Alternative titles; symbols
SNOMEDCT: 239873007; ICD10CM: M17, M17.9;
Cytogenetic location: 3p24.3 Genomic coordinates (GRCh38): 3:16,300,001-23,800,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p24.3 | {Osteoarthritis susceptibility 6} | 612401 | 2 |
For a phenotypic description and a discussion of genetic heterogeneity of osteoarthritis, see OS1 (165720).
In a case-control genomewide association study for knee osteoarthritis using approximately 100,000 single-nucleotide polymorphisms (SNPs) and involving 3,586 individuals, Miyamoto et al. (2008) found strongest association with SNPs on chromosome 3p24.3 in the novel gene DVWA (COL6A4P1; 612397). Several DVWA SNPs were significantly associated with knee osteoarthritis in 2 independent Japanese case-control cohorts. This association was replicated in a Japanese population cohort and in a Han Chinese case-control cohort (combined P = 7.3 x 10(-11)). DVWA protein binds to beta-tubulin (TUBB; 191130), and the binding is influenced by 2 highly associated missense SNPs in almost complete linkage disequilibrium, rs11718863 (Y169N) and rs7639618 (C260Y), located in the second von Willebrand factor A (VWA) domain of the DVWA protein. The tyr169-cys260 isoform of DVWA, which was overexpressed in knee osteoarthritis, showed weaker interaction with beta-tubulin than 3 other tested isoforms.
Meulenbelt et al. (2009) genotyped 1,120 knee osteoarthritis (OA) cases, 1,482 hip OA cases, and 2,147 controls, all of white European descent, at 3 SNPs (rs7639618, rs11718863, and rs9864422) in the DVWA gene. Metaanalysis including data from Miyamoto et al. (2008) provided evidence for global association of rs7639618 with knee OA (odds ratio of 1.29, p = 2.70 x 10(-5)). This effect, however, showed moderate heterogeneity, and rs7639618 was not independently associated with knee OA in Europeans. No association was observed with hip OA in Europeans. The authors suggested that there may be global relevance for rs7639618 among knee OA cases; however, the apparent lower effect size in combination with the higher risk allele frequency in the European samples highlighted the ethnic differences in effects of discovered OA susceptibility genes.
Meulenbelt, I., Chapman, K., Dieguez-Gonzalez, R., Shi, D., Tsezou, A., Dai, J., Malizos, K. N., Kloppenburg, M., Carr, A., Nakajima, M., van der Breggen, R., Lakenberg, N., Gomez-Reino, J. J., Jiang, Q., Ikegawa, S., Gonzalez, A., Loughlin, J., Slagboom, E. P. Large replication study and meta-analyses of DVWA as an osteoarthritis susceptibility locus in European and Asian populations. Hum. Molec. Genet. 18: 1518-1523, 2009. [PubMed: 19181678] [Full Text: https://doi.org/10.1093/hmg/ddp053]
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 Genet. 40: 994-998, 2008. [PubMed: 18622395] [Full Text: https://doi.org/10.1038/ng.176]