Scientists have identified two key genes behind one of the most common forms of inflammatory arthritis, opening the door to long-awaited treatments for a disease that affects millions over the age of 60.
Key Points at a Glance
- Two genes — ENPP1 and RNF144B — found to cause calcium pyrophosphate deposition disease (CPPD)
- ENPP1 is responsible for generating key components of CPP crystals
- Discovery offers promising targets for drug development
- Study included over 550,000 U.S. veterans of European and African ancestry
- First genome-wide association study (GWAS) ever conducted on CPPD
Researchers have uncovered a genetic foundation for calcium pyrophosphate deposition disease (CPPD), also known as pseudogout, a common yet poorly understood form of inflammatory arthritis. This major breakthrough could lead to the development of the first targeted treatments for CPPD — a condition that affects up to 30% of adults over 80 and currently has no cure.
Published in the Annals of the Rheumatic Diseases, the study marks the first genome-wide association study (GWAS) to examine CPPD disease across diverse genetic populations. The researchers discovered two genetic culprits: ENPP1, a gene that regulates the production of inorganic pyrophosphate — a critical component of the harmful crystals that form in the joints — and RNF144B, a gene believed to play a role in inflammation.
ENPP1 stood out as the most significant find. Dr. Tony Merriman, lead investigator from the University of Alabama at Birmingham and University of Otago, explained, “The protein encoded by ENPP1 controls the production of compounds that combine with calcium to form the CPP crystals. These crystals are the key trigger of the intense inflammation seen in CPPD.”
While the role of RNF144B remains less clear, its involvement in inflammatory processes adds another piece to the puzzle. Together, these genes offer new targets for therapy — especially promising since some ENPP1 inhibitors are already under development for other conditions like cancer and infectious diseases.
Dr. Sara Tedeschi, co-investigator and rheumatologist at Brigham and Women’s Hospital and Harvard Medical School, emphasized the clinical potential: “Patients with CPPD disease are desperate for better options. Trials testing ENPP1 inhibitors in CPPD would be a logical and exciting next step.”
CPPD is caused by the buildup of calcium pyrophosphate crystals in joints, which activate immune pathways that release IL-1β, a pro-inflammatory cytokine. This results in sudden, painful joint inflammation. Historically referred to as pseudogout, it often mimics the symptoms of gout but has different underlying causes and treatment strategies. Currently, patients are treated with general anti-inflammatory drugs like colchicine or prednisone, which offer only symptomatic relief.
The research analyzed genetic data from the Million Veteran Program, which includes over 550,000 participants from the U.S. Veterans Health Administration, predominantly male and of both European and African descent. Remarkably, the same two genes were linked to CPPD across both genetic populations, making the discovery robust and broadly applicable.
Professor Josef Smolen, Editor-in-Chief of the journal, called the findings “crucial,” noting the unmet need for effective treatment strategies in CPPD. “This study points to two promising biological targets, which is particularly vital given the limited options currently available,” he said.
Beyond its clinical implications, the research represents a major milestone in arthritis genomics. It confirms that CPPD has a distinct genetic architecture and reinforces the power of GWAS in uncovering hidden drivers of complex diseases.
“This was a ‘eureka moment’ for us,” said Dr. Merriman. “It’s not often that a genetic study delivers such clear and actionable targets. We’re excited for the potential it holds to transform care for millions of people suffering from this often-overlooked condition.”
Source: Elsevier
