University of Oxford, Institute of Molecular Medicine, Oxford, UK
SIR, Primary osteoarthritis (OA) is a common multifactorial genetic disease, with heritability estimates ranging from 30 to 70% depending upon the joint site affected [1]. Several genome-wide linkage scans for OA susceptibility loci have been performed, with linkages reported to loci on chromosomes 2, 4, 6, 7, 11, 16 and the X [27]. Linkage of OA to chromosome 2q has been communicated in four independent studies: Wright et al. [2] reported linkage to markers mapping to 2q23q35 in 66 nodal OA sibling pairs ascertained in the Nottingham region of the UK; Leppävuori et al. [6] reported linkage to 2q12q21 in sibling pairs derived from 27 Finnish families that had a high prevalence of hand OA; our group reported linkage to 2q12q31 in 311 UK sibling pairs concordant for hip OA [5]; finally, a group from the Netherlands have identified linkage of early-onset, generalized OA to 2q24.3q32.3 in several large Dutch pedigrees in which the OA segregates as a Mendelian trait (Ingrid Meulenbelt, personal communication). Overall, these studies indicate that chromosome 2q harbours an OA susceptibility locus.
In our original linkage analysis of 2q we genotyped 16 microsatellite markers in 311 families that each contained at least one affected sibling pair concordant for hip OA ascertained by the need for hip replacement surgery (hip-only families) [5]. We obtained a maximum multipoint LOD score (MLS) of 2.2 between markers D2S117 and D2S325, which are located 201 and 211 cM from the 2p-telomere, respectively. However, there was some evidence for linkage across 50 cM of chromosome 2q. This implied that either more than one OA locus on chromosome 2q was segregating in our families or that there is only one locus, and that its position was poorly defined by our original study. The latter is a distinct possibility, as the original study employed a relatively crude microsatellite marker density of one marker every 8 cM, with relatively large gaps of up to 23 cM between certain markers.
As indicated in our previous report [5], it is essential that we distinguish between these two possibilities before embarking on time-consuming and expensive linkage disequilibrium/association analysis. Therefore, we have carried out a more refined linkage analysis of chromosome 2q in our hip-only families. This has involved: (i) a reassessment of the clinical status of the original 311 hip-only families to remove from the study seven families that are now considered to have had secondary OA or other forms of arthritis; (ii) an analysis of the full-sib status of our affected sibling pairs by the genotyping of 50 unlinked microsatellite markers (ftp://linkage.rockefeller.edu/software/relative/), which revealed that four of our original 311 hip-only families were comprised of half-sibs and which were therefore excluded; (iii) a reassessment of all 2q markers used in our original study to exclude two markers with ambiguous genome map positions (D2S202 and D2S72); (iv) an increase in the density of 2q markers genotyped to 28 markers, at an average spacing of one marker every 4.6 cM; (v) the inclusion of an additional 78 hip-only families, making a total cohort of 378 families that each contain at least one pair of affected siblings concordant for primary hip OA ascertained by hip replacement surgery.
This refined analysis suggests that there is only one OA susceptibility locus on 2q that is segregating in our hip-only families. This locus is located 175.5184.1 cM from the 2p-telomere, at 2q24.3q31.1, with an MLS of 1.6 between markers D2S2330 and D2S326 (Fig. 1). This linkage encompasses two of the three markers that were positive in the Wright et al. [2] study and overlaps with the linkage detected by the Netherlands group at 2q24.3q32.3. Therefore, it appears likely that the Nottingham group, the Netherlands group and our group have all identified the same 2q OA susceptibility locus. Our refined analysis has limited the size of the linked interval to 8.6 cM, which is narrow enough for linkage disequilibrium/association analysis to be undertaken. A search of the Ensembl database (http://www.ensembl.org/) reveals that approximately 85 known genes map within the 2q24.3q31.1 bands of chromosome 2q. None of these are obvious candidates in that they do not encode for structural or regulatory molecules of the cartilage extracellular matrix, suggesting that if an OA susceptibility gene does reside within this region of 2q, then it may encode for a protein involved in a novel disease pathway.
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Notes
Correspondence to: J. Loughlin, University of Oxford, Institute of Molecular Medicine, Oxford OX3 9DS, UK.
References
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