09 Oct 2013

Low back pain can make life unbearable for millions of people worldwide and presents a huge socio-economic and health-care burden. One of the major causes of this back pain is lumbar disc degeneration (LDD). Medical experts have long been trying to find the root causes, for LDD and to improve diagnosis and treatments. Today HKU scientists and clinicians announce the results of a large-scale international study with more than 4000 sample subjects in Hong Kong, Northern China, Japan and Finland, with the discovery of a new genetic variant with an enzyme called “carbohydrate sulfotransferase 3 (CHST3) associated with an increased risk to develop LDD. This result provides new insights into the etiology of LDD and is significant for the diagnostic, prevention and treatments for LDD in the future. The discovery is published in the international prestigious journal, Journal of Clinical Investigation this morning.

Research Background
LDD is so common that almost everyone will have some degree by the time they are 50 years or older. The previous studies show that environmental and lifestyle factors can affect the onset and progression of disc degeneration, but family and twin studies have shown a strong genetic predisposition in the development of LDD. Many gene factors are thought to be involved, but so far few have been found. Also other mechanisms involved in the molecular pathogenesis of LDD are yet to be found.

Research Implications
The ground-breaking study, using a population cohort recruited since 2003, was led by investigators from the Departments of Biochemistry and Orthopaedics & Traumatology, The University of Hong Kong Li Ka Shing Faculty of Medicine, with collaborators from the Laboratory for Bone and Joint Diseases at the RIKEN Center for Integrative Medical Sciences, Japan and University of Oulu, Finland.

Dr Danny Chan, Associate Professor and Dr Song You-qiang, Associate Professor of the Department of Biochemistry, HKU Li Ka Shing Faculty of Medicine are the lead authors of the paper. They say,“Our finding provides a key functional link of this variant form of the CHST3 gene to LDD and shows for the first time a new mechanism involved in the molecular pathogenesis of LDD. More importantly, this reaffirms the need to address and identify all the genetic risk factors for LDD.” Professor Kenneth Cheung Man-chee, Jessie Ho Professor in Spine Surgery, Clinical Professor and Head of the Department of Orthopaedics and Traumatology is a principal investigator in the research program. He points out that this research has changed the mindset of clinicians in their understanding and treatment of the disease, contributing to the development of potential prevention and treatment strategies.

Research methods and findings
The research team scanned the entire genetic material (genome) of Hong Kong families with early-onset and severe LDD and thousands of additional individuals from different populations that included Southern Chinese from Hong Kong, Northern Chinese, Japanese and Finnish, totaling 4043 subjects, and also more than 28,000 control subjects. The study revealed that among the different populations, a genetic variant for a gene that codes for an enzyme, “carbohydrate sulfotransferase 3” (CHST3), is associated with the development of LDD. In the Hong Kong population, the estimated frequency of the risk variant is 43% for LDD subjects.

The central part of the normal disc has a gel-like property that provides a cushioning effect, acting as a shock absorber as well as facilitating motion and function of the spine in daily activity. The CHST3 enzyme is essential for ensuring that the macromolecular components can function properly by keeping it hydrated. The variant form of the genes causes changes in the amount of CHST3, leading to a reduction of water in the central compartment of the disc, which is a hallmark of disc degeneration.

To take advantage of this prominent result, the research team will further perform bigger genome-wide studies and whole genome sequencing of LDD patients, aiming to “track down” more susceptibility genes as the next step. With a clear understanding of the genetic risk factors, the investigators are hopeful that their finding will help in the formulation of preventive measures, and the development of therapeutic interventions and treatments.

About the research team
The study was led by investigators from the Departments of Biochemistry and Orthopaedics & Traumatology, The University of Hong Kong Li Ka Shing Faculty of Medicine, with collaborators from the Laboratory for Bone and Joint Diseases at the RIKEN Center for Integrative Medical Sciences, Japan and University of Oulu, Finland. This research is supported by the Hong Kong University Grants Council’s Area of Excellence (AoE) scheme that made it possible to establish the Hong Kong cohort and perform large-scale genetic studies. The research in Hong Kong has also gained international recognition and attracted support from AOSPINE international.

The key research members are: Dr Song You-qiang, Associate Professor, Dr Danny Chan, Associate Professor, Professor Kathryn Cheah, Chair Professor of Biochemistry, the Department of Biochemistry and Director of the AoE programme, Professor Kenneth Cheung Man-chee, Jessie Ho Professor in Spine Surgery, Clinical Professor and Head of the Department of Orthopaedics and Traumatology, and Professor Sham Pak-chung, Chair Professor of Psychiatric Genomics, the Department of Psychiatry, HKU Li Ka Shing Faculty of Medicine.

Please visit the website at http://www.jci.org/articles/view/69277?key=b9c471a7a29b24516318 for the journal paper.

To use the press release photo(s) for any publishing, publicity and related purpose, photo courtesy should be given to “Li Ka Shing Faculty of Medicine, The University of Hong Kong”