Background Spondyloarthritis (SpA) is a chronic inflammatory disorder with high heritability but with complex genetics. Besides the major histocompatibility complex (MHC), more than 25 loci have already been associated to the disease using an unrelated case-control design but they explain only a minor fraction of total heritability.
Objectives We conducted a family-based genome-wide association study (GWAS) to identify new non-MHC genetic factors associated with SpA.
Methods Nine hundred and six subjects from 156 French multiplex families, including 438 affected with SpA, were genotyped using Affymetrix 250K microarray. After quality control, 230,801 single-nucleotide polymorphism (SNPs) were kept for further analyses. Association was tested with Unphased. The best-associated non-MHC SNPs were then genotyped sequentially in two independent familial trio cohorts, one from France and the other from North America (including 215 and 294 subjects, respectively) in order to replicate associations.
Results Forty-three non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1x10-4). In the extension studies, association was replicated at a nominal p-value <0.05 for 16 SNPs in the second cohort and for 3 of these 16 SNPs in the third cohort. Pooled analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=6.2 x 10-7). Such association was independent of HLA-B27.
Conclusions We report here for the first time a family-based GWAS study on SpA and identified a highly associated polymorphism in MAPK14 that codes for the p38-a MAP kinase, a key kinase in immune cell signalling. Further analyses are needed to understand the functional significance of this genetic association.
Disclosure of Interest None declared