Population analysis of protection by HLA-DR and DQ genes from insulin-dependent diabetes mellitus in Swedish children with insulin-dependent diabetes and controls.
A negative association between insulin-dependent diabetes mellitus (IDDM) and HLA-DR, DQA1 or DQB1 was found in a large population-based investigation of childhood-onset patients (more than 420 patients) and controls (more than 340 controls) from Sweden. The relative risk was decreased for several haplotypes that were negatively associated with IDDM: DR15-DQA1*0102-DQB1*0602, DR7-DQA1*0201-DQB1*0303, DR14-DQA1*0101-DQB1*0503, DR11-DQA1*0501-DQB1*0301, DR13-DQA1*0103-DQB1*0603 and DR4-DQA1*0301-DQB1*0301. In a relative predispositional effect (RPE) analysis, however, only the DR15-DQA1*0102-DQB1*0602 haplotype was significantly decreased, which suggests that the major protective effect for IDDM is carried by this haplotype. This was supported by the observation that all genotypes which were negatively associated with IDDM, except DR7/13, included at least one allele from the DR15-DQA1*0102-DQB1*0602 haplotype. Relative predispositional effect (RPE) analysis of genotypes showed further that the DR15-DQA1*0102-DQB1*0602 haplotype was also negatively associated with IDDM when combined with any other haplotype, whether negatively or positively associated with IDDM. This supports previous suggestions that DR15-DQA1*0102-DQB1*0602 acts dominantly. However, both the stratification and the predispositional allele test failed to distinguish the negative association between IDDM and DR15 from that of DQB1*0602. On the other hand, these tests indicated that DQA1*0102 was not likely to explain the negative association between IDDM and the DR15-DQA1*0102-DQB1*0602 haplotype. We conclude that the major protective effect for IDDM in the population of Swedish children is conferred by the DR15-DQA1*0102-DQB1*0602 haplotype in a dominant fashion, the DQB1*0602 allele being the allele most likely to be responsible for the protective effect of this haplotype, although an effect of the DR15 allele could not be excluded.
Kockum
I
I
Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
Sanjeevi
C B
CB
Eastman
S
S
Landin-Olsson
M
M
Dahlquist
G
G
Lernmark
A
A
D000293:Adolescent; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D005787:Gene Frequency; D005819:Genetic Markers; D005820:Genetic Testing; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D012307:Risk Factors; D013548:Sweden
D005819:Genetic Markers; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens