Fragmentation of Two Quantitative Trait Loci Controlling Collagen-Induced Arthritis Reveals a New Set of Interacting Subloci

Abstract

Linkage analysis of F2 crosses has led to identification of large numbers of quantitative trait loci (QTL) for complex diseases, but identification of the underlying genes has been more difficult. Reasons for this could be complications that arise from separation of interacting or neighboring loci. We made a partial advanced intercross (PAI) to characterize and fine-map linkage to collagen-induced arthritis in two chromosomal regions derived from the DBA/1 strain and crossed into the B10.Q strain: Cia7 on chromosome 7 and a locus on chromosome 15. Only Cia7 was detected by a previous F2 cross. Linkage analysis of the PAI revealed a different linkage pattern than the F2 cross, adding multiple loci and strong linkage to the previously unlinked chromosome 15 region. Subcongenic strains derived from animals in the PAI confirmed the loci and revealed additional subloci. In total, no less than seven new loci were identified. Several loci interacted and three loci were protective, thus partly balancing the effect of the disease-promoting loci. Our results indicate that F2 crosses do not reveal the full complexity of identified QTLs, and that detection is more dependent on the genetic context of a QTL than the potential effect of the underlying gene.

Definition of arthritis candidate risk genes by combining rat linkage-mapping results with human case-control association data

“…This mapping resolution is high compared to previous results in arthritis using AIL, or partial AIL,45 46 47 48 49 and it approaches the mapping results for Ncf1 and APLEC in congenic strains (<0.6Mb).…”

Identifying a major locus that regulates spontaneous arthritis in IL-1ra-deficient mice and analysis of potential candidates

“…We did not obtain as many QTLs for spontaneous arthritis compared to studies using models of CIA (Otto et al ., 1999; Yu et al ., 2006; Ahlqvist et al ., 2007). One possible explanation is that CIA may be regulated by more QTLs than spontaneous arthritis under IL-1ra deficiency.…”

“…identified a total of 12 separate QTLs associated with proteoglycan-induced arthritis (Otto et al ., 1999) and MHC-independent QTLs (Otto et al ., 2000). Many QTLs have been finely mapped (Backdahl et al ., 2003; Yu et al ., 2006; Ahlqvist et al ., 2007), and their potential molecular mechanisms and interactions have been studied (Bahabri et al ., 1998; Adarichev et al ., 2003; Glant et al ., 2004; Johannesson et al ., 2005; Martin et al ., 2005; Jensen et al ., 2006; Laragione et al ., 2007). For example, Yu et al .…”

“…Genes that regulate QTL including neutrophil cytosolic factor-1 and Forkhead box O3A were also studied (Olofsson et al ., 2003; Jonsson et al ., 2005). Many QTLs have also been identified from mice, mainly from CIA models (Otto et al ., 1999; Martinez et al ., 2001; Hegen et al ., 2003; Yu et al ., 2006; Ahlqvist et al ., 2007). …”

Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis

“…79 Large rodent offspring generated in experimental intercrosses facilitated the identification of epistatic loci outside the MHC (Cia7 with Cia26) 80 and between MHC and non-MHC CIA and AIA loci. [40][41][42] Furthermore, studies in advanced intercross lines, 72,81 bi-congenic 82 and subcongenic strains 31 identified interacting loci in different chromosomes or within the same chromosome. Therefore, epistatic interactions and their functional characterization can be more easily and convincingly characterized in rodents and subsequently tested in RA in a gene-gene specific manner.…”