Researchers Find Novel Candidate Gene, Pathway for Severe Radiographic Damage in AS

The Ryanodine receptor 3 (RYR3) gene is a novel candidate gene for severe radiographic damage in patients with ankylosing spondylitis (AS), according to study results published online ahead of print in the Annals of the Rheumatic Diseases.

“Although no previous study has investigated the relationship between RYR3 and AS, there have been several studies that may support our results, including RYR3 is related to calcification in patients with breast cancer and fibro-calcific aortic valve disease. Moreover, transforming growth factor-beta (TGFβ) reduces RYR3 and inhibits matrix mineralization in osteoblast differentiation,” wrote researchers from South Korea. “Considering that TGFβ plays a role in inflammation and AS acting on the formation/repair of cartilage and bone, … our results might provide a clue to elucidate the underlying pathogenesis of radiographic damage in AS.”

The study included genome-wide single nucleotide polymorphism data for 444 patients with AS. Researchers aimed to identify clinical and genetic factors linked with severe radiographic damage.

After adjustment for sex, age, and disease duration, clinical factors significantly associated with final modified Stoke Ankylosing Spondylitis Spinal Scores (mSASSS) included baseline mSASSS, peripheral joint arthritis, uveitis, and smoking, according to the study. After adjustment for those clinical factors, the RYR3 gene was associated with severe radiographic damage.

“Further, rhodamine B (a ligand of RYR3)-induced matrix mineralization was confirmed using human AS-osteoprogenitor cells,” researchers wrote. “And knockdown of RYR3 inhibits matrix mineralisation in SaOS2 cell lines.”

The study also identified the PI3K-Akt signaling pathway as a candidate pathway of severe radiographic damage.

“Our results may pave a way for better personalized medicine by identifying patients at high risk of severe structural damage, but also open up new opportunities for drug development for radiographic damage in AS,” researchers wrote.

Reference
Nam B, Jo S, Bang SY, et al. Clinical and genetic factors associated with radiographic damage in patients with ankylosing spondylitis. Ann Rheum Dis. Published online December 21, 2022. doi: 10.1136/ard-2022-222796