A GENOME-WIDE SCREEN FOR SUSCEPTIBILITY LOCI IN ANKYLOSING-SPONDYLITIS

Objective. To localize the regions containing genes that determine sus ceptibility to ankylosing spondylitis (AS), Methods. One hundred five white British families with 121 affected sibling pairs with AS were re cruited, largely from the Royal National Hospital for Rheumatic Diseas es AS database, A genome-nide linkage screen was undertaken using 254 highly polymorphic microsatellite markers from the Medical Research Co uncil (UK) (MRC) set, The major histocompatibility complex (MHC) regio n was studied more intensively using 5 microsatellites lying within th e HLA class III region and HLA-DRB1 typing, The Analyze package was us ed for a-point analysis, and GeneHunter for multipoint analysis, Resul ts. When only the MRC set was considered, 11 markers in 7 regions achi eved a P value of less than or equal to 0.01. The maximum logarithm of odds score obtained was 3.8 (P = 1.4 x 10(-5)) using marker D6S273, w hich lies in the HLA class III region, A further marker used in mappin g of the MHC class III region achieved a LOD score of 8.1 (P = 1 x 10( -9)). Nine of 118 affected sibling pairs (7.6%) did not share parental haplotypes identical by descent across the MHC, suggesting that only 31% of the susceptibility to AS is coded by genes linked to the MHC. T he maximum non-MHC LOD score obtained was 2.6 (P = 0.0003) for marker D16S422. Conclusion. The results of this study confirm the strong link age of the MHC with AS, and provide suggestive evidence regarding the presence and locat ion of non-MHC genes influencing susceptibility to the disease.