IMMUNOGENETICS OF TYPE 1 DIABETES IN A BEDOUIN FAMILY

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DESCRIPTION: (Adapted from the Investigator's abstract): Over 2 million Americans suffer from type 1 diabetes, most of the them children and young adults. In addition to the burden of daily insulin injection to sustain life, patients with diabetes face a high risk for blindness, kidney failure, heart disease, stroke, and amputations. A better understanding of the genetic causes of type 1 diabetes should lead to novel gene therapies for halting beta-cell destruction during the pediatric period or for preventing the destruction of residual beta -cells in patients who are already affected with the disease. Further, the ability to predict who will develop the disease depends on the ability to test for each of the multiple genes that are thought to be involved. These high-risk individuals represent the best target populations for testing experimental treatment and prevention strategies in the most efficient manner. Individuals carrying HLA-DR3 and/or DR4 are at high risk for disease, but there is general agreement that other, unknown genes are also involved. However, it has been difficult to identify non-MHC genes, most likely due to genetic heterogeneity of type 1 diabetes in the population under study. Based on genetic linkage studies in a remarkable Bedouin Arab family with 20 relatives affected with type 1 diabetes, a diabetes susceptibility locus (IDDM17) has been mapped to the long arm of chromosome 10 (10q25.1). Significant (p=0.00004) nonparametric linkage scores (NPLs) and parametric LOD scores were observed for marker D10S554, which was also in linkage disequilibrium with IDDM17. D10S554 and flanking markers map to a 1,240 kb YAC. The family previously studied consists of about 200 members, who are members of a large Bedouin Arab tribe with about 15,000 members. Remarkably, 8 of the 20 affected relatives were diagnosed between 1990 and 1999. Another, closely related branch of the tribe have a similarly high incidence of type 1 diabetes. The specific aims of this study are: (1) to determine the ability to predict the development of type 1 diabetes in the extended family based on HLA genotype, chromosome 10 haplotype (IDDM17), and the expression of islet-cell autoantibodies; and (2) identify the gene corresponding to IDDM17 by the position cloning.