HLA heterozygosity in insulin-dependent diabetes is most frequent at the DQ locus.
Restriction fragment length polymorphism using an HLA-DQ beta-chain genomic probe showed that 63 children with insulin-dependent (type 1) diabetes mellitus (IDDM) were all (100%) positive for the BamH1 fragments 12 kb and/or 4 kb compared to 98% (62/63) for HLA-DR3 and/or 4 and 75% (47/63) for HLA-B8 and/or 15. The 36 (56%) DR3-positive children were all 4-kb-positive; however, a total of 44 (70%) children were 4-kb-positive (P less than 0.02). The 55 (87%) DR4-positive children were all 12-kb-positive, but a total of 56 (89%) were 12-kb-positive (NS). The heterozygosity at the HLA region increased from 11/63 (18%) for HLA-B8/15 to 29/63 (46%) for HLA-DR3/4 (P less than 0.0004) and to 37/63 (59%) for the HLA-DQ 4 kb/12 kb fragments (P less than 0.02). The test of an equal probability of a positive result under the adjacent pair of tests indicates that the increased risk of developing IDDM in association with HLA-DQ is to a great extent due to heterozygosity at this locus. There were no differences between the 4 kb/12 kb and the DR3/4-positive IDDM children with respect to fasting or meal-stimulated C peptide, insulin requirement, or levels of insulin antibodies formed during the first 12 months of insulin therapy. Our results support the hypothesis that HLA-DQ is closely associated with an increased risk of childhood IDDM, and when typed for at this locus parameters of the clinical course were homogeneous, suggesting that factors other than HLA-DQ may determine previously observed differences between IDDM children in clinical or functional parameters.
Michelsen
B
B
Hagedorn Research Laboratory, Gentofte, Denmark.
Wassmuth
R
R
Ludvigsson
J
J
Lernmark
A
A
Nepom
G T
GT
Fisher
L
L
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics; D006683:HLA-DQ Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D011110:Polymorphism, Genetic
D015235:HLA-B Antigens; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens