Disclosures: Sawalha reports no relevant financial disclosures.
January 06, 2021
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Genetic biomarker linking Takayasu arteritis, IBD may guide targeted therapies

Disclosures: Sawalha reports no relevant financial disclosures.
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When a disease has no clear etiology and no cure — as is the case with Takayasu arteritis — any advance feels like a big advance.

Results of a recent genome-wide association study in the American Journal of Human Genetics yielded information that is likely to give patients new hope and researchers new direction: The genetic signatures in Takayasu closely resemble those of inflammatory bowel disease, a much more treatable condition.

Results of a recent genome-wide association study in the American Journal of Human Genetics yielded information that is likely to give patients new hope and researchers new direction: The genetic signatures in Takayasu closely resemble those of inflammatory bowel disease, a much more treatable condition. Source: Adobe Stock

Patients with Takayasu arteritis experience granulomatous inflammation of the aorta and its major branches that can lead to elevated rates of myocardial infarction, stroke, major blood loss and organ damage, among other outcomes. However, symptoms can vary, making it a challenge in the clinic. Patients may experience low-grade fevers, swollen glands, anemia, dizziness, and night sweats, along with muscle aches, and even arthritis in some cases.

It is due to this clinical complexity that the breakthroughs provided by studies like the one published by Amr H. Sawalha, MD, chief of the division of pediatric rheumatology and director of the Comprehensive Lupus Center of Excellence at the University of Pittsburgh School of Medicine, and colleagues, are so important.

Amr H. Sawalha

In their study, Sawalha and colleagues examined genetic data from a cohort of 6,670 individuals from Turkey, Canada, China, Italy, the U.K. and the U.S. — 1,226 of whom had Takayasu arteritis. Using data from these five diverse populations, the researchers detected HLA-associated risk factors, along with susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21. Moreover, susceptibility was reinforced in IL12B, PT K2B, and chr21q22.

Looking deeper into functional analysis findings, the researchers drew a link to ETS2 as a possible causal gene for the chr21q22 association, which may offer insight into underlying disease mechanisms. All of this information allowed the researchers to develop a genetic risk score that may involve more than 60 candidate loci.

Perhaps the more critical finding is that Takayasu arteritis is most closely genetically related to IBD, which may open doors toward both understanding of Takayasu and provide the clinical and research communities with new therapeutic approaches.

Healio Rheumatology sat down with Sawalha to discuss the findings of the current study and what these results could signify for clinicians treating this disease.

Q. How were the genetic links found that could help predict susceptibility to Takayasu arteritis?

Sawalha: We used a genome-wide association study approach, which allows us to examine a very large number of genetic variants across the human genome and determine the variants that are more common in patients with Takayasu arteritis than in healthy individuals from the same populations. With this approach we estimate the strength of the genetic associations we identified.

Q. What does the genetic risk for Takayasu tell us about the disease mechanisms behind other immune-mediated diseases?

Sawalha: The genetic signature we identified provided us with very important new insights regarding what immune mechanisms might underlie the disease process in Takayasu arteritis. For example, our genetic data pointed out specific biological pathways involved and highlighted a role for monocytes and B cells in Takayasu arteritis.

Q. What does the association between Takayasu arteritis and IBD tell us, and how is it important?

Sawalha: This is very important as it tells us that, from a disease causation perspective, there are common mechanisms between the two disease conditions. This analysis was done using genetic data from the entire genome and by comparing Takayasu arteritis to hundreds of diseases and traits across hundreds of thousands of genetic markers.

A very important implication of this finding is that we can prioritize disease targets and treatment options that were successful in IBD for clinical trials in Takayasu arteritis. It is easier to do studies in IBD as it is much more common than Takayasu arteritis. Therefore, we can use knowledge already established in IBD trials to prioritize how we think about investigating Takayasu arteritis, using a more informed approach for which targets and treatment options to take into clinical trials in Takayasu arteritis.

Q. This study included genetic information from five different populations worldwide, which is exceptionally diverse for genetic studies. Why was this important to acquire?

Sawalha: It is very important to generate knowledge that is applicable to as many populations as possible in any disease. Otherwise, we run the risk that information generated and subsequent treatments developed based on this knowledge will only help a subset of patents affected by this disease. The other advantage in doing so in genetic studies is that by including multiple ancestral groups we are more likely to identify disease-causing variants in genetic regions identified by taking advantage of genetic variability and genetic structure difference across populations.

Q. Would we be able to extrapolate these findings for Takayasu arteritis to other types of vasculitis?

Sawalha: Not directly, but we can use the data generated in conjunction with other genetic data generated in other types of vasculitis to explore differences and similarities in genetic etiologies. Further, if we combine these data with other genetic data in other vasculitis conditions, we will have larger power to detect additional genetic loci that might be important in Takayasu arteritis and other types of vasculitis.

Q. Could you talk about the genetic risk score you developed?

Sawalha: The genetic risk score takes into account all the genetic variants we identified to predispose to Takayasu arteritis. We take the number of genetic risk variants present in each individual into account and how much genetic risk each variant carries and sum up the genetic risk in each individual. It is important to note that we do not believe there is a diagnostic utility from such score at this time. Maybe this can be developed in the future but this is not going to be simple and will likely need to incorporate other non-genetic data to potentially become useful in a clinical sense.

Q. What are the next steps? Where will this research take us?

Sawalha: There will be many potential next steps. For example, one next step will be to identify if any of the genetic loci or a combination of genetic loci identified predispose to specific disease manifestations in Takayasu arteritis, or predict disease complications or response to therapy. Are there some genetic loci that can predict whether a patient will respond to a specific therapy, for example?

Other next steps should include detailed functional studies to understand how the genetic loci identified affect the immune response, and what can be done to correct this resulting aberration. In addition, our genetic data and analysis identified pathways and molecules that can be targeted for therapy in Takayasu arteritis, so next steps can also include designing clinical trials to target these pathways and molecules in patients with Takayasu arteritis.

For more information:

Amr H. Sawalha, MD, can be reached at 4401 Penn Ave., Pittsburgh, PA 15224; email: asawalha@med.umich.edu.