Genetic variation including nonsynonymous polymorphisms of a major aggrecanase, ADAMTS-5, in susceptibility to osteoarthritis.

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.

• Authors: Julio Rodriguez-Lopez, Zehra Mustafa, Manuel Pombo-Suarez, Konstantinos N Malizos, Ignacio Rego, Francisco J Blanco, Aspasia Tsezou, John Loughlin, Juan J Gomez-Reino, Antonio Gonzalez
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 58 Issue 2 Pg. 435-41 (Feb 2008) ISSN: 0004-3591 [Print] United States
• PMID: 18240210 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ADAM Proteins
• ADAMTS5 Protein
• ADAMTS5 protein, human

Topics

• ADAM Proteins (genetics)
• ADAMTS5 Protein
• Aged
• Female
• Genetic Predisposition to Disease
• Genetic Variation
• Haplotypes
• Humans
• Linkage Disequilibrium
• Male
• Middle Aged
• Osteoarthritis (genetics)
• Polymorphism, Single Nucleotide