HKU Bulletin December 2014 (Vol. 16 No.1)

was less water in the disc. It had a frequency of 43 per cent among the LDD subjects and its presence increased the likelihood of developing LDD by 30 per cent. The findings were published in the Journal of Clinical Investigation . “For the first time, we have shown the key functional link between this variant form of the CHST3 gene and LDD,” Professor Chan said. “There’s also a clear correlation from our genetic study showing that the more severe the degeneration, the more severe the pain.” Searching for other culprits Research is now turning to more detailed investigations of the risk and protective factors in LDD. The 3,500 cohort is receiving a second round of MRIs to see who has experienced disc degeneration. Professor Chan and his colleagues are also casting their net wider to see if they can identify more susceptibility genes, under a HK$74.5 million Theme-based Research Scheme to analyse genomic variations in degenerative skeletal disorders. “We want to understand a group of individuals who are rapid progressors – individuals with some genetic factors that mean once discs become bad, they become very bad, very quickly. Drug companies are also interested because if they want to test a drug, they don’t want to wait 10 or 15 years, they want to see an outcome in two or five years. “We also want to look at protective factors. Some people do not have disc degeneration or they have a bad disc but no pain. Why is that? Because at the end of the day, that is the issue – the pain.” Ultimately, they hope to improve prospects for patients who have few options for treatment or alleviating their pain. “At the moment, disc problems are treated with surgery,” Professor Chan said. “It’s a salvage operation, not a cure. That’s why clinicians really want a biological treatment.” Every little step in that direction will help as HKU researchers continue their investigations into back pain. people from the general population. The researchers recruited 3,500 subjects in Hong Kong and worked with collaborators in Finland and Japan who were also studying genetic variations in their populations. Magnetic resonance imaging (MRI) was conducted on each of the subjects to determine their degree of disc degeneration and establish the overall level of degeneration in the population. Then, genetic investigations were undertaken on 4,043 individuals from families with early-onset and severe LDD and 28,000 control subjects, encompassing southern Chinese, northern Chinese, Finnish and Japanese subjects. The team scanned through their entire genome, SNP by SNP (a SNP, or single- nucleotide polymorphism, is a variation in a DNA sequence), and pinpointed a likely cause from among 850,000 SNPs related to the damaged discs. The variant they found was in a gene that codes for the enzyme carbohydrate sulfotransferase 3 (CHST3), which helps to keep the disc hydrated so it maintains a gel-like property and can act as a shock absorber. The variant changed the amount of CHST3 so there Healthy Degenerated Disc signal intensity loss Disc bulge Modic changes Schmorl ' s nodes Most of us will suffer low back pain as we get older, but some will experience greater pain than others and some will suffer well before they hit middle age. All of that means there is something more going on than simple ageing. So what exactly is the cause of the lumbar disc degeneration (LDD) that causes back pain? Researchers in the Li Ka Shing Faculty of Medicine have been pursuing that question, with some important success. Starting more than a decade ago, under the umbrella of a HK$50 million Area of Excellence scheme on developmental genomics and the skeleton, a team of scientists, clinicians and geneticists began working painstakingly to recruit a large population cohort, examine each individual’s degree of disc degeneration, and sift through the hundreds of thousands of genetic variations related to the discs to uncover a likely cause of degeneration. Recently they identified a genetic risk variant among LDD patients, which was discovered in a study led by Professor Danny Chan and Dr Song Youqiang, both of the Department of Biochemistry. It is not likely the only variant, but the finding is important in helping to fill out the picture of the causes of LDD. “To understand the cause of disc degeneration is tough work,” Professor Chan said. “By the time it becomes apparent, you are already looking at the end stage. You can’t look at the early stage because you can’t remove pieces of young people’s spines to study them. This is where genetics come in.” Thousands of subjects Earlier studies on twins had pointed to a genetic cause but no one had done a population cohort study before – recruiting Investigations into the genetic causes of low back pain have yielded an important discovery. THE BACK TRACKERS Disc degeneration, which leads to back pain, can be caused by various factors including obesity, metabolism, ageing and genetics. Professor Chan’s team conducted magnetic resonance imaging (MRI) on each of the 3,500 subjects in Hong Kong to determine their degree of disc degeneration. To understand the cause of disc degeneration is tough work. By the time it becomes apparent, you are already looking at the end stage. You can’t look at the early stage because you can’t remove pieces of young people’s spines to study them. This is where genetics come in. Professor Danny Chan 18 | 19 The University of Hong Kong Bulletin | December 2014 Research