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Maier, Lisa M.; Smyth, Deborah J.; Vella, Adrian; Cooper, Jason D.; Pask, Rebecca; Lowe, Christopher; Hulme, John S.; Smink, Luc J.; Fraser, Heather I.; Moule, Carolyn; Hunter, Kara; Chamberlain, Giselle; Walker, Neil M.; Nutland, Sarah; Undlien, Dag E.; Rønningen, Kjersti S.; Guja, Cristian; Ionescu-Tîrgovişte, C; Savage, David A.; Strachan, David P.; Peterson, Laurence B.; Todd, John A.; Wicker, Linda S.; Twells, Rebecca C.J.

doi:10.1186/1471-2156-6-9

Cited by 18 publications

(12 citation statements)

References 30 publications

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“…Infection of (NOD x NOD.B6 Idd10 ) F1 mice also induced significantly more severe liver disease compared to parental NOD mice suggesting that allelic variations within the Idd10 region drive susceptibility to PBC in a gene dose dependent manner (not shown). As introgression of the B6 Idd10 allele protects from spontaneous type 1 diabetes (T1D) (43, 44, 47), we tested the effect of N. aro infection on T1D in NOD.B6 Idd10 mice (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

“…Although we have begun to identify the environmental agent and cellular mechanisms that induce liver specific immunopathology, the factors underlying genetic susceptibility to this model of PBC remain unknown. Our previous studies suggested that NOD.B6 Idd10/18 mice, which are partially protected from T1D as compared to the NOD parental strain (43–44), develop more severe liver lesions following N. aro infection than NOD mice (42). Therefore, we reasoned that the Idd10/18 region might harbor susceptibility alleles that determine the severity of bile duct disease upon infection with N. aro .…”

Section: Introductionmentioning

confidence: 99%

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Identification of Cd101 as a Susceptibility Gene for Novosphingobium aromaticivorans-Induced Liver Autoimmunity

Mohammed

Fusakio

Rainbow

et al. 2011

The Journal of Immunology

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Environmental and genetic factors define the susceptibility of an individual to autoimmune disease. Although common genetic pathways affect general immunological tolerance mechanisms in autoimmunity, the effects of such genes could vary under distinct immune challenges within different tissues. Here we demonstrate this by observing that autoimmune type 1 diabetes (T1D) protective haplotypes at the susceptibility region 10 (Idd10) introgressed from chromosome 3 of B6 and A/J mice onto the NOD background increase the severity of autoimmune primary biliary cirrhosis (PBC) induced by infection with Novosphingobium aromaticivorans (N. aro), an ubiquitous alphaproteobacterium, when compared to mice having the NOD and NOD.CAST Idd10 T1D susceptible haplotypes. Substantially increased liver pathology in mice having the B6 and A/J Idd10 haplotypes correlates with reduced expression of CD101 on dendritic cells (DCs), macrophages and granulocytes following infection, delayed clearance of N. aro and the promotion of overzealous, IFN-γ- and IL-17-dominated T cell responses essential for the adoptive transfer of liver lesions. CD101-knockout mice generated on the B6 background also exhibit substantially more severe N.aro-induced liver disease correlating with increased IFN-γ and IL-17 responses compared to wild type mice. These data strongly support the hypothesis that allelic variation of the Cd101 gene, located in the Idd10 region, alters the severity of liver autoimmunity induced by N. aro.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of Cd101 as a Susceptibility Gene for Novosphingobium aromaticivorans-Induced Liver Autoimmunity

Mohammed

Fusakio

Rainbow

et al. 2011

The Journal of Immunology

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“…There is no evidence to date for association of human VAV3 with T1D (61, 63) (www.t1dbase.org). However, regions synonymous with Vav3 have been identified by linkage analysis in the biobreeding diabetes-prone rat model of T1D: Iddm26 is 41 Mb, contains 450 genes, and overlaps Idd10, Idd18.2, Idd18.3 , and Idd18.1 (64); and a second unnamed region is 26 Mb, contains 196 genes, and overlaps Idd18.2, Idd18.3 and Idd18.1 (65).…”

Section: Discussionmentioning

confidence: 99%

Nonobese Diabetic Congenic Strain Analysis of Autoimmune Diabetes Reveals Genetic Complexity of the Idd18 Locus and Identifies Vav3 as a Candidate Gene

