Presentation: Fine Mapping across the MHC with 2,095 SNPs Identifies at least Two Regions of Susceptibility Independent of the DRB1 Locus (2007)

850 Fine Mapping across the MHC with 2,095 SNPs Identifies at least Two Regions of Susceptibility Independent of the DRB1 Locus

PURPOSE: In order to identify putative RA susceptibility genes that are present in the Class I or central MHC regions we performed a case-control association study using a dense SNP map across the extended MHC region.
METHODS: RA cases (N=833) from the North American Rheumatoid Arthritis Consortium (NARAC) and the National Inception Cohort of Rheumatoid Arthritis Patients, and 1251 matched controls were studied. Broad level HLA-DRB1 typing and high-resolution DRB1*04 typing were performed in all samples. We tested a total of 2095 SNPs across 7.5Mb MHC locating from 6p22.2 (26.03 Mb) to 6p21.32 (33.59 Mb) derived from the Illumina 550K Beadchip. We used PHASE and fastPHASE to reconstruct major haplotypes and measured LD of SNPs with major DRB1 types using HelixTree 5.0.2 software.
RESULTS: For an initial analysis, we analyzed a subset of the data by matching cases and controls by DRB1 genotype (both alleles matched one to one) 443 cases with 443 controls. This avoids spurious signals that may arise from linkage disequilbrium between DRB1 alleles and other regions in the MHC. This analysis revealed the presence of several regions of association with RA, independent of DRB1 genotype. We also observed extended LD on many DR3 haplotypes, reflecting the relatively high frequency of the A1-B8-DR3 (8.1) haplotype in this caucasian population. Using tagging SNPs corresponding to the 8.1 haplotype, we identified a region of approximately 300kb in the central MHC from MICA to TNF that is associated with RA, independent of DR3 or any other DRB1 allele (p~10-15). This confirms our previous findings based on microsatellite typing which suggested the presence of additional risk genes on a segment of 8.1 haplotype within central MHC. In addition, we identified risk haplotypes within the class I region that are associated with RA, and are commonly, but not exclusively, found on DRB1*0404 risk haplotypes. Resequencing of candidate genes within these two regions is underway, in order to identify the specific risk alleles.
CONCLUSION: Using state-of-the art dense SNP mapping technologies, we confirmed the presence of at least two independent risk regions in the central MHC and class I regions, emphasizing the complexity of MHC associations with RA, independent of the classical DRB1 alleles.

 H. Lee, None.

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