1. ¹Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway
2. ²Institute of Immunology, Faculty Division Rikshospitalet, University of Oslo, Oslo, Norway
3. ³Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
4. ⁴Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
5. ⁵Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden

Correspondence: MC Eike, Institute of Immunology, Rikshospitalet University Hospital, Sognsvannsveien 20, Oslo N-0027, Norway. E-mail: Morten.Eike@rr-research.no

Received 16 June 2008; Revised 18 August 2008; Accepted 27 August 2008; Published online 2 October 2008.

Abstract

The major histocompatibility complex (MHC) is known to harbour genetic risk factors for type 1 diabetes (T1D) additional to the class II determinants HLA-DRB1, -DQA1 and -DQB1, but strong linkage disequilibrium (LD) has made efforts to establish their location difficult. This study utilizes a dataset generated by the T1D genetics consortium (T1DGC), with genotypes for 2965 markers across the MHC in 2321 T1D families of multiple (mostly Caucasian) ethnicities. Using a comprehensive approach consisting of complementary conditional methods and LD analyses, we identified three regions with T1D association, independent both of the known class II determinants and of each other. A subset of polymorphisms that could explain most of the association in each region included single nucleotide polymorphisms (SNPs) in the vicinity of HLA-G, particular HLA-B and HLA-DPB1 alleles, and SNPs close to the COL11A2 and RING1 genes. Apart from HLA-B and HLA-DPB1, all of these represent novel associations, and subpopulation analyses did not indicate large population-specific differences among Caucasians for our findings. On account of the unusual genetic complexity of the MHC, further fine mapping is demanded, with the possible exception of HLA-B. However, our results mean that these efforts can be focused on narrow, defined regions of the MHC.