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.
Eike
M C
MC
Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway. Morten.Eike@rr-research.no
Becker
T
T
Humphreys
K
K
Olsson
M
M
Lie
B A
BA
D000483:Alleles; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D059951:HLA-G Antigens; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D006801:Humans; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex / Q000235:genetics*; D018895:Microsatellite Repeats; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D015203:Reproducibility of Results; D044465:White People / Q000235:genetics
D005819:Genetic Markers; D006680:HLA Antigens; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I