Comprehensive linkage and association analyses identify haplotype, near to the TNFSF15 gene, significantly associated with spondyloarthritis

• Published in: PLoS genetics 2009-06, Vol.5 (6), p.e1000528-e1000528
• Main Authors: Zinovieva, Elena, Bourgain, Catherine, Kadi, Amir, Letourneur, Franck, Izac, Brigitte, Said-Nahal, Roula, Lebrun, Nicolas, Cagnard, Nicolas, Vigier, Agathe, Jacques, Sébastien, Miceli-Richard, Corinne, Garchon, Henri-Jean, Heath, Simon, Charon, Céline, Bacq, Delphine, Boland, Anne, Zelenika, Diana, Chiocchia, Gilles, Breban, Maxime
• Format: Article
• Language: English
• Subjects: Adult; Case-Control Studies; European Continental Ancestry Group - genetics; Female; Genes; Genetic Predisposition to Disease; Genetics; Genetics and Genomics/Genetics of Disease; Genetics and Genomics/Medical Genetics; Genomes; Genomics; Haplotypes; Humans; Immunology/Genetics of the Immune System; Inflammatory bowel disease; Linkage Disequilibrium; Male; Middle Aged; Pedigree; Polymorphism, Single Nucleotide; Psoriasis; Rheumatology/Autoimmunity, Autoimmune, and Inflammatory Diseases; Rheumatology/Inflammatory and Psoriatic Arthritis; Spondylarthritis - genetics; Tumor Necrosis Factor Ligand Superfamily Member 15 - genetics
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1000528

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 x 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