New genetic associations predict susceptibility to Takayasu arteritis

A team of international collaborators, headed by scientists from the University of Pittsburgh School of Medicine, have detected novel genetic associations that can estimate the susceptibility of individuals to Takayasu arteritis—a rare inflammatory disease.

New genetic associations predict susceptibility to Takayasu arteritis
Amr Sawalha, M.D., professor of pediatrics and medicine at Pitt, and chief, Division of Pediatric Rheumatology, UPMC Children’s Hospital of Pittsburgh. Image Credit: UPMC.

The study was recently published in the American Journal of Human Genetics.

The new study was conceptualized by Amr Sawalha, MD, professor of pediatrics and medicine at the University of Pittsburgh, and chief of the Division of Pediatric Rheumatology at UPMC Children’s Hospital of Pittsburgh.

Dr Sawalha collected samples from a total of 1,226 individuals afflicted with Takayasu arteritis across five different populations worldwide, rendering them the world’s largest collection of samples.

In individuals with Takayasu arteritis, inflammation impairs many large vessels, including the aorta, which can cause the rupture of crucial blood vessels or lead to the reduced blood supply to the brain, limbs, and other vital organs and, thus increase the risk of a stroke, heart attack, organ damage, or major blood loss in patients.

Many of us who treat patients with Takayasu arteritis are frustrated because we don’t really know how the disease works. We don’t have good tools to predict a disease flare-up. Some patients have a very active disease without clear symptoms or an increase in inflammatory markers.”

Amr Sawalha, MD, Professor of Pediatrics and Medicine, University of Pittsburgh

By conducting a genome-wide association analysis in patients with Takayasu arteritis and healthy individuals, the team identified some differences in many areas of the genome that indicate the role of specific immune cells in this kind of disorder. They also detected new pathways and molecules that can be targeted for treatment.

The researchers subsequently compared the genetics of Takayasu arteritis with a genetic predisposition to scores of other traits, evaluating the shared genetics between Takayasu arteritis and other diseases mediated by the immune system.

We found that, genetically speaking, Takayasu arteritis was closest to Crohn’s disease. This suggests that we can try developing treatments based on what we know works for inflammatory bowel disease, which is a much more common condition.”

Amr Sawalha, MD, Professor of Pediatrics and Medicine, University of Pittsburgh

Information about the genetic predisposition to Takayasu arteritis was quite limited, until this latest report. This was because scientists found it difficult to obtain a large number of samples that are sufficient to represent the genetic design of ancestrally varied populations.

Sawalha added that the new study was achieved only with the help of global collaborations. Sawalha’s team collected data and samples from patients in Italy, China, Canada, and Turkey, the United Kingdom, and across the United States. It included patients from populations that were under-represented in genetic analyses.

In the days to come, investigators hope to apply their information to identify the genetic determinants of the manifestation of the disease itself—for example, which arteries might be impacted, which people are prone to develop severe disease, and which type of patients will probably carry the disease silently without exhibiting easily detectable molecular markers.

This study opens a lot of possibilities. Expanded knowledge of the genetic component of Takayasu arteritis will help us develop more effective therapies moving forward.”

Amr Sawalha, MD, Professor of Pediatrics and Medicine, University of Pittsburgh

Source:
Journal reference:

Ortiz-Fernández, L., et al. (2020) Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study. American Journal of Human Genetics. doi.org/10.1016/j.ajhg.2020.11.014.

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