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A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis


Osteoarthritis (MIM 165720), characterized by degeneration of articular cartilage, is the most common form of human arthritis and a major concern for aging societies worldwide1,2,3. Epidemiological and genetic studies have shown that osteoarthritis is a polygenic disease1,4,5. Here, we report that the gene encoding growth differentiation factor 5 (GDF5) is associated with osteoarthritis in Asian populations. A SNP in the 5′ UTR of GDF5 (+104T/C; rs143383) showed significant association (P = 1.8 × 10−13) with hip osteoarthritis in two independent Japanese populations. This association was replicated for knee osteoarthritis in Japanese (P = 0.0021) and Han Chinese (P = 0.00028) populations. This SNP, located in the GDF5 core promoter, exerts allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele showing reduced activity. Our findings implicate GDF5 as a susceptibility gene for osteoarthritis and suggest that decreased GDF5 expression is involved in the pathogenesis of osteoarthritis.

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Figure 1: LD blocks, genomic structures and allelic association around GDF5.
Figure 2: Analysis of GDF5 promoter activity in HCS-2/8 cells.

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We thank individuals for participating the study. We also thank K. Toyoshima, A. Kotani, K. Nakamura, A. Fukuda, A. Kawakami, H. Mototani and E. Nakashima for help in collecting samples and performing the experimental study and Y. Takanashi and T. Kusadokoro for technical assistance.

Author information

Authors and Affiliations



Y.M. performed the Japanese knee osteoarthritis association study and prepared the manuscript. A.M. performed the hip association study, in vitro functional assay and prepared the manuscript. D.S. performed the Chinese association study. T.K., Y.T., S.S., M.F., A.S., A.U., S.Y., K.O. and Y.N. managed DNA sample and clinical information, and contributed data interpretation. K.O. and M.T. contributed to cell experiments. T.T. contributed to data analysis and manuscript preparation. Q.J. managed the Chinese association study. S.I. planned and supervised the whole project.

Corresponding author

Correspondence to Shiro Ikegawa.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Confirmation of the allelic difference of rs143383 (+104C/T) in OUMS-27 and HeLa cells (PDF 73 kb)

Supplementary Table 1

Initial association of GDF5 with osteoarthritis of the hip joint (PDF 20 kb)

Supplementary Table 2

Replication of association of GDF5 with osteoarthritis of the hip joint in an independent population (PDF 20 kb)

Supplementary Table 3

List of polymorphisms in GDF5 and flanking regions (PDF 24 kb)

Supplementary Table 4

Clinical parameters and and the genotype of rs143383 (+104T/C) (PDF 19 kb)

Supplementary Table 5

Association of rs143383 with osteoarthritis after stratification by sex (PDF 95 kb)

Supplementary Table 6

Assessment of the population stratification (PDF 25 kb)

Supplementary Table 7

Haplotype association analysis (PDF 17 kb)

Supplementary Table 8

Clinical parameters (PDF 44 kb)

Supplementary Note (PDF 13 kb)

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Miyamoto, Y., Mabuchi, A., Shi, D. et al. A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat Genet 39, 529–533 (2007).

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