DNA polymorphism analysis of HLA class II genes in unrelated children and in first-degree relatives with type I diabetes.
Eighty unrelated diabetic children, seventy healthy controls and hundred and ten affected and unaffected first-degree relatives of twenty multiplex families were investigated by restriction fragment length polymorphism analysis of HLA class II genes using five probe/enzyme systems: DRB and DQB/Taq I, DRB and DQB/EcoRI and DQB/BamHI according to standard procedures described in the 10th Histocompatibility Workshop protocol. Comparison between the unrelated diabetic patients and the controls confirmed the positive association of type 1 diabetes with DR3(w17)DQw2 Dw24 or Dw25 and DR4DQw8 and the negative association with DR2(w15)DQw6, DR4DQw7 and DR7DQw2 haplotypes. In multiplex families, similar allele associations were found and the distinction between haplotypes present in diabetic patients and those that segregated to healthy family members allowed to observe striking differences between the "affected" and "unaffected" haplotypes, particularly for the subtypes of DR3(w17) DQw2, DR4DQw3 and DR2DQw1 haplotypes. Heterozygous siblings who carried both DR3DQw2 and DR4DQw8 subtypes disclosed a highly increased risk and more than 80% of DR3/DR4 affected siblings received a paternal DR4DQw8 together with a maternal DR3DQw2. These observations indicate that several genetic aspects influence susceptibility to type 1 diabetes: 1) some particular HLA class II subsets; 2) the parental origin of the predisposing genes; 3) the synergistic effect of both haplotypes, in particular DR3DQw2 and DR4DQw8. These results may help to better specify susceptibility markers for risk prediction in siblings.
Département de Diabétologie, Hôpital des Enfants Malades, Paris, France.
J
J
Jos
D
D
Farkas
M F
MF
de Tand
J
J
Cartron
O
O
Cohen-Hagenhauer
E
E
Tozzo
I
I
Deschamps
D000293:Adolescent; D000483:Alleles; D002648:Child; D004247:DNA / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005190:Family; D005260:Female; D005802:Genes, MHC Class II; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D012150:Polymorphism, Restriction Fragment Length; D012016:Reference Values
D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D004247:DNA