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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2006-2-22
pubmed:abstractText
High-resolution mapping and identification of the genes responsible for type 1 diabetes (T1D) has proved difficult because of the multigenic etiology and low penetrance of the disease phenotype in linkage studies. Mouse congenic strains have been useful in refining Idd susceptibility loci in the NOD mouse model and providing a framework for identification of genes underlying complex autoimmune syndromes. Previously, we used NOD and a nonobese diabetes-resistant strain to map the susceptibility to T1D to the Idd4 locus on chromosome 11. Here, we report high-resolution mapping of this locus to 1.4 megabases. The NOD Idd4 locus was fully sequenced, permitting a detailed comparison with C57BL/6 and DBA/2J strains, the progenitors of T1D resistance alleles found in the nonobese diabetes-resistant strain. Gene expression arrays and quantitative real-time PCR were used to prioritize Idd4 candidate genes by comparing macrophages/dendritic cells from congenic strains where allelic variation was confined to the Idd4 interval. The differentially expressed genes either were mapped to Idd4 or were components of the IFN response pathway regulated in trans by Idd4. Reflecting central roles of Idd4 genes in Ag presentation, arachidonic acid metabolism and inflammation, phagocytosis, and lymphocyte trafficking, our combined analyses identified Alox15, Alox12e, Psmb6, Pld2, and Cxcl16 as excellent candidate genes for the effects of the Idd4 locus.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0022-1767
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
176
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2976-90
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:16493056-Animals, pubmed-meshheading:16493056-Chromosome Mapping, pubmed-meshheading:16493056-Dendritic Cells, pubmed-meshheading:16493056-Diabetes Mellitus, Type 1, pubmed-meshheading:16493056-Female, pubmed-meshheading:16493056-Gene Expression Profiling, pubmed-meshheading:16493056-Genetic Markers, pubmed-meshheading:16493056-Genetic Predisposition to Disease, pubmed-meshheading:16493056-Genomics, pubmed-meshheading:16493056-Interferons, pubmed-meshheading:16493056-Macrophages, pubmed-meshheading:16493056-Male, pubmed-meshheading:16493056-Mice, pubmed-meshheading:16493056-Mice, Congenic, pubmed-meshheading:16493056-Mice, Inbred C57BL, pubmed-meshheading:16493056-Mice, Inbred DBA, pubmed-meshheading:16493056-Mice, Inbred NOD, pubmed-meshheading:16493056-Signal Transduction
pubmed:year
2006
pubmed:articleTitle
Molecular genetic analysis of the Idd4 locus implicates the IFN response in type 1 diabetes susceptibility in nonobese diabetic mice.
pubmed:affiliation
Program in Developmental Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't