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

Bäckdahl, Liselotte; Guo, Jian; Jagodic, Maja; Bečanović, Kristina; Ding, Bo; Olsson, Tomas; Lorentzen, Johnny C.

doi:10.1136/ard.2008.090803

Cited by 12 publications

(9 citation statements)

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“…There is in fact evidence that loci close to APLEC can regulate both arthritis and encephalomyelitis. 36,37 Nonetheless, the recent report that deletion of mouse Dcir1 influences arthritis and autoimmunity, 38 combined with our similar results regarding rat APLEC 5,6 and the association of RA with human APLEC and DCIR, 6 do point to evolutionarily conserved functions.…”

Section: Discussionsupporting

confidence: 68%

The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

Guo

Verdrengh²,

Tarkowski³

et al. 2009

Genes Immun

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Genetic variation in the antigen-presenting lectin-like receptor gene complex (APLEC) associates with autoimmunity and arthritis in rats and humans. We hypothesized that the encoded C-type lectin-like receptors might influence innate immunity and responses to infectious agents. To test this hypothesis, we compared in vivo and in vitro phenotypes in DA rats and APLEC-congenic rats. Survival rates following infection with Staphylococcus aureus and Herpes simplex virus differed significantly between the two strains. Likewise, differential delayed type hypersensitivity (DTH), an immunological reaction involving T lymphocytes and macrophages, was observed in response to provocation with the chemical oxazolone. Unstimulated bone marrow-derived macrophages from the two strains appeared to already have polarized activation states with different mRNA levels of CD163 and Dectin-1 receptors. Following stimulation with a panel of microbial agents, differences in induced mRNA and protein levels were shown for interleukin (IL)-6 and IL-10 following stimulation with lipopolysaccharide, mannan and b-glucan. Expression levels of APLEC gene mRNAs also differed, and both strains had a notably dichotomous expression of the genes, with general downregulation of all four Dcir genes and upregulation of Mincle and Mcl. We suggest that human APLEC genes may similarly regulate infectious diseases, DTH and general macrophage activation status.

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Section: Discussionsupporting

confidence: 68%

The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

Guo

Verdrengh²,

Tarkowski³

et al. 2009

Genes Immun

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“…This was consistent with other microarray results in experimental mice model [40]. Backdahl et al [41], recently reported that Clec4a1 was a candidate gene in inflammatory disease such as rheumatoid arthritis. Mafb is one of transcription factors involved during macrophage differentiation and/or inflammatory response [42].…”

Section: Discussionsupporting

confidence: 86%

Oral administration of docosahexaenoic acid attenuates colitis induced by dextran sulfate sodium in mice

Cho

Gil

Chun

2010

Molecular Nutrition Food Res

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“…In experimental arthritis a QTL has been identified in both DA/PVG and DA/F344 crosses on chromosome 10 [14, 50, 60]. This arthritis specific QTL was fine-mapped in pristine-induced arthritis using an AIL G10 [14].…”

Section: Resultsmentioning

confidence: 99%

“…The influence of genomic variations on the development of inflammatory disease by different genomes and MHC haplotypes. The illustration is an adaptation from [14]. …”

Section: Introductionmentioning

confidence: 99%

Identification of candidate risk gene variations by whole-genome sequence analysis of four rat strains commonly used in inflammation research

et al. 2014

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BackgroundThe DA rat strain is particularly susceptible to the induction of a number of chronic inflammatory diseases, such as models for rheumatoid arthritis and multiple sclerosis. Here we sequenced the genomes of two DA sub-strains and two disease resistant strains, E3 and PVG, previously used together with DA strains in genetically segregating crosses.ResultsThe data uncovers genomic variations, such as single nucleotide variations (SNVs) and copy number variations that underlie phenotypic differences between the strains. Comparisons of regional differences between the two DA sub-strains identified 8 genomic regions that discriminate between the strains that together cover 38 Mbp and harbor 302 genes. We analyzed 10 fine-mapped quantitative trait loci and our data implicate strong candidates for genetic variations that mediate their effects. For example we could identify a single SNV candidate in a regulatory region of the gene Il21r, which has been associated to differential expression in both rats and human MS patients. In the APLEC complex we identified two SNVs in a highly conserved region, which could affect the regulation of all APLEC encoded genes and explain the polygenic differential expression seen in the complex. Furthermore, the non-synonymous SNV modifying aa153 of the Ncf1 protein was confirmed as the sole causative factor.ConclusionThis complete map of genetic differences between the most commonly used rat strains in inflammation research constitutes an important reference in understanding how genetic variations contribute to the traits of importance for inflammatory diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-391) contains supplementary material, which is available to authorized users.

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

Abstract: 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.

Cited by 12 publications

References 55 publications

The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

Oral administration of docosahexaenoic acid attenuates colitis induced by dextran sulfate sodium in mice

Identification of candidate risk gene variations by whole-genome sequence analysis of four rat strains commonly used in inflammation research

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