Genomic linkage mapping in rats with and without induced arthritis has isolated a set of candidate risk genes for rheumatoid arthritis (RA) susceptibility in humans, report scientists.
Johnny Lorentzen, from the Karolinska Institute in Stockholm, Sweden, and co-authors explain that “a limiting factor in the comparative genetic approach is the time-consuming production of congenic strains for positional mapping.”
In view of this issue, the researchers aimed to define candidate risk genes in regions of rat (Rattus norvegicus) chromosomes 4 and 10 (RNO 4 and 10) that influenced experimental RA, and to determine corresponding human chromosomal regions that link to, and associate with, RA.
Lorentzen et al injected 422 AIL rats with pristane and genotyping of microsatellite markers was performed over genomic regions with documented impact on arthritis, located on chromosomes 4, 10, and 12.
Linkage between genotypes and phenotypes was determined by R/quantitative trait loci (QTL) and the potential association with RA of single nucleotide polymorphisms (SNPs) in homologous human chromosome regions was evaluated using data from the the Wellcome Trust Case Control Consortium (WTCCC).
The researchers found that a 57% high frequency of arthritis was observed in these rats and maximum linkage to pristane-induced arthritis occurred less than 130 kb from the known genetic arthritis determinants neutrophil cytosolic factor 1 (Ncfl) and the antigen-presenting lectin-like receptor gene complex (APLEC), thus demonstrating accurate mapping precision.
Five novel quantitative trait loci were mapped on chromosomes 4 and 10 (Pia27, Pia28, Pia29, Pia30, and Pia31, respectively) with narrow confidence intervals. The authors found that a subset of Pia 27, Pia 27a, and Pia 28 link to chronic arthritis in females.
The team concludes in the Annals of Rheumatic Diseases that “high-resolution mapping in AIL populations defines limited sets of candidate risk genes, some of which appear also to associate with RA and thus may give clues to evolutionarily conserved pathways that lead to arthritis.”