Objective More than 40 loci have been associated with ankylosing spondylitis (AS), but less is known about genetic associations in spondyloarthritis (SpA) as a whole. We conducted a family-based genome-wide association study (GWAS) to identify new non-major histocompatibility complex (MHC) genetic factors associated with SpA.
Methods 906 subjects from 156 French multiplex families, including 438 with SpA, were genotyped using Affymetrix 250K microarrays. Association was tested with Unphased. The best-associated non-MHC single nucleotide polymorphisms (SNPs) were then genotyped in two independent familial cohorts (including 215 French and 294 North American patients with SpA, respectively) to replicate associations.
Results 43 non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1×10−4). In the extension studies, association was replicated at a nominal p value of p<0.05 for 16 SNPs in the second cohort and for three SNPs in the third cohort. Combined analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=3.5×10−7). Such association appeared to be independent of HLA-B27.
Conclusions We report here for the first time a family-based GWAS study on SpA and identified an associated polymorphism near MAPK14. Further analyses are needed to better understand the functional basis of this genetic association.
- Ankylosing Spondylitis
- Gene Polymorphism
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Handling editor Tore K Kvien
MB and H-JG contributed equally.
Contributors All the authors contributed to the manuscript based on (1) substantial contributions to conception and design, acquisition of data or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published.
Funding This work was supported by grant from Agence Nationale de la Recherche (grant ANR 2010 GEMISA). Félicie Costantino was supported by a grant from the Société Française de Rhumatologie (SFR). Alice Talpin and Elena Zinovieva were supported by a grant from Arthritis Fondation Courtin.
Competing interests None declared.
Ethics approval Local ethical committees of Cochin Hospital (Paris, France), Ambroise Paré Hospital (Boulogne-Billancourt, France) and University of Texas Medical School (Houston, Texas, USA).
Provenance and peer review Not commissioned; externally peer reviewed.