Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B

Genes Immun. 2009 Jan;10(1):56-67. doi: 10.1038/gene.2008.74. Epub 2008 Oct 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • European Continental Ancestry Group / genetics
  • Genetic Markers
  • Genetic Predisposition to Disease
  • HLA Antigens / genetics*
  • HLA Antigens / immunology
  • HLA-A Antigens / genetics
  • HLA-A Antigens / immunology
  • HLA-B Antigens / genetics*
  • HLA-B Antigens / immunology
  • HLA-G Antigens
  • Haplotypes
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Linkage Disequilibrium
  • Major Histocompatibility Complex / genetics*
  • Microsatellite Repeats
  • Physical Chromosome Mapping
  • Polymorphism, Single Nucleotide*
  • Regression Analysis
  • Reproducibility of Results

Substances

  • Genetic Markers
  • HLA Antigens
  • HLA-A Antigens
  • HLA-B Antigens
  • HLA-G Antigens
  • Histocompatibility Antigens Class I