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High Resolution Mapping of Cia3: A Common Arthritis Quantitative Trait Loci in Different Species¹

Section of Immunogenetics, University of Rostock, Germany

Murine collagen induced arthritis (CIA) is a widely used model of rheumatoid arthritis (RA). Identification of CIA susceptibility genes will aid in the understanding of RA pathogenesis and development of therapeutic targets. This study aims to identify and refine quantitative trait loci (QTL) controlling CIA. Major CIA clinical traits were evaluated in both (DBA/1xFVB/N) F₂ and advanced intercross line (AIL) mice; QTLs were confirmed and refined in AIL. To search for candidate genes, we applied multiple approaches, including gene expression profiling, identification of nonsynonymous polymorphism, and comparative genomic mapping. We identified six suggestive QTLs controlling CIA clinical traits in the F₂ progeny; one of these was confirmed and refined in AIL. This QTL is located on chromosome 6 and overlaps with Cia3, which was identified previously. We refined the 2-log support interval of Cia3 into a 5.6 Mb genomic region; 15 of 77 genes are differentially expressed or carry nonsynonymous polymorphisms between two parental strains. The counterpart genomic region of Cia3 on the rat and human genomes are linked to RA. Twenty-nine of 77 genes are located in the arthritis-linked genomic regions of all three species. Five of those 29 genes are differentially expressed or carry nonsynonymous polymorphisms between parental strains: Timp4, Tmem40, Mbd4, Cacna1c, and Lrtm2. Taken together, we refined Cia3 into a 5.6 Mb genomic region on mouse chromosome 6 and identified candidate genes. This will aid in the search for susceptibility gene(s) controlling arthritis development within Cia3 and its counterpart regions in rat and human genomes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by the EU FP6 contract MRTN-CT-2004-005693 (EURO-RA).

² Address correspondence and reprint requests to Dr. Saleh M. Ibrahim at the current address: Genetics Group, Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. E-mail address: saleh.ibrahim{at}uk-sh.de

³ Abbreviations used in this paper: RA, rheumatoid arthritis; QTL, quantitative trait loci; CIA, collagen-induced arthritis; AIL, advanced intercross line; chr., chromosome; SNP, single nucleotide polymorphism.

⁴ The online version of this article contains supplementary material.