growth and proliferation. This protein is particularly important to control the production of blood cells, including platelets, and red and white blood cells, from their stem cell progenitors located within the bone marrow.
Mutations in JAK2 have been linked to different types of blood cancers, and alterations in the signaling cascade it participates in are associated with certain autoimmune disorders.
To study the possible contribution of rs1887428 to the development of IBD, investigators used a series of assays and gene sequencing methods.
They discovered two transcription factors — proteins that control the activity of certain genes — that recognize the DNA sequence in which this SNP is located.
While one of the transcription factors called RBPJ was found to associate with the high-risk JAK2 allele containing rs1887428, the other transcription factor called CUX1 interacted with the normal allele. Of note, alleles are different versions of the same gene.
In addition, the researchers found that even though rs1887428 had a mild direct impact on the activity of JAK2, its effect could be amplified by other proteins involved in the JAK signaling cascade, including STAT5B.
“We conclude that the associated [transcription factors], RBPJ and CUX1, and target genes of this presumed-causal SNP, including the downstream pathway member, STAT5B, reveal novel insights into the molecular mechanisms of IBD,” the researchers wrote.
“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 study.
“Drugs targeting JAK2 may provide some benefit for those patients suffering from IBD who carry mutations that upregulate [activate] the JAK2 pathway, though such precision-based approaches would need to be validated in clinical studies,” he added.
The team noted the methods used in this study may be used to explore the role of other SNPs potentially associated with other types of autoimmune diseases.
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