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Invited Review

Quest for arthritis-causative genetic factors in the rat

Physiological Genomics Laboratory, Department of Physiology, Pharmacology, Metabolism and Cardiovascular Sciences, University of Ohio Health Science Campus, Toledo, Ohio

Experimental rat models of arthritis are extensively studied with a view to understand the genetic underpinnings of rheumatoid arthritis (RA). Genome scans using these models have led to the detection of arthritis regulatory quantitative trait loci (QTLs) on all but three chromosomes of the rat. Whereas some of the QTLs are model specific, others overlap between models. Some arthritis susceptibility and/or severity QTLs identified by genetic linkage analyses are corroborated by substitution mapping using congenic strains, whereas others are not. In these cases, testing alternate arthritis models proved to be useful to identify QTL effects. Nevertheless, development and testing of congenic substrains containing progressively shorter introgressed regions have not only fine mapped the location of the arthritis QTLs but also resulted in the identification of multiple QTLs within several originally identified individual QTL. Most of these studies progressed rapidly since 2001, when the rat genome sequence was published. Proof of principle for substitution mapping as a successful method for QTL gene discovery is provided by the positional cloning of Ncf1 as one of the arthritis QTLs in rats. This finding is encouraging for similar sustained dissection of all the other arthritis QTLs mapped in the rat. Identification of rat arthritis QTLs is expected to pave the way for discovery of yet-unidentified arthritis-causative genetic elements and/or pathways for RA in humans and potential development of targeted therapeutics. This review catalogs some of the recent advances made in QTL discovery projects of experimentally induced rat models of arthritis.

gene; quantitative trait locus; linkage; congenic; inflammation; rheumatoid arthritis; substitution; mapping