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Chinese Population Study Finds Genetic Mutation in Lumbar Disc Degeneration



INVESTIGATORS involved in the gene sequencing study are (from the left) Drs. Song You-qiang, Kenneth Cheung Man-chee, Kathryn Cheah, Sham Pak-Chung, and Danny Chan.

Independent linkage and genome-wide association studies identified a single nucleotide polymorphism, or SNP, on chromosome 10 at the site (loci) of a gene that encodes for the enzyme carbohydrate sulfotransferase 3 (CHST3), in families with a history of early-onset lumbar disc degeneration.

The largest genome-wide association study to date has found a common mutation in individuals with early-onset lumbar disc degeneration. The mutation compromises the ability of a key enzyme that provides hydration to the jelly-like protective padding within discs which protects them from compressive damage.

An international research team led by scientists at the University of Hong Kong reviewed 4,043 cases of lumbar disc degeneration (LDD), and compared their genetic and association data with those of 28,599 control subjects.

All patients (cases and controls) underwent MRI scans of the lumbar spine and the results were graded using the Schneiderman classification system, which is based on research showing that MRI has 99 percent accuracy in detecting abnormal disc degeneration. LDD was diagnosed based on signal intensity changes within the nucleus pulposus of those with intervertebral disc degeneration, including lumbar disc herniation and radiculopathy.

Cohorts were recruited on the basis of lumbar disc herniation characterized by radiculopathy requiring surgical treatment, but without necessarily having had surgery.

Independent linkage and genome-wide association studies (GWAS) identified a single nucleotide polymorphism, or SNP, on chromosome 10 at the site (loci) of a gene that encodes for the enzyme carbohydrate sulfotransferase 3 (CHST3), in families with a history of early-onset LDD.

Heterozygous individuals with mutations in CHST3 showed early indication of disc abnormalities consistent with degeneration. In a cohort of 669 cases with LDD and 5,306 control individuals, the rs1245582 mutation was associated with a risk ratio of 1.20, or twice the risk.

The team looked at early-onset cases to reduce the chance of heterogeneity — when a single disorder may be caused by any one of a number of mutations — and because heterogeneity tests were not found to be significant.

“With respect to our Southern Chinese population cohort, their LDD scores with age adjustment were considered to be mild for their age group (30–35 years old). They would therefore be considered to have earlier onset of disc degeneration resulting from reduced CHST3 activity. This is consistent with our hypothesis that reduced expression of CHST3 mRNA is a risk factor for LDD,” the authors wrote in the report published in the Nov. 1 issue of the Journal of Clinical Investigation.


The enzyme CHST3 catalyzes proteoglycan sulfation. LDD is often characterized by the gradual loss of proteoglycan. The enzyme is integral in maintaining sufficient water content within the nucleus pulposus, a soft, gelatinous substance that hydraulically distributes pressure in all directions within each disc. As it gradually loses the ability to retain water, compressed discs can become damaged and progressively degenerate, often resulting in chronic back pain and radiculopathy.

Although some genetic mutations have been reported in patients with LDD, the etiology of the disorder remains largely unknown. Millions of individuals suffer from the LDD, especially older persons; however it is generally attributed to normal aging of spinal discs and vertebrae.

“While we have shown a strong association between lumbar disc degeneration and back pain, and genetic diagnosis may be a possibility in the future, more work will be needed before this [is confirmed] and screening methods are initiated,” lead author and team geneticist Song You-qiang, PhD, an associate professor of biochemistry at the University of Hong Kong, in Pokfulam, told Neurology Today in an e-mail.

His colleague Danny Chan, PhD, an associate professor of biochemistry and an expert in bone and cartilage matrix biology, added, “Our findings provide a key functional link of this variant form of the CHST3 gene to lumbar disc degeneration, and this variant is likely to affect hydration and function of the disc tissue.”

Kenneth Cheung, MD, professor of orthopedics and chief of the department of orthopedics and traumatology, said the findings indicate that intervertebral disc degeneration is not simply a matter of normal aging or wear and tear, but that genetic factors are involved.


The strongest genome-wide linkage was observed in one Chinese family, but a meta-analysis in multiethnic population groups also identified the same site (rs4148941) in the CHST3 gene, the researchers reported.

Because rs4148941 lies within a potential microRNA (mRNA) binding site, the scientists next examined in vitro the interaction between mRNA transcribed from the susceptibility allele of rs4148941. Once enhanced and compared with transcripts from other alleles, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of subjects carrying the allele.

Using a four-stage GWAS allowed the identification of the SNP (rs1245582) as being closely associated with LDD, with CHST3 as the nearest gene. This technique also helped reduce the likelihood of false-positive associations, with population stratification in the first stage and reduction in number of SNPs required for genotyping in the second stage.

While there was an age difference between LDD cases and control groups in the first two stages, it was not a confounding factor, according to the analysis, with the association remaining significant after being adjusted not only for age, but also gender and body mass.

In the third and fourth stages, the rs1245582 SNP did not show significant association, except in one study cohort, but when the significance threshold was set to p<0.05, the risk allele frequency showed a common trend throughout all LDD cases, the researchers said.

“The fact that [the SNP] was within a large LD block that contained only CHST3 provided us with a match in the gene list from our linkage analysis, and the confidence to carry out a detailed association study that substantiated CHST3 as a novel risk factor with genome-wide statistical significance,” they wrote.


“This is a really exciting study,” said James C. Iatridis, PhD, professor of orthopedics and neurosurgery, and director of Spine Research at the Icahn School of Medicine at Mount Sinai in New York City. “The role of genetics in LDD is well-known, but this study got my attention because of the rigor of the analysis and the relevance of their findings, which makes sense from a disc degeneration perspective,” he told Neurology Today in a telephone interview.

“A mutation of CHST3 on chromosome 10 may be a causative factor in LDD since it can disrupt proteoglycan sulfation, and one of the earliest changes with LDD is loss of proteoglycan and water in the nucleus pulposus.”

The findings were also robustly analyzed to avoid false positives, he noted.

“This is encouraging, but all genetic studies need to be validated within multiple populations.”

Currently there are few treatments for lumbar degeneration until late-stage disease, when spinal fusion may be indicated, but with identification of a susceptibility gene treatment may be able to begin earlier, and be less invasive in affected individuals, he told Neurology Today.

“The ability to identify patients is the big question though,” noted Dr. Iatridis. “Today there is no good way to identify them. To identify a potential gene at least gives us a vision and, if the findings are confirmed, this could give us a good road map.”


•. Song YQ, Karasugi T, Cheung MC, et al. Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant. J Clin Invest 2013;123:4909–4917.
•. Unger S, et al. Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features. Am J Med Genet 2010;152A:2543–2549.
•. Jim JJ, et al. The TRP2 allele of COL9A2 is an age-dependent risk factor for the development and severity of intervertebral disc degeneration. Spine 2005;30:2735–2742.