Abstract
Spondyloarthritis (SpA) is a chronic inflammatory disorder with a strong genetic predisposition dominated by the role of HLA-B27. However, the contribution of other genes to the disease susceptibility has been clearly demonstrated. We previously reported significant evidence of linkage of SpA to chromosome 9q31–34. The current study aimed to characterize this locus, named SPA2. First, we performed a fine linkage mapping of SPA2 (24 cM) with 28 microsatellite markers in 149 multiplex families, which allowed us to reduce the area of investigation to an 18 cM (13 Mb) locus delimited by the markers D9S279 and D9S112. Second, we constructed a linkage disequilibrium (LD) map of this region with 1,536 tag single-nucleotide polymorphisms (SNPs) in 136 families (263 patients). The association was assessed using a transmission disequilibrium test. One tag SNP, rs4979459, yielded a significant P-value (4.9×10−5). Third, we performed an extension association study with rs4979459 and 30 surrounding SNPs in LD with it, in 287 families (668 patients), and in a sample of 139 cases and 163 controls. Strong association was observed in both familial and case/control datasets for several SNPs. In the replication study, carried with 8 SNPs in an independent sample of 232 cases and 149 controls, one SNP, rs6478105, yielded a nominal P-value<3×10−2. Pooled case/control study (371 cases and 312 controls) as well as combined analysis of extension and replication data showed very significant association (P<5×10−4) for 6 of the 8 latter markers (rs7849556, rs10817669, rs10759734, rs6478105, rs10982396, and rs10733612). Finally, haplotype association investigations identified a strongly associated haplotype (P<8.8×10−5) consisting of these 6 SNPs and located in the direct vicinity of the TNFSF15 gene. In conclusion, we have identified within the SPA2 locus a haplotype strongly associated with predisposition to SpA which is located near to TNFSF15, one of the major candidate genes in this region.
Highlights
Spondyloarthritis (SpA) is one of the most frequent varieties of articular inflammatory disorders with an estimated prevalence of 0.3% in the western European adult population [1]
Depending on its clinical features, SpA is classically subdivided into the following subsets: ankylosing spondylitis (AS), which is the prototypical form characterized by predominant axial skeletal involvement and advanced radiographic sacroiliitis, psoriatic arthritis (PsA), arthritis associated with inflammatory bowel disease (AIBD), reactive arthritis (ReA), and undifferentiated SpA
The MHC class I HLA-B27 allele is a very strong risk factor for its development, but other genetic factors located outside the MHC play a role in disease susceptibility
Summary
Spondyloarthritis (SpA) is one of the most frequent varieties of articular inflammatory disorders with an estimated prevalence of 0.3% in the western European adult population [1]. It is characterized by a predominant axial skeleton inflammation, by a frequent occurrence of enthesitis and peripheral arthritis, and by a high rate of extra-articular features, the most characteristic of which are acute anterior uveitis, psoriasis, and inflammatory bowel diseases (such as ulcerative colitis or Crohn’s disease (CD)) [2]. We have previously shown, by analyzing a large number of pedigrees with multiple cases of SpA, that all subtypes are likely to be determined by a core set of predisposing factors and may be studied together in genetic studies [3,4,5].
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