JUL 13, 2020 12:52 PM PDT

New Therapeutic Targets For Lupus Are Identified

WRITTEN BY: Carmen Leitch

The human genome is full of places where the sequence varies slightly from one individual to another. Advances in computational and genetic technologies have enabled scientists to search the genome to look for places where these small sites of variability are linked to disease susceptibility. Many of these variations are in parts of the genome that do not code for proteins but instead have regulatory or other unknown functions, or sometimes the variations can influence each other. As such, many genome-wide association studies (GWAS) have not always been able to pinpoint the exact changes that are ultimately responsible for contributing to disease risk.

Scientists searching for new ways to treat an autoimmune disorder called systemic lupus erythematosus (SLE) have looked to the genome for ideas but have taken a different approach. In new work reported in Nature Communications, researchers studied genomic variations that may influence SLE through genetic regulation. While taking the three-dimensional structure of the genome into account, they searched for variants that may control the expression of genes. Places that seem very far apart when looking at the genetic sequence as a straight line might actually be very close together once the genome is packaged into a compact three-dimensional form like it has to be inside of cells.

In this study, the investigators focused on genetic variations in the genome of a cell that has a central role in the immune response that is linked to lupus, called follicular helper T cells. They found that genetic variants that are linked to SLE and play regulatory roles don't affect the gene they're closest too. Instead, they associate with genes that are far off, some of which have also been previously connected to SLE.

"Prior to this study, no 3D structural genomic maps had been generated for this lupus-relevant cell type before," said the co-senior author of the study Andrew D. Wells, Ph.D., Co-Director of the Center for Spatial and Functional Genomics at Children's Hospital of Philadelphia (CHOP). "With our approach, we believe we were in a position to identify genes and pathways that had no prior known role in lupus."

The research revealed 393 genetic variants and the genes they are close to in 3D, and therefore, may be involved in regulating. Two enzymes not previously linked to SLE, kinases called HIPK1 and MINK1, were linked to lupus. These kinases interfere with the production of a cytokine called interleukin-21, which helps control antibody production.

"We believe that HIPK1 and MINK1 may serve as valuable therapeutic targets for lupus, a disease that is in dire need of new treatment options," Wells said. "We also want to take the methods we used in this study and apply them to other autoimmune diseases and help pinpoint more causal variations that may have otherwise remained obscured by GWAS alone."

Wells and colleagues are now hoping to engineer mice to study how HIPK1 is related to lupus and antiviral immunity.

Image credit: Pixabay

Sources: AAAS/Eurekalert! Via Children's Hospital of Philadelphia, Nature Communications

About the Author
  • Experienced research scientist and technical expert with authorships on 28 peer-reviewed publications, traveler to over 60 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
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