Open AccessConditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B
Author(s) -
Morten Christoph Eike,
Tim Becker,
Keith Humphreys,
Marita Olsson,
Benedicte A. Lie
Publication year - 2008
Publication title -
genes and immunity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.35
H-Index - 100
eISSN - 1476-5470
pISSN - 1466-4879
DOI - 10.1038/gene.2008.74
Subject(s) - biology , major histocompatibility complex , human leukocyte antigen , linkage disequilibrium , single nucleotide polymorphism , genetics , haplotype , genetic association , allele , mhc class i , population , genotype , gene , antigen , demography , sociology
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.