1. ¹Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Perth, Australia
2. ²School of Surgery and Pathology, University of Western Australia, Nedlands, Australia
3. ³Centre Nationale de Genotypage, Batiment G2, Evry, France
4. ⁴Department of Endocrinology, Royal Perth Hospital, Perth, Australia
5. ⁵Department of Endocrinology, Princess Margaret Hospital, Subiaco, Australia

Correspondence: Associate Professor P Price, Level 2, Medical Research Foundation Building, Royal Perth Hospital, GPO Box X2213, Perth, WA 6000, Australia. E-mail: pprice@cyllene.uwa.edu.au

Received 22 December 2004; Revised 22 February 2005; Accepted 3 March 2005; Published online 28 April 2005.

Abstract

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.191 words