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NIH-led research team uses genomics to discover new inflammatory disease

Using a new genomic approach, a research team led by National Institutes of Health investigators has identified a new hereditary inflammatory disease in men. Their discovery was detailed in a New England Journal of Medicine study published October 27.

The team called the new disease VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome). The severe condition has devastating consequences; so far, 40% of VEXAS patients who the team studied have died.

Nearly 125 million people in the U.S. live with some form of chronic inflammatory disease. Chronic inflammation can have many underlying causes: infections that don’t go away, abnormal immune reactions to normal tissues, certain diseases or conditions, or changes in certain genes. Chronic inflammatory diseases often have similar symptoms, which makes it difficult for doctors to diagnose the specific disease.

Genes related to ubiquitylation - a process that alters proteins to regulate their function or tag them for degradation - have been shown to play a role in some inflammatory diseases. To investigate whether genes related to ubiquitylation play a role in patients with undiagnosed inflammatory disease, the NIH-led team studied the genomes of more than 2,500 patients. More than 1,400 of these individuals had undiagnosed recurrent fevers and body-wide inflammation. The rest, part of the NIH Undiagnosed Diseases Program, had unusual and unclassified disorders.

The study was funded by multiple NIH Institutes: the National Human Genome Research Institute (NHGRI), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Dental and Craniofacial Research (NIDCR), Office of the Director (OD), National Institute of Allergy and Infectious Diseases (NIAID), and NIH Clinical Center (CC). The NIH researchers included Drs. Peter Grayson of NIAMS, Daniel Kastner of NHGRI, and Achim Werner of NIDCR.

The team focused on a set of about 840 genes related to ubiquitylation. Out of those, one stood out: the UBA1 gene. Three middle-aged men had rare and potentially damaging genomic mutations in the gene. UBA1 holds the instructions to make the E1 enzyme, which is needed to initiate ubiquitin signaling in cells.

Men normally carry only one copy of this gene since it resides in the X chromosome. However, DNA-sequencing revealed that each of the men appeared to carry two different versions of the gene. Further investigation showed that that some cells in their bodies carried the UBA1 gene in its normal form, while others carried the gene in a mutated form. This phenomenon is known as mosaicism, where a cell picks up a genetic mutation at some time during early development.

The mutated gene was found in the patients’ myeloid cells, which are responsible for systemic inflammation and act as the first line of defense against infections.

The researchers then discovered an additional 22 men with the UBA1 gene mutations, most of them participants in other NIH studies. Symptoms of the 25 patients included blood clots in veins, recurrent fevers, lung abnormalities, and unusual vacuoles (cavity-like structures) in myeloid cells.

“By using this genomic approach, we have managed to find a thread that ties together patients carrying all of these seemingly unrelated, disparate diagnoses,” Kastner said.

The researchers hope that this new genomic strategy will help health care professionals improve disease assessments and treatments for various inflammation-related conditions.

Read more: https://www.nih.gov/news-events/nih-research-matters/new-inflammatory-di...

Read the study: https://www.nejm.org/doi/full/10.1056/NEJMoa2026834

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