Genome Analysis Identifies New JIA-linked Genetic Variants, Targets

Genome Analysis Identifies New JIA-linked Genetic Variants, Targets
5
(1)

A large-scale genome analysis has identified five genetic variants newly associated with disease susceptibility in multiple subtypes of juvenile idiopathic arthritis (JIA). 

The analysis also revealed several genes potentially involved in disease regulation that have promise as therapeutic targets.

The study, “Combined genetic analysis of juvenile idiopathic arthritis clinical subtypes identifies novel risk loci, target genes and key regulatory mechanisms,” was published in the Annals of the Rheumatic Diseases.

To date, 17 single nucleotide polymorphisms (SNPs) — variations in a single nucleotide, the DNA building blocks — have been linked to JIA susceptibility, with an overlap in sites between two common JIA subtypes, oligoarthritis and rheumatoid factor-negative polyarthritis. However, no such clear overlap has been reported among the other JIA subtypes.

Studies of JIA causes and regulatory factors are limited by the disease’s distinct subtypes that exhibit diverse symptoms and prognoses. As such, genetic studies have been focusing on specific subtypes rather than the disease as a whole.

Genome-wide association studies (GWAS) are used to analyze genetic profiles associated with diseases. Researchers at the University of Manchester, in the U.K., and their collaborators hypothesized that combining all JIA subtypes using GWAS would allow for the identification of new shared disease-related genetic sites and variations as well as potential therapeutic targets.

Genomic data from 3,305 JIA patients and 9,196 healthy controls were analyzed against more than seven million SNPs. 

Results showed five new disease-associated SNPs, including SNPs in or near five protein-coding genes. The researchers also found that most genetic sites linked to JIA susceptibility are shared across multiple disease subtypes. In addition, most of the strongest JIA-related associations were detected in the analysis that contained all seven subtypes, suggesting that the joint analysis improved the ability to identify genetic sites of JIA risk. 

SNPs associated with JIA susceptibility were enriched in functional and regulatory genetic regions, including the binding sites for the transcription factors (proteins that regulate gene activity) RELA and EBF1. The SNPs were also enriched in DNA regulatory elements called enhancers that bind transcription factors and increase gene activity.

Tissue-specific enrichment was observed in blood, thymus, and gastrointestinal tissue, as well as subsets of immune T-cells. A similar SNP enrichment was observed across multiple cell types in DNA regulatory elements called promoters that mark the site where DNA is transcribed to RNA. These results indicate that genetic functional and regulatory elements in specific tissues are involved in JIA susceptibility.

Having identified JIA-associated SNPs, the researchers next sought to identify target genes by identifying which SNPs correlate with changed activity in a specific gene. A total of 15 potential target genes were identified. Of these, 11 had JIA-associated SNPs in or near their regulatory regions.

One such gene, IL6ST, is a particularly promising therapeutic target due to its involvement in the interleukin-6 (IL-6) immune signaling pathway that has been linked to systemic JIA prognosis. Existing therapies target the IL-6 pathway, including Actemra (tocilizumab), while Enspryng (satralizumab) has been approved in Japan for the treatment of neuromyelitis optica — a rare autoimmune disorder affecting the eyes and spinal cord.

“Our findings provide genetic support for the study of satralizumab as a new therapeutic target for JIA,” the researchers wrote.

“Our results highlight the utility of joint analysis considering all JIA subtypes to maximise discovery, shifting the classical paradigm on which previous JIA genetic studies were based, and illustrate the potential of integrative approaches to gain further insights into the genetic susceptibility of the disease, which may in turn inform future therapeutic drug targets and pathways,” they added.

How useful was this post?

Click on a star to rate it!

Average rating 5 / 5. Vote count: 1

No votes so far! Be the first to rate this post.

As you found this post useful...

Follow us on social media!

We are sorry that this post was not useful for you!

Let us improve this post!

Tell us how we can improve this post?