Polymorphic analysis of the human MHC-linked heat shock protein 70 (HSP70-2) and HSP70-Hom genes in insulin-dependent diabetes mellitus (IDDM).
In the present study we characterized the frequencies of two polymorphisms within the MHC-linked heat shock protein (HSP) 70 genes in patients with insulin-dependent diabetes mellitus (IDDM) (n = 114) and healthy control individuals (n = 110). Significant differences in genotype and allelic frequencies were observed for both polymorphisms between randomly selected patients and controls. However, for the HSP70-2 polymorphisms this was solely due to linkage disequilibrium with DR3. The rate HSP70-Hom 2-allele was significantly more frequent in controls than in patients. It showed strong association with certain tumour necrosis factor (TNF) (class III) and HLA-B and -A (class I) alleles independent of HLA-DQ and -DR alleles. By typing 257 individuals from 55 IDDM multiple-case families two extended MHC-haplotypes, including class II-, TNF- and class I-markers, carrying the rare HSP70-Hom allele were defined. One was only transmitted to diabetic offspring, whereas the other was only transmitted to unaffected offspring. The functional implication of the polymorphism in the heat shock-inducible HSP70-2 gene was analysed by studying HSP70-2 mRNA expression after heat shock in peripheral blood mononuclear cells from individuals with different HSP70-2 genotypes. Preliminary data showed that individuals homozygous for the PstI 8.5-kb allele consistently had slightly lower expression than heterozygous and 9.0-kb homozygous individuals.
Pociot
F
F
Steno Diabetes Center, Gentofte, Denmark.
Rønningen
K S
KS
Nerup
J
J
D000328:Adult; D000483:Alleles; D001483:Base Sequence; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation
D006360:Heat-Shock Proteins; D012333:RNA, Messenger