Presentation: Haplotype-Based Gene Mapping within Two Major Loci on Chromosomes 3 and 19 for Murine Proteoglycan-Induced Arthritis (PGIA) Identified Several Sub-Loci 2 Mb in Size (2007)

849 Haplotype-Based Gene Mapping within Two Major Loci on Chromosomes 3 and 19 for Murine Proteoglycan-Induced Arthritis (PGIA) Identified Several Sub-Loci 2 Mb in Size

PURPOSE: To search for genes causing murine proteoglycan-induced arthritis (PGIA), we developed a novel in silico method analyzing association between all available polymorphisms in murine strains and arthritis susceptibility.
METHODS: Mice from 12 murine strains were immunized with human cartilage proteoglycan aggrecan: 6 strains were susceptible to arthritis, and another 6 strains were resistant. Total serum antibody levels, antibody isotype composition, level of auto-antibodies to proteoglycan, production of IL-4 and IFN-gamma by lymphocytes stimulated with proteoglycan were measured. Analysis of association was performed with Fisher test and linear regression models implemented in “R” language for statistical computing using all available polymorphisms (~300,000) for chromosomes 3 and 19.
RESULTS: Chromosome 3-wide analysis of association between 170,000 single nucleotide polymorphisms (SNPs) and PGIA identified 3 chromosome intervals each less than 2 Mb in size. Each locus demonstrated highly significant (p < 10^-6) association with murine arthritis. Peaks were found within 123-125, 151-153, and 156-157 Mb intervals. Chromosome 19-wide association analysis (130,000 SNPs) identified single locus around 25 Mb significantly associated with PGIA (p < 10^-6). The locus size is 1.2 Mb, and it contains 16 genes. All newly-identified sub-loci align with the fine structure of loci on chromosomes 3 and 19, which were found earlier using genetic linkage analysis of the (BALB/c x DBA/2)F2 population.
CONCLUSIONS: Novel approach allows significant acceleration of positional cloning of genes controlling complex autoimmune diseases and direct advance to gene and intra-gene level.

 V.A. Adarichev, None; T.T. Glant, None.