Non-MHC Risk Alleles in Rheumatoid Arthritis and in the Syntenic Chromosome Regions of Corresponding Animal Models

Figure 1

Summary of the genotypes and corresponding clinical phenotypes of parent stains and Pgia26 (3G0) and Pgia26 subloci that were identified in IVSC lines with overlapping chromosome intervals. The original mChr3 region (3G0: 90.4–156.5 Mbp in size) was reduced and separated into several subloci in 27 interval-specific subcongenic (IVSC) lines (3G1-3G27). For simplicity, only a 16.5 Mbp region is shown. Green columns represent BALB/c, and yellow columns represent the DBA/2 chromosome regions. Horizontal black lines with numbers at the right side (and with marker names) are shown. The short red lines crossing the IVSC chromosome region indicate the position between the two markers, where the DBA/2 allele continued as BALB/c [84]. The blue-framed red rectangular area indicates the position of the Pgia26d locus (between 101.4 and 107.2 Mbp); in the worst case, this region may include the entire flanking region between 99.9 and 108.8 Mbp where the disease-promoting gene(s) in BALB/c mice is located (or reciprocally, the suppressive genes in DBA/2). This area contains the most prominent Ptpn22 (protein tyrosine phosphatase non-receptor-22) identified in human GWAS with SNPs, an allele that is associated with many autoimmune diseases. The mutation affecting R620W amino acid appears to affect both peripheral and central B-cell tolerance [120]. Under the worst scenario, this region contains 128 protein-coding genes, 19 miRNAs, 13 pseudogenes, and 9 non-protein-coding transcripts (http://www.ensembl.org/Mus_musculus/Info/Index). Other Pgia26 subloci (with large scales) are presented in Figure 2 with the corresponding human, rat, and mouse RA risk alleles. Another disease-suppressive region (inherited from the DBA/2 strain), between 92.7 Mbp and 96.4/99.9 Mbp position (framed), is currently under sequencing and examination.