A role for heat shock proteins (HSPs) in autoimmunity has recently been suggested by several authors. Autoantibodies against HSPs have been associated with such autoimmune diseases as systemic lupus erythematosus, polymyositis, and the NOD mouse model of diabetes. Moreover, genes for the major 70,000-Mr HSP (HSP70) are located within the MHC. To investigate a potential association of an HSP70–2 gene polymorphism with insulin-dependent diabetes mellitus (IDDM), we analyzed restriction-fragment–length polymorphism (RFLP) of this gene in 29 families with one or more member affected by IDDM. With the enzyme PstI, as reported previously, two HSP70–2 alleles of 8.5- and 9.0-kb were found. The 8.5-kb allele was found more frequently on diabetic haplotypes compared with control haplotypes (41 of 66 [62%] vs. 20 of 46 [43%], P = 0.03). This association was due to the conservation of alleles on extended haplotypes we previously reported to be associated with diabetes on initial analysis of families. Twenty-three of 26 diabetic DR3 haplotypes and 3 of 3 normal DR3 haplotypes and all instances of [HLA-B8, SC01, DR3] and [HLA-B18, F1C30, DR3] had the 8.5-kb allele, whereas 0 of 9 normal DR2 haplotypes and 0 of 2 diabetic DR2 haplotypes had the 8.5-kb allele (P = 8 × 10−7 DR3 vs. DR2 haplotypes). The alleles were equally distributed among DR4 haplotypes. Our studies indicate that the 8.5-kb allele is part of [HLA-B8, SC01, DR3] and [HLA-B18, F1C30, DR3] haplotypes, and the 9.0-kb allele is associated with DR2 but no independent association (greater than DR association) is found between HSP70–2 alleles and diabetes.

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