Analysis of overlapping cosmid clones has enabled the identification and precise mapping of three hsp 70 genes (hsp 70-1, hsp 70-2, and hsp 70-hom) within the class III region of the human MHC (39). Hsp 70-1 and hsp 70-2 encode an identical protein, whereas hsp 70-hom encodes a previously unknown protein. These genes map close to each other, about 90 kb telomeric to the C2 gene and about 280 kb centromeric to the tumor necrosis factor a (TFN-a) gene. A restriction fragment length polymorphism (RFLP) of hsp 70 gene(s) in the MHC has been described using an hsp 70 probe, ph 2.3, and the restriction enzyme Pstl (40). The two alleles, represented by a 9.0- or an 8.5-kb fragment, occur with frequencies of 0.62 and 0.38, respectively. Because a member of the hsp 70 family is involved in the handling and presentation of antigen peptides to the T-cell receptor (11,12), we hypothesized that hsp 70 gene expression could play a role in the development of autoimmunity in SLE. Indeed, several groups have reported an increase in the frequency of the Pstl 8.5-kb allele of the hsp 70-2 gene associated with a C4A deletion in type I diabetes and Graves' disease (41,42). In addition, Pociot et al. (43) have observed decreased hsp 70-2 mRNA expression in individuals who are homozygotes for the pstl 8.5-kb allele as compared with homozygotes for the pstl 9.0-kb allele.
Using pH 2.3 and Pstl in studies of hsp 70 gene polymorphism in SLE, genomic DNA from 49 individuals with SLE and 45 healthy controls with no family history of autoimmune disease have been analyzed. As expected, we observed two alleles, 8.5 and 9.0 kb, resulting in three genotypes (9.0/9.0, 9.0/ 8.5, and 8.5/8.5). There was a statistically significant association between the absence of the 9.0-kb allele and SLE (p = 0.0474). Conversely, the presence of 8.5-kb allele was associated with SLE (p = 0.039), and its allelic frequency was increased in patients with SLE relative to the control subjects (p = 0.0066). When the data were analyzed with respect to race, the increase in the 8.5 allele was associated with SLE in African-Americans (p = 0.042) but not whites. Because multiple associations with specific MHC genes have been described in SLE, we next examined the extended haplotype of our patient and control populations. Linkage of the hsp 70-2 polymorphism with C4A deletion, DR3, or an NCOI polymorphism of TNF-a was not demonstrable. Taken together, these data suggest that a polymorphism of the hsp 70-2 gene in the class III region of the MHC is a new susceptibility marker for SLE, particularly in African-Americans.
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