Type 1 diabetes (T1D) is a complex trait associated mainly with genes within the human leukocyte antigens (HLA) region on the short arm of chromosome 6. Several studies have provided evidence that in addition to the HLA class I A, B and HLA class II DQ, DR genes, HLA contains another uncharacterized gene or genes associated with T1D. Recently, the new discovered family of HLA genes called MIC (major histocompatibility complex class I chain-related gene) has been shown to be associated with susceptibility to various autoimmune diseases in Caucasians. Among this family, MICA and MICB are two functional genes that express molecules that act as a ligand for cells expressing a common activatory natural killer-cell receptor (NKG2D). Study of the interaction of MIC withy NKG2D showed that MICA alleles have variable strength of binding. This difference in binding affinities of MICA alleles for NKG2D could have significant effects in NK-cell activation and in the modulation of T-cell responses, in particular under suboptimal MIC expression. Interaction of MICA alleles that have high affinity to NKG2D could play a role in autoimmune pathogenesis of T1D. MICA and, to a lesser extent, MICB genes are polymorphic, with the former represented by 54 alleles whose variability is scattered within exon 2-5 of the gene. The long-term objective of this project is to develop resources for the purpose of identifying genes that modify the risk for T1D among African Americans In addition to HLA genes, non-HLA candidate genes will be tested for their potential effect.
The specific aims of this project are: 1) Ascertain and establish a renewable source of DNA on 200 clinically and genetically well-characterized African American simplex and multiplex families with T1D in which HLA DRB1, DQB1 polymorphisms is well defined to serve as a resource for whole-genome scans for linkage to T1D and for the study of targeted candidate genes. 2) Determine whether MICA and MICB are candidate genes for T1D. 3) Test linkage disequalibrium between MIC genes and HLA Class 1 A, B and Class II DR, DQ genes. 4) Determine whether variation in MIC genes can be used to refine clinical phenotype of T1D in African Americans.
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