Cdcs1 a major colitis susceptibility locus in mice; Subcongenic analysis reveals genetic complexity

Bleich, André; Büchler, Gwen; Beckwith, Jason; Petell, Lydia M.; Affourtit, Jason P.; King, Benjamin L.; Shaffer, Daniel J.; Roopenian, Derry C.; Hedrich, Hans J.; Sundberg, John P.; Leiter, Edward H.

doi:10.1002/ibd.21146

Cited by 28 publications

(36 citation statements)

References 37 publications

(50 reference statements)

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“…4C). The QTL on chromosome 3 localized to 58 cM, with a LOD score of 12. lines (derived from C3H/HeJBir and B6 animals) defined three Cdcs1 subloci that independently affect susceptibility to intestinal inflammation (16). The most proximal sublocus, Cdcs1.1 (located between 88.1 and 108.8 Mbp), controls cecal inflammation and the other two subloci, Cdcs1.2 (120-123 Mbp) and Cdcs1.3 (125.6-128 Mbp), affect colitis severity.…”

Section: Resultsmentioning

confidence: 99%

“…However, there were a few notable exceptions: Rwdd3 in Cdcs1.2, and Ap1ar and Camk2d in Cdcs1.3 were more strongly expressed in cells from Cdcs1 c/c animals, and these differences (Rwdd3 3.9-fold, P < 0.0001; Ap1ar 3.6-fold, P < 0.0001; Camk2d 1.7-fold, P = 0.009) remained statistically significant after Bonferroni correction for multiple comparisons. Further exploration of the functional outcome of sequence polymorphisms (16) and differential expression of the Cdcs1 locus genes is in progress.…”

Section: Resultsmentioning

confidence: 99%

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Severity of innate immune-mediated colitis is controlled by the cytokine deficiency-induced colitis susceptibility-1 ( Cdcs1 ) locus

Ermann

Garrett

Kuchroo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Genetic modifier loci influence the phenotypic expression of many Mendelian traits; insight into disease pathogenesis gained from their identification in animal disease models may impact the treatment of human multigenic disorders. We previously described an innate immune-driven model of spontaneous ulcerative colitis in T-bet −/− .Rag2 −/− double-deficient mice that resembles human ulcerative colitis. On a BALB/c background, this disease is highly penetrant and results in the development of colorectal cancer. However, we observed that colitis in T-bet −/− .Rag2 −/− mice on a C57BL/6 background was significantly less severe. Quantitative trait locus analysis using an N2 backcross strategy revealed a single major quantitative trait locus on chromosome 3 that mapped to the Cdcs1 (cytokine deficiency-induced colitis susceptibility-1) locus previously identified in the Il10 −/− and Gnai2 −/− colitis models. Congenic introduction of the susceptible Cdcs1 interval from C3H/He into the C57BL/6 background restored colitis severity. Bone marrow reconstitution experiments further mapped the effect of host genetics on disease severity to the hematopoietic compartment. There were distinct differences in the expression of several Cdcs1 genes in bone marrow-derived dendritic cells from Cdcs1 congenic mice. We conclude that the Cdcs1 locus controls colitis severity in T-bet −/− .Rag2 −/− mice through innate immune cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Severity of innate immune-mediated colitis is controlled by the cytokine deficiency-induced colitis susceptibility-1 ( Cdcs1 ) locus

Ermann

Garrett

Kuchroo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The absence of allelic Cdcs1 in the N5 generation and a different impact of GPX-deficiency relative to IL-10 may explain why we would characterize the effect as additive and a major effect locus. Also, the results from B6;C3Bir IL-10 KO, Gnai2 and dextran sodium sulfate-induced colitis studies suggest that colitis is governed by at least 13 genes in mice scattered throughout the genome present in complex loci (24, 27, 43, 48). We noticed that 6 of these loci might have been sites of residual B6 alleles in 129 N5 ( Cdcs1, 2, 3, 4, 5, 9 ) although the frequency of B6 alleles corresponding to Cdcs1 (chromosome 3) and Cdcs2 (chromosome 1) were too low to account for the phenotype of the cohort.…”

Section: Discussionmentioning

confidence: 99%

“…Leiter, Sundberg and their associates have been the only group to study IBD genes in IL-10 null mice (25). They identified ten susceptibility loci, named cytokine-deficiency-induced colitis susceptibility ( Cdcs ) loci by comparing the colitis between the sensitive C3H/HeJBir (C3Bir) and resistant B6 mice (25, 27). Here, we have used forward genetics to identify a GPx-deficiency-associated colitis locus ( Gdac ), which differentiates disease severity between B6 and 129 strains of DKO mice.…”

Section: Introductionmentioning

confidence: 99%

Colitis locus on chromosome 2 impacting the severity of early-onset disease in mice deficient in GPX1 and GPX2

Esworthy

Kim

Larson

et al. 2011

Inflammatory Bowel Diseases

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Background Genetic background has a profound effect on inflammatory bowel disease. The Gpx1 and Gpx2 double knockout (GPX1/2-DKO) mice on a mixed C57BL/6 (B6) and 129S1/SvimJ (129) background had spontaneous ileocolitis. The DKO mice on a B6 background had mild ileocolitis. We characterized the 129 DKO mice to identify a genetic locus affecting disease severity. Methods We backcrossed B6;129 DKO mice to 129 and analyzed for ileocolitis penetrance and severity at N5, N7 and N10. By correlating disease severity with single-nucleotide polymorphism (SNP) markers, we identified a colitis locus. Results As early as 9 days of age, 129 DKO N5 and N10 mice showed disease signs and morbidity. The N10 DKO mice had the severest colitis with nearly complete penetrance and high morbidity compared with other generations or backgrounds. 129 DKO mice had elevated colonic KC and SAA3 expression, shorter colon length, and cecal E. coli overgrowth compared to B6 DKO mice. Analysis of the B6 loci in 129 N5, N7 and N10 cohorts pointed to a region of chromosome 2: 119 Mbp contributing to mild symptoms. Conclusions GPX1/2-DKO mice on 129 genetic background have the most aggressive colitis compared to B6;129 and B6 colonies. A B6 locus significantly contributing the resistance resides on chromosome 2: 119 Mbp. This region coincides with cytokine-deficiency-induced-colitis-susceptibility, Cdcs3, identified in the resistant B6 and sensitive C3H/HeJBir (C3Bir) with IL-10 deficiency. A three-way SNP analysis between 129, B6 and C3Bir locus points the major candidate genes to B2m, Dnajc17, Duox2, Pla2g4b, Pla2g4e, Pla2g4f and Slc30a4.

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“…Importantly, the Cdcs1 interval spans between 62 and 70 cM with the peak marker at 61.8 cM,28,36 thus overlapping at its proximal end with the interval mapped scoring the lymphatic vessel traits. Further subcongenic analysis revealed high genetic complexity of Cdcs1 with likely more than one gene contributing to the phenotype 37. In this study, we have evaluated the thus-far neglected inflammatory changes that occur in the lymphatic vasculature, in contrast to the earlier investigations of the `classical' colitis symptoms of epithelial damage and inflammatory cell accumulation.…”

Section: Discussionmentioning

confidence: 99%

Quantitative lymphatic vessel trait analysis suggests Vcam1 as candidate modifier gene of inflammatory bowel disease

et al. 2010

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Inflammatory bowel disease (IBD) is a chronic debilitating disease resulting from a complex interaction of multiple genetic factors with the environment. To identify modifier genes of IBD, we used an F2 intercross of IBD-resistant C57BL/6J-Il10 À/À mice and IBD-susceptible C3H/HeJBir-Il10 À/À (C3Bir-Il10 À/À ) mice. We found a prominent involvement of lymphatic vessels in IBD and applied a scoring system to quantify lymphatic vascular changes. Quantitative trait locus (QTL) analyses revealed a large-effect QTL on chromosome 3, mapping to an interval of 43.6 Mbp. This candidate interval was narrowed by fine mapping to 22 Mbp, and candidate genes were analyzed by a systems genetics approach that included quantitative gene expression profiling, search for functional polymorphisms, and haplotype block analysis. We identified vascular adhesion molecule 1 (Vcam1) as a candidate modifier gene in the interleukin 10-deficient mouse model of IBD. Importantly, VCAM1 protein levels were increased in susceptible C3H/HeJ mice, compared with C57BL/6J mice; systemic blockade of VCAM1 in C3Bir-Il10 À/À mice reduced their inflammatory lymphatic vessel changes. These results indicate that genetically determined expression differences of VCAM1 are associated with susceptibility to colon inflammation, which is accompanied by extensive lymphatic vessel changes. VCAM1 is, therefore, a promising therapeutic target for IBD.

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Cdcs1 a major colitis susceptibility locus in mice; Subcongenic analysis reveals genetic complexity

Cited by 28 publications

References 37 publications

Severity of innate immune-mediated colitis is controlled by the cytokine deficiency-induced colitis susceptibility-1 ( Cdcs1 ) locus

Severity of innate immune-mediated colitis is controlled by the cytokine deficiency-induced colitis susceptibility-1 ( Cdcs1 ) locus

Colitis locus on chromosome 2 impacting the severity of early-onset disease in mice deficient in GPX1 and GPX2

Quantitative lymphatic vessel trait analysis suggests Vcam1 as candidate modifier gene of inflammatory bowel disease

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