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Different Species Common Arthritis High Resolution Mapping of Cia3: A Common Arthritis Quantitative Trait Loci in Different Species This information is current as Xinhua Yu, Haidong Teng, Andreia Marques, Farahnaz of September 27, 2021. Ashgari and Saleh M. Ibrahim J Immunol 2009; 182:3016-3023; ; doi: 10.4049/jimmunol.0803005 http://www.jimmunol.org/content/182/5/3016 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2009/02/18/182.5.3016.DC1 Material References This article cites 36 articles, 9 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/182/5/3016.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology High Resolution Mapping of Cia3: A Common Arthritis Quantitative Trait Loci in Different Species1 Xinhua Yu, Haidong Teng, Andreia Marques, Farahnaz Ashgari, and Saleh M. Ibrahim2 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/1 FVB/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 Downloaded from arthritis-linked genomic regions of all three species. Five of those 29 genes are differentially expressed or carry nonsynonymous poly- morphisms 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 Journal of Immunology, 2009, 182: 3016–3023. 3 heumatoid arthritis (RA) is a chronic inflammatory auto- defined as a QTL. Therefore, the number of susceptibility genes could http://www.jimmunol.org/ immune joint disease influenced by genetic and environ- be much larger than the number of the identified QTLs. On the other R mental factors (1). The genetic contribution to RA suscep- hand, identification of susceptibility genes within the QTLs is still a tibility is estimated to be as much as 60%, of which the HLA DRB1 challenging task, with the exceptions of few genes with very strong locus is thought to account for 30–50% (2, 3). However, identification effect on the disease, e.g., NCF1 (7). In most cases, a single quanti- of non-MHC RA susceptibility genes has been challenging due to tative trait gene contributes only mildly or moderately to the outcome genetic heterogeneity and incomplete penetrance, as well as the effect of the complex traits. To accelerate progress in the identification of of environmental factors on RA development. Presently, only a few susceptibility genes, several complementary approaches have been genes have been convincingly showed to be associated with RA, in- suggested, such as identification of polymorphisms in coding or reg- cluding PADI4, PTPN22, and CTLA4 (4, 5, 6). Genetic analysis of ulatory region, in vitro functional studies, transgenesis, knock-in mod- by guest on September 27, 2021 well-defined experimental models of autoimmune arthritis provides els, deficiency-complementation testing, mutational analysis, and ho- an alternative strategy to study the genetic basis of RA. A good ex- mology searches (10). In addition, advanced progress in mouse ample is identification of NCF1 as a novel susceptibility gene in au- genetics also accelerates progress in the identification of the quanti- toimmune arthritis (7). Animal models of RA have been used to iden- tative trait genes. For example, genomes of the 16 commonly used tify susceptibility genes, and multiple quantitative trait loci (QTLs) mouse inbred strains have been recently sequenced, and 8.27 million have been identified (see Ref. 8, 9). SNPs have been identified (11). Therefore, polymorphisms within a Despite the many advantages of animal models, identification of QTL identified in those 16 strains or their substrains can be obtained, susceptibility genes in animal models is limited by two factors. On which will considerably help in the identification of candidate genes. one hand, linkage analysis is not as powerful as case-control associ- Previously we performed a genome-wide linkage analysis in a F2 ation studies. As a consequence, a genomic region containing a sus- progeny to identify QTLs controlling collagen-induced arthritis (CIA) ceptibility gene that has very small effect on disease might not reach and generated an advanced intercross line (AIL) to refine those QTLs the significant threshold of the linkage analysis, and thus will not be (12, 13). In the F2 progeny, we identified one QTL with a strong effect on CIA clinical traits, Cia2, that contributes to only 16% of the phe- Section of Immunogenetics, University of Rostock, Germany notype variant (12). This suggests that there could be additional sus- ceptibility gene(s) whose effect is masked by Cia2, and thus failed to Received for publication September 10, 2008. Accepted for publication December 24, 2008. reach a significant threshold. In this study, we investigated six The costs of publication of this article were defrayed in part by the payment of page genomic regions that showed suggestive level of linkage to CIA in F2 charges. This article must therefore be hereby marked advertisement in accordance mice. We used the AIL to confirm those suggestive QTLs and refine with 18 U.S.C. Section 1734 solely to indicate this fact. the positive(s) into a small genomic region. Also, we investigated the 1 This study was supported by the EU FP6 contract MRTN-CT-2004-005693 candidate genes for one confirmed and refined QTL by defining dif- (EURO-RA). ferentially expressed genes, identifying the nonsynonymous polymor- 2 Address correspondence and reprint requests to Dr. Saleh M. Ibrahim at the current address: Genetics Group, Department of Dermatology, University of Lu¨beck, Ratzeburger phisms, and performing comparative genomic mapping. Allee 160, 23538 Lu¨beck, Germany. E-mail address: [email protected] 3 Abbreviations used in this paper: RA, rheumatoid arthritis; QTL, quantitative Materials and Methods trait loci; CIA, collagen-induced arthritis; AIL, advanced intercross line; chr., Phenotypic traits of CIA chromosome; SNP, single nucleotide polymorphism. ϫ Two mouse populations used in this study, 290 (DBA/1 FVB/N)F2 ϫ Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 mice and 308 (DBA/1 FVB/N)F11/12 AIL mice, were generated www.jimmunol.org/cgi/doi/10.4049/jimmunol.0803005 The Journal of Immunology 3017 Table I. List of QTLs controlling clinical traits of CIA Chr. Marker LOD Score Traits Susceptible Allele Overlap with CIA QTLs severity, onset, susceptibility DBA/1 Cia2, Cia4 ءءD2Mit81 10.4 2 severity FVB/N Cia3 ءD6Mit328 2.37 6 severity FVB/N ءD7Mit248 2.12 7 severity DBA/1 Cia8 ءD10Mit261 2.1 10 severity FVB/N Cia40 ءD11Mit126 2.08 11 susceptibility FVB/N ءD18Mit222 2.43 18 onset FVB/N ءD19Mit90 2.66 19 .suggestive ,ء highly significant and ,ءء previously in our laboratory. Detailed information of mice characteris- reevaluated using the scoring system that was applied in AIL mice (13). tics and induction of CIA were described previously (12, 13). Three The onset trait of the F2 and AIL mice were calculated previously (12, clinical traits of CIA were used for linkage analysis: severity, onset, and 13). Susceptibility is a qualitative trait, with a score of 0 and 1 for the susceptibility. The CIA severity (maximal score) in the F2 progeny was healthy and diseased mice, respectively. Table II. ANOVA analysis of chromosomes with evidence of linkage in F2 and AIL Downloaded from F2 mice AIL mice Chr. Markers Position (Mb) F p value Markersa Position (Mb) F p value 6 D6Mit67 97.7 2.92 0.053000 D6Mit67 97.7 0.63 0.531 D6Mit328 112.7 5.52 0.004400 D6Mit328 112.7
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