Fraser

Dendrou

Healy

et al. 2010

The Journal of Immunology

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We have used the public sequencing and annotation of the mouse genome to delimit the previously resolved type 1 diabetes (T1D) Idd18 interval to a region on chromosome 3 that includes the immunologically relevant candidate gene, Vav3. To test the candidacy of Vav3, we developed a novel congenic strain which enabled the resolution of Idd18 to a 604 kb interval, designated Idd18.1, which contains only two annotated genes: the complete sequence of Vav3, and the last exon of the gene encoding NETRIN G1, Ntng1. Targeted sequencing of Idd18.1 in the NOD mouse strain revealed that allelic variation between NOD and C57BL/6J (B6) occurs in non-coding regions with 138 single nucleotide polymorphisms (SNPs) concentrated in the introns between exons 20 and 27, and immediately after the 3′ UTR. We observed differential expression of VAV3 RNA transcripts in thymocytes when comparing congenic mouse strains with B6 or NOD alleles at Idd18.1. The T1D protection associated with B6 alleles of Idd18.1/Vav3 requires the presence of B6 protective alleles at Idd3, which are correlated with increased IL-2 production and regulatory T cell function. In the absence of B6 protective alleles at Idd3, we detected a second T1D protective B6 locus, Idd18.3, which is closely linked to, but distinct from, Idd18.1. Therefore, genetic mapping, sequencing, and gene expression evidence indicate that alteration of VAV3 expression is an etiological factor in the development of autoimmune beta-cell destruction in NOD mice. This study also demonstrates that a congenic strain mapping approach can isolate closely linked susceptibility genes.

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“…The loci identified in the NOD mouse as high priority candidates for human T1D studies include solute carrier family 11 member 1 ( Slc11a1 ), which was formerly known as natural resistance-associated macrophage protein 1 ( Nramp1 ) [4]. Slc11a1 is encoded in the Idd5.2 region on mouse chromosome 1.…”

Section: Introductionmentioning

confidence: 99%

“…They also genotyped the non-synonymous SNP (nsSNP) rs17235409 (D543N) and the microsatellite (GT)n in 1,632 families and did not obtain any evidence of association [4]. Nor did they obtain evidence of association with the nsSNP rs17235409 (D543N), which was genotyped in an additional 1,995 cases and 2,101 controls [4].…”

Section: Introductionmentioning

confidence: 99%

Evidence of association with type 1 diabetes in the SLC11A1 gene region

et al. 2011

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BackgroundLinkage and congenic strain analyses using the nonobese diabetic (NOD) mouse as a model for human type 1 autoimmune diabetes (T1D) have identified several NOD mouse Idd (insulin dependent diabetes) loci, including Slc11a1 (formerly known as Nramp1). Genetic variants in the orthologous region encompassing SLC11A1 in human chromosome 2q35 have been reported to be associated with various immune-related diseases including T1D. Here, we have conducted association analysis of this candidate gene region, and then investigated potential correlations between the most T1D-associated variant and RNA expression of the SLC11A1 gene and its splice isoform.MethodsNine SNPs (rs2276631, rs2279015, rs1809231, rs1059823, rs17235409 (D543N), rs17235416 (3'UTR), rs3731865 (INT4), rs7573065 (-237 C→T) and rs4674297) were genotyped using TaqMan genotyping assays and the polymorphic promoter microsatellite (GT)n was genotyped using PCR and fragment length analysis. A maximum of 8,863 T1D British cases and 10,841 British controls, all of white European descent, were used to test association using logistic regression. A maximum of 5,696 T1D families were also tested for association using the transmission/disequilibrium test (TDT). We considered P ≤ 0.005 as evidence of association given that we tested nine variants in total. Upon identification of the most T1D-associated variant, we investigated the correlation between its genotype and SLC11A1 expression overall or with splice isoform ratio using 42 PAXgene whole blood samples from healthy donors by quantitative PCR (qPCR).ResultsUsing the case-control collection, rs3731865 (INT4) was identified to be the variant most associated with T1D (P = 1.55 × 10-6). There was also some evidence of association at rs4674297 (P = 1.57 × 10-4). No evidence of disease association was obtained at any of the loci using the family collections (PTDT ≥ 0.13). We also did not observe a correlation between rs3731865 genotypes and SLC11A1 expression overall or with splice isoform expression.ConclusionWe conclude that rs3731685 (INT4) in the SLC11A1 gene may be associated with T1D susceptibility in the European ancestry population studied. We did not observe a difference in SLC11A1 expression at the RNA level based on the genotypes of rs3731865 in whole blood samples. However, a potential correlation cannot be ruled out in purified cell subsets especially monocytes or macrophages.

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Untitled

Cited by 18 publications

References 30 publications

Identification of Cd101 as a Susceptibility Gene for Novosphingobium aromaticivorans-Induced Liver Autoimmunity

Identification of Cd101 as a Susceptibility Gene for Novosphingobium aromaticivorans-Induced Liver Autoimmunity

Nonobese Diabetic Congenic Strain Analysis of Autoimmune Diabetes Reveals Genetic Complexity of the Idd18 Locus and Identifies Vav3 as a Candidate Gene

Evidence of association with type 1 diabetes in the SLC11A1 gene region

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