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Genetic variation including nonsynonymous polymorphisms of a major aggrecanase, ADAMTS-5, in susceptibility to osteoarthritis
dc.creator | Rodriguez-Lopez, J. | en |
dc.creator | Mustafa, Z. | en |
dc.creator | Pombo-Suarez, M. | en |
dc.creator | Malizos, K. N. | en |
dc.creator | Rego, I. | en |
dc.creator | Blanco, F. J. | en |
dc.creator | Tsezou, A. | en |
dc.creator | Loughlin, J. | en |
dc.creator | Gomez-Reino, J. J. | en |
dc.creator | Gonzalez, A. | en |
dc.date.accessioned | 2015-11-23T10:46:31Z | |
dc.date.available | 2015-11-23T10:46:31Z | |
dc.date.issued | 2008 | |
dc.identifier | 10.1002/art.23201 | |
dc.identifier.issn | 0004-3591 | |
dc.identifier.uri | http://hdl.handle.net/11615/32664 | |
dc.description.abstract | Objective. Given the recent characterization of ADAMTS-5 as the main aggrecanase of cartilage destruction in mouse models, we explored whether genetic variation and, in particular, putative damaging polymorphisms in the ADAMTS-5 gene modify susceptibility to osteoarthritis (OA). Methods. Two likely deleterious nonsynonymous single-nucleotide polymorphisms (SNPs) were identified in ADAMTS-5 by bioinformatics analysis, rs2830585 in exon 5 affecting a thrombospondin 1 motif, and rs226794 in exon 7. Exploration of their role was carried out in 3 steps, discovery, extension, and replication, on samples obtained from 4 European Caucasian collections, comprising a total of 2,715 patients with knee, hip, or hand OA and 1,185 OA-free controls. In addition, 6 tagSNPs were studied to fully evaluate genetic variation in the ADAMTS-5 locus. Results. Initial analyses of 2 sample collections (n = 277 and n = 159) showed a trend toward decreased frequency of the putative deleterious allele of rs226794 among patients with severe knee OA (P = 0.047 versus controls). However, results in patients with knee OA from 2 additional sample collections (n = 360 and n = 265) did not confirm this trend. No association was found-with hip OA or hand OA. None of the other SNPs or haplotypes constructed with these SNPs showed a significant association with OA susceptibility. Conclusion. Use of several collections of OA samples allowed us to obtain sound evidence against the participation of genetic variation in ADAMTS-5 in OA susceptibility. These results indicate the need to further explore the function of this aggrecanase in human OA to determine whether it is as critical as has been observed in mouse models. | en |
dc.source.uri | <Go to ISI>://WOS:000253260700012 | |
dc.subject | CARTILAGE | en |
dc.subject | DEGRADATION | en |
dc.subject | ASSOCIATION | en |
dc.subject | ASPORIN | en |
dc.subject | REPEAT | en |
dc.subject | Rheumatology | en |
dc.title | Genetic variation including nonsynonymous polymorphisms of a major aggrecanase, ADAMTS-5, in susceptibility to osteoarthritis | en |
dc.type | journalArticle | en |
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