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Originally published online as doi:10.1189/jlb.0904524 on January 3, 2005

Published online before print January 3, 2005
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(Journal of Leukocyte Biology. 2005;77:579-585.)
© 2005 by Society for Leukocyte Biology

CBLB variants in type 1 diabetes and their genetic interaction with CTLA4

Regine Bergholdt, Camilla Taxvig, Stefanie Eising, Jørn Nerup and Flemming Pociot1

Steno Diabetes Center, Gentofte, Denmark

1Correspondence: Steno Diabetes Center, 2, Niels Steensensvej, DK-2820 Gentofte, Denmark. E-mail: fpoc{at}steno.dk

Type 1 diabetes (T1D) is a multifactorial disease with genetic and environmental components involved. Recent studies of an animal model of T1D, the Komeda diabetes-prone rat, have demonstrated that the Casitas-B-lineage lymphoma b (cblb) gene is a major susceptibility gene in the development of diabetes and other autoimmune features of this rat. As a result of the inhibitory role of Cbl-b in T cell costimulation, dysregulation of Cbl-b may also contribute to autoimmune diseases in man. Different isoforms of Cbl-b exist; we evaluated expression levels of two known transcript variants. Constitutive expression of both isoforms was demonstrated, as well as an increased expression, after cytokine exposure, of an isoform lacking exon 16, suggesting a possible role of this variant in the pathogenesis of autoimmunity. We screened coding regions of the human CBLB gene for mutations in a panel of individuals affected with several autoimmune diseases. Eight single nucleotide polymorphisms (SNPs) were detected. One SNP in exon 12 of the CBLB gene was significantly demonstrated to be associated to T1D in a large Danish T1D family material of 480 families. Evidence for common genetic factors underlying several autoimmune diseases has come from studies of cytotoxic T lymphocyte antigen 4 (CTLA4), which encodes another negatively regulatory molecule in the immune system. Gene-gene interactions probably play substantial roles in T1D susceptibility. We performed stratification of CBLB exon 12 SNP data, according to an established CTLA4 marker, CT60, and evidence for a genetic interaction between the CTLA4 and CBLB genes, involved in the same biological pathway of T cell receptor signaling, was observed.

Key Words: T cell regulation • mutational screening • gene-gene interaction




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