Almost 125 million people in the United States are living with some type of chronic inflammatory disease. However, researchers are having a hard time diagnosing their specific health condition because they are experiencing overlapping symptoms.

Research scientists at the National Institutes of Health (NIH) addressed the challenge by taking a different or unique approach.

In a report published in the New England Journal of Medicine, the research scientists disclosed that they found a new inflammatory condition called vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome (VEXAS). 

VEXAS causes symptoms that included blood clots in veins, recurrent fevers, pulmonary abnormalities, and vacuoles (unusual cavity-like structures) in myeloid cells.

How did the NIH research scientists discover this new inflammatory disease?

The Genome Link

Instead of focusing on the symptoms of patients with undiagnosed inflammatory disease, the NIH researchers studied the genome sequences obtained from more than 2,500 individuals with undiagnosed inflammatory diseases. The researchers paid special attention to a set of 800 genes related to the process of ubiquitylation, which helps regulate both various protein functions inside a cell and the overall immune system.

This was the first time the research scientists used genome sequencing as an approach to diagnosing an unknown illness. They normally discover previously unknown disease by studying patients with similar symptoms, then find the gene or multiple genes that may be causing the disease. Their usual approach was not working.

“We had many patients with undiagnosed inflammatory conditions who were coming to the NIH Clinical Center, and we were just unable to diagnose them,” said David B. Beck, M.D., Ph.D., a clinical fellow at NHGRI. and lead author of the paper.

On the other hand, Dr. Beck, the lead author of the study explained, “That’s when we had the idea of doing it the opposite way. Instead of starting with symptoms, start with a list of genes. Then, study the genomes of undiagnosed individuals and see where it takes us.”

VEXAS explained

Every person has a complete set of DNA called its genome. And each cell in the body contains a complete copy of the approximately 3 billion DNA base pairs, or letters, that make up the human genome.

Using DNA-sequencing methodologies, the researchers found that the mosaicism was indeed present in the patients’ myeloid cells, which are responsible for systemic inflammation and act as the first line of defense against infections.

Sequencing determines the exact order of the bases in a strand of DNA. The research scientists found which cells are responsible for systemic inflammation and act as the first line of defense against infections. They also identified the gene that is intricately linked to VEXAS, which is caused by a variety of mutations in the UBA1 gene. 

As mentioned above, the symptoms of VEXAS include blood clots in veins, persistent fevers, pulmonary abnormalities (high blood pressure in lung arteries), and vacuoles which are cavity-like structures in myeloid cells.

VEXAS is a life-threatening disease.  So far, 40% of VEXAS patients studied by the team have died.

Researchers believe that the genome-first strategy will help healthcare professionals to improve diagnosis and provide better treatment for thousands of patients who have VEXAS inflammation-related conditions. 

The NIH is a huge medical research agency under the U.S. Department of Health and Human Services. It includes 27 institutes and centers.

The National Human Genome Research Institute (NHGRI), part of NIH, was responsible for the groundbreaking “Human Genome Project” completed in 2003. 

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