The long term objective of this project is to identify the genomic basis of HLA association with susceptibility to insulin dependent diabetes mellitus (IDDM) and auto-immune-type vitiligo (ATV) and determine the relationship of HLA genotype frequency differences between African Americans and Caucasians to population differences in the incidence of IDDM. The analysis of HLA variability in disease association is enhanced in African Americans because of the greater degree of HLA polymorphisms found in this population. The polymerase chain reaction technique and hybridization with sequence specific oligonucleotide probes will be used to define HLA- DR and DQ alleles in Africa-American patients with IDDM and ATV in a case-control study. Family members will also be ascertained to determine HLA haplotypes. We hypothesize structural homologies among susceptibility alleles and protective alleles and/or haplotypes.
The specific aims are to define DRB1, DRB3, DRB4, DRB5, DQA1, and QB1 alleles and haplotypes in patients and controls; determine the frequency of alleles at each of these loci in IDDM and ATV; analyze the cis-trans-dose effect of DQA1 Arg52 and DQB1 Asp57 alleles in IDDM patients and controls, and estimate the IDDM genotype specific incidence for African Americans in Washington, D.C. Allelic hypervariable region sequence homology of DR4 early age of onset and DR6 late age of onset susceptibility alleles in ATV will be analyzed and compared with DR4 susceptibility allele(s) in IDDM. Also, susceptible and protective alleles/haplotypes, with a focus on the DRB1*0302,DQB1*0402,DQA1*0401 unique polymorphism in African Americans, will be evaluated relative to association with disease heterogeneity. This project focuses on the definition of genomic polymorphisms in HLA class II genes known to be associated with susceptibility to autoimmune disease. Unique HLA polymorphisms in African Americans will be used to assess the relative effect of DQA1, DQB1, and DRB alleles in susceptibility to IDDM and ATV. The molecular characterization of HLA-DR and DQ alleles and haplotypes at the DNA level will refine the definition of disease- associated alleles and/or sequence motifs and may be of great importance in better understanding the significance of immunogenetic factors in the pathogenesis of IDDM and ATV. Moreover, new information generated on diseases susceptibility motifs may be instructive in the design of gene therapy approaches to these types of autoimmune diseases.
