Landmark study reveals genetic risk factors for spinal osteoarthritis

Scientists from the LKS Faculty of Medicine of the University of Hong Kong (HKUMed), contributing as part of the “Genetics of Osteoarthritis (GO)” consortium to the world’s largest study involving more than 800,000 individuals, have identified genetic risk factors – variants associated with genes SOX5 and CHST3, key regulators of intervertebral disc development, involved in spinal osteoarthritis (OA). The results are now published inCELL, a leading scientific journal.

Osteoarthritis is the degeneration of the joints and a major cause of pain and disability in the elderly. There is no cure for osteoarthritis because the causes are complex and the mechanisms are unclear. Therefore, identifying risk factors for the disease is crucial and urgent to guide the development of new treatments that will benefit patients.

Research methods and results

Osteoarthritis affects several joints such as the knee, hip, hand, and spine. This landmark study analyzed 826,690 individuals from nine populations, including Hong Kong Chinese in southern China, Japanese, and Europeans, and found 100 genetic variants of osteoarthritis risk, of which 52 were new; and identified new drug targets.

The HKUMed team helped identify the SOX5 gene, which is known to be essential for the development of intervertebral discs, to be involved in spinal osteoarthritis. The study also found that osteoarthritis of the spine was genetically correlated with osteoarthritis in other joints, including the hip, knee, finger and thumb. Interestingly, it was also found that the CHST3 gene was among the top three genes most confidently linked to osteoarthritis of the hip. The Hong Kong team previously found that CHST3 was associated with degeneration of the intervertebral discs that causes back pain.

“This study demonstrates the power of genetics to discover biological mechanisms and identify new therapeutic targets for complex human diseases, when researchers are ready to share data collected in different countries,” noted Professor Sham Pak-chung. , Suen Chi-Sun Professor of Clinical Sciences. , Head of Research and Training at the Center for PanorOmic Sciences and Full Professor of Psychiatric Genomics, Department of Psychiatry, HKUMed; Co-director of the State Key Laboratory of Brain and Cognitive Sciences, HKU, which has led the genetic analyzes of osteoarthritis of the spine.

These results suggest a strong link between degeneration of intervertebral discs, osteoarthritis and back pain. In addition, osteoarthritis of the spine was genetically correlated not only with back pain, but also pain in the knees, hips and neck / shoulders. The study also showed that body weight rather than body fat was genetically correlated with osteoarthritis, and that weight-bearing and non-weight joints differed in terms of genetic influences.

The putative osteoarthritis genes identified in the study have a variety of biological functions, including key molecules in skeletal formation and development, and pathways that control how cells respond to stress. These biological processes are modifiable and represent potential targets for treatment. Encouragingly, the study showed that some of the putative OA genes could be targeted by existing drugs or small molecules.

Osteoarthritis has such a debilitating impact on our daily lives. Based on our results, I’m sure a treatment can be developed to alleviate some of the back pain caused by osteoarthritis, which will have a huge impact on millions of people. “

Professor Kathryn Cheah Song Eng, Jimmy and Emily Tang Professor in Molecular Genetics, Full Professor of Biochemistry, School of Biomedical Sciences, HKUMed and Study Coordinator

“Of particular importance is the association of spinal degeneration with degeneration of the hip and knee joints, which implies that treatments that help the hip and knee joint may be helpful for the spine. vertebral and vice versa. This opens up all kinds of possibilities for the benefit of both groups of patients, ”commented Professor Kenneth Cheung Man-chee, Professor Jessie Ho in Spine Surgery, Full Professor and Head of the Department of Orthopedics and Medicine. trauma, HKUMed, who pioneered the establishment of the Hong Kong Degenerative Disc Disease Population Cohort Study.

“Osteoarthritis is a complex disease involving many factors. This collaborative effort illustrates the benefit and power of large-scale international data sharing from cohort studies, and thinking outside the box to extract additional information so that large-scale development goals can be achieved. treatments that will benefit patients, ”noted Professor Danny Chan, SY and HY Cheng Professor in Stem Cell Biology and Regenerative Medicine, Acting Director of the School of Biomedical Sciences and Associate Dean (Postgraduate Studies in Research ), HKUMed, who is an expert in joint development and intervertebral disc degeneration and also helped establish the Hong Kong cohort.

Importance of the study

To date, no genetic factor for osteoarthritis of the spine has been identified. The study represents a major breakthrough and paves the way for new research to find new, more effective treatments for people with the disease. Since SOX5 is a primary regulator of many genes, this study provides the basis for the identification of downstream genetic factors that impact the development of spinal osteoarthritis. Genes identified for OA in other joints that are validated as therapeutic targets may also be relevant for OA of the spine as well as degeneration of intervertebral discs. Translation ideas that harness knowledge of genetic risk factors into potential drugs for osteoarthritis, which, if effective, could dramatically improve the quality of life of patients with osteoarthritis.

“Patients with back pain constitute an important part of musculoskeletal disorders. Of the two main causes, disc degeneration and osteoarthritis, the first can be identified by MRI, while osteoarthritis is difficult to pinpoint. Thus, only symptomatic treatment is possible using anti-inflammatory drugs and various physiotherapy modalities. The clarification of the genes responsible for osteoarthritis of the spine is a big step forward towards the possibility of more specific treatments, such as new drugs, ”said Professor John Leong Chi-yan, professor emeritus and honorary professor of the Department of Orthopedics and Traumatology, HKUMed; former president of the hospital administration.

“This is a big step forward in understanding this debilitating disease and could not have been achieved without this international team effort,” said Prof Eleftheria Zeggini, GO consortium leader and director of the Institute for Translational Genomics at Helmholtz Zentrum München.