Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A
Nejentsev S., Howson JMM., Walker NM., Szeszko J., Field SF., Stevens HE., Reynolds P., Hardy M., King E., Masters J., Hulme J., Maier LM., Smyth D., Bailey R., Cooper JD., Ribas G., Campbell RD., Clayton DG., Todd JA., Burton PR., Cardon LR., Craddock N., Deloukas P., Duncanson A., Kwiatkowski DP., McCarthy MI., Ouwehand WH., Samani NJ., Donnelly P., Barrett JC., Davison D., Easton D., Evans D., Leung HT., Marchini JL., Morris AP., Spencer CCA., Tobin MD., Attwood AP., Boorman JP., Cant B., Everson U., Hussey JM., Jolley JD., Knight AS., Koch K., Meech E., Nutland S., Prowse CV., Taylor NC., Walters GR., Watkins NA., Winzer T., Jones RW., McArdle WL., Ring SM., Strachan DP., Pembrey M., Breen G., St Clair D., Caesar S., Gordon-Smith K., Jones L., Fraser C., Green EK., Grozeva D., Hamshere ML., Holmans PA., Jones IR., Kirov G., Moskvina V., Nikolov I., O Donovan MC., Owen MJ., Collier DA., Elkin A., Farmer A., Williamson R., McGuffin P., Young AH., Ferrier IN., Ball SG., Balmforth AJ., Barrett JH., Bishop DT., Iles MM.
The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region’s extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group.