Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B
doi: 10.1038/gene.2008.74
pmid: 18830248
Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B
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.
- University of Oslo Norway
- Karolinska Institute Sweden
- Chalmers University of Technology Sweden
- University of Bonn Germany
Genetic Markers, HLA-G Antigens, HLA-A Antigens, Histocompatibility Antigens Class I, Reproducibility of Results, Physical Chromosome Mapping, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, Major Histocompatibility Complex, Diabetes Mellitus, Type 1, Haplotypes, HLA Antigens, HLA-B Antigens, Humans, Regression Analysis, Genetic Predisposition to Disease, Alleles, Microsatellite Repeats
Genetic Markers, HLA-G Antigens, HLA-A Antigens, Histocompatibility Antigens Class I, Reproducibility of Results, Physical Chromosome Mapping, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, Major Histocompatibility Complex, Diabetes Mellitus, Type 1, Haplotypes, HLA Antigens, HLA-B Antigens, Humans, Regression Analysis, Genetic Predisposition to Disease, Alleles, Microsatellite Repeats
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