Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Abstract

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 4-11 . Owing to the region's extreme gene density, the multiplicity of diseaseassociated 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; P combined =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

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

“…9 Furthermore, it indicates that our susceptibility locus maps away from the classical MHC, although additional risk loci are also believed to exist there, in particular for HLA-B. 25,[27][28][29] It is interesting to note that conditional logistic regression analyses in the T1DGC dataset showed that the associations with the PRSS16 SNPs and one of the BTN SNPs were independent of HLA-B, and also of the other class I loci. The associations with the PRSS16 SNPs also seemed independent of the earlier reported UBD and HLA-G associations, though some dependency was seen in the regression analyses between one of the HLA-G SNPs and one of the PRSS16 SNPs, even though there was hardly any LD between these SNPs