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New progress from a ‘joint’ venture

21.06.2010
The discovery of novel risk factors for osteoarthritis illuminates a probable role for the immune system in the pathology of this joint disorder

The debilitating knee, hip, wrist or back pain associated with osteoarthritis (OA) is commonplace within diverse populations around the world and represents a broadly recognized hallmark of old age, yet remarkably little is known about the origins of this disease.

Most evidence suggests that OA arises from a mix of genetic and environmental factors, but researchers of this disease, including Shiro Ikegawa of the RIKEN Center for Genomic Medicine in Tokyo, have found it a considerable challenge to uncover risk factor genes. “It is our long-standing dream to know the ‘real cause’ of this disease,” says Ikegawa, “but it has proven very difficult.”

Advances in techniques for genomic analysis have now enabled his group and a team of collaborators from across Japan and Europe to achieve an important breakthrough on this front1. They screened over 4,000 Japanese individuals—906 with OA of the knee, and 3,396 unaffected control subjects—in an effort to identify genome sequence variations that exhibit a statistically significant association with this condition. Of fifteen candidates identified in this initial search, two of these ‘single nucleotide polymorphisms’ (SNPs) warranted further close scrutiny.

Unexpectedly, the researchers found that both of these SNPs are located within a region of chromosome 6 containing numerous genes involved in the immune response: the rs7775228 variation occurs near genes that help instruct immune cells to ignore host proteins, while rs10947262 falls within a gene that controls T cell activation. “OA has long been thought of as having only limited association with immunological abnormalities,” explains Ikegawa, “but it turns out this is not the case.” These results are also in keeping with a handful of recent studies that have hinted at an inflammatory component of OA pathology.

Intriguingly, the team noted that simultaneous variations at both sites were more significantly associated with OA among Japanese subjects than either of the two SNPs individually. On the other hand, the disease association of this particular combination of SNPs—also known as a ‘haplotype’—was less notable among a European sample group.

Many more risk factors likely remain to be discovered—including some that may be specific to OA affecting individual body parts—and Ikegawa and colleagues are now moving on to larger scale association studies to characterize additional genes. He adds that such efforts are only a beginning. “Association is just statistics,” he says. “After finding associations, we need to prove functionality of the genes and SNPs to achieve our final goal of treating OA.”

The corresponding author for this highlight is based at the Laboratory for Bone and Joint Disease, RIKEN Center for Genomic Medicine

Journal information

1. Nakajima, M., Takahashi, A., Kou, I., Rodriguez-Fontenla, C., Gomez-Reino, J.J., Furuichi, T., Dai, J., Sudo, A., Uchida, A., Fukui, N. et al. New sequence variants in HLA Class II/III region associated with susceptibility to knee osteoarthritis identified by genome-wide association study. PLoS ONE 5, e9723 (2010)

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Further information:
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Further reports about: Medicine SNP genomic immune cell risk factor single nucleotide polymorphism

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