The DR4-DQA1*0301-DQB1*0302 haplotypes conferring susceptibility to T1DM were those bearing DRB1*0401 (OR = 12), DRB1*0404 (OR = 4.7) and DRB1*0402 (OR = 4.5).
HLA-DQA1 *0102-DQB1 *0602 and -DQA1 *0501-DQB1 *0301 in trans complementation with DRB1 *0401-DQB1 *0302 were also significantly less frequent in IDDM patients (P<3x 10(-7) and P<0.02).
These data suggest that the interaction between VDR and HLA alleles is mediated by VDRE present in the promoter region of HLA-DRB1 0301 allele, which may be detrimental for the manifestation of T1D in the absence of 1,25-(OH)(2)D(3) in early childhood due to poor expression of DRB1 0301 in the thymus resulting in autoimmunity.
Human leukocyte antigen typing showed haplotype DRB1*09:01-DQB1*03:03, which was reported to be closely associated with type 1 diabetes mellitus in Japan.
In the Japanese T1D group the association was with haplotype DRB1*0802-DQB1*0302 (P = 0.0008), while in the Swedish T1D patients binding to the b96.11-defined epitope as associated with the presence of high-risk HLA genotypes DR3-DQB1*0201 and/or DR4-DQB1*0302 (P = 0.02).
For DRB1*03:01/*04:01 heterozygotes, however, the HLA-DRB3 allele did not significantly modify the T1D risk of the DRB1*03:01 haplotype (OR 7.7 for *02:02; 6.8 for *01:01).
Family analysis revealed involvement of multiple DR3+ve haplotypes with T1DM in North Indian children with A26-B8-DRB1*03 (25% vs 3.5%, chi2=16.9, p=3.96E-05) and Ax-B50-DRB1*03 (25% vs 0.7%, chi2=44.7, p=9.88E-11) being the most frequent haplotypes encountered among patients.
Multivariate logistic regression analysis revealed that DQ-LTR13 is not independently associated with type 1 diabetes and AAD after correction for DQB1*0302 and DRB1*0403.
Human leukocyte antigen (HLA) class II DRB1 and DQB1 represent the major type I diabetes (T1D) genetic susceptibility loci; however, other genes in the HLA region are also involved in T1D risk.
The frequency of DRB1*04:05-DQB1*04:01, a susceptible haplotype for type 1 diabetes, was significantly lower in patients with AA (TRAb-positive: 8.5%; TRAb-negative: 11.9%) than in those with type 1 diabetes (29.5%, Pc < .0003 and Pc < .0008, respectively).
B and C allele associations were tested for certain T1D-associated DRB1-DQB1 haplotypes, with the following results: B*3801 is protective on DRB1*0401-DQB1*0302 haplotypes, both C*0701 and C*0702 are predisposing on DRB1*0404-DQB1*0302 haplotypes, and B*3906 is predisposing on DRB1*0801-DQB1*0402 haplotypes.
HLA DRB1*0405, DRB1*0901 and DRB1*0802-DQB1*0302 haplotypes were positively associated with T1D, while the DRB1*15 haplotypes were negatively associated.
Third, tests of strongest association allowed the following ranking of alleles or haplotypes DQB1*0302-DQA1*0301 (DQ8) > DQB1*0302 > DRB1*0401 > DRB1*0404 and the association of DRB1*0401 has a significant effect in DQ8 positive IDDM patients.
DRB1*0301-DQA1*0501-DQB1*0201 was the most frequent haplotype in both groups but we found a higher proportion of protective T1D haplotypes and Asp(beta57) in the Ab neg group, but in all the cases in combination with susceptible T1D haplotypes.
HLA-B39 was more frequent in DRB1*0404-DQB1*0302-positive IDDM haplotypes compared with control ones (37.0% vs. 14.3%, P = 0.049), suggesting an involvement of the region telomeric to HLA-DRB1 in the susceptibility to IDDM.
Because of the strong association of T1D with DRB1*03:01 and DRB1*04:01, we stratified our analyses based on families whose probands were positive for DRB1*03:01 or DRB1*04:01.