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Pinpointing susceptibility to knee arthritis

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Identification of a previously unknown gene linked to knee arthritis provides new therapeutic target

Molecular geneticists in Japan and China have identified a previously unknown gene associated with susceptibility to osteoarthritis (OA), a common disease affecting the functioning of knee and hip joints through abnormal wearing of the cushioning cartilage. The researchers have named the newly identified gene DVWA (double von Willebrand factor A) and suggest that it codes for a protein involved in the formation of cartilage. The discovery could lead to genetic diagnosis of some forms of knee OA, and possible development of a therapeutic drug.

More than one adult in 10 over the age of 50 suffers from OA, a painful condition that restricts movement. Genetic susceptibility to OA is largely a mystery, although a few genes are already known to be associated with it.

In a recent paper in Nature Genetics (1), researchers from RIKEN’s Center for Genomic Medicine in Tokyo and Yokohama together with colleagues from several medical schools describe how they screened about 100,000 point mutations or single nucleotide polymorphisms (SNPs) from the Japanese SNP database to find the previously unknown gene.

Initially the researchers screened the genomes of 94 Japanese sufferers of knee OA and about 650 controls against the whole set of SNPs. About 2% of these SNPs were significantly correlated with OA. These were then tested against the genomes of an independent group of about 900 Japanese OA patients and 1,100 controls, and a third group of more than 400 Han Chinese OA sufferers and a similar number of controls. Several of the SNPs significantly associated with knee OA occurred in the DVWA gene. This association was independent of age, body mass index and sex.

The researchers determined in the laboratory that the DVWA protein binds to a protein building block of microtubules, â-tubulin. Microtubules are structural components of cells, which are associated with internal transport and have also been reported to play a role in the differentiation of cartilage-forming cells. Two of the SNPs of DVWA significantly weaken its protein product’s capacity to bind to â-tubulin.

“We are now planning to check the replication of our results in other ethnic groups to examine whether DVWA is a ‘global’ gene or not,” says Shiro Ikegawa, who led the research project. “And we also intend to clarify our proposed molecular mechanism as to how SNPs of the gene make people susceptible to OA.”

1. Miyamoto, Y., Shi, D., Nakajima, M., Ozaki, K., Sudo, A., Kotani, A., Uchida, A., Tanaka, T., Fukui, N., Tsunoda, T., Takahashi, A., Nakamura, Y., Jiang, Q. & Ikegawa, S. Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis. Nature Genetics 40, 994–998 (2008).

Saeko Okada | Quelle: ResearchSEA
Weitere Informationen: www.rikenresearch.riken.jp/research/557/
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