Does a central MHC gene in linkage disequilibrium with HLA-DRB*0401 affect susceptibility to type 1 diabetes?

Subtypes of HLA-DR4 are associated with susceptibility or protection against type 1 diabetes (T1DM). We addressed whether this reflects linkage disequilibrium with the true susceptibility locus by studying broader MHC haplotypes marked by alleles of HLA-B, IKBL ( adjacent to TNFA) and complement C4. The study used a largely Caucasian cohort from Western Australia. HLA-DRB1* 0401 and HLA-DRB1* 0405 marked susceptibility to T1DM. In Caucasians, DRB1*0401 occurs predominantly in the 44.1 ancestral haplotype (AH; HLA-A2, B44, DRB1* 0401, DQB1* 0301) and the 62.1AH ( HLA-A2,B15( 62), DRB1* 0401, DQB1* 0302). HLA- B15 marked susceptibility and HLA- B44 marked with resistance to T1DM in patients and controls preselected for HLA- DRB1* 0401. A gene between TNFA and HLA- B on the 8.1AH ( HLA- A1, B8,; DR3, DQ2) modifies the effects of the class II alleles. Here, alleles characteristic of the 62.1AH (C4B3, IKBL_446* T and HLA- A2, B15) were screened in donors preselected for HLA- DRB1* 0401. C4B3 was associated with diabetes, consistent with a diabetes gene telomeric of MHC class II. However, increases in carriage of IKBL_446* T and HLA- A2, B15 were marginal, as too few control subjects were available with the diabetogenic alleles. However, with these tools, selection of HLA- DRB1* 0401, DQB1* 0302 donors who are positive and negative for C4B3 will allow bidirectional mapping of diabetes genes in the central MHC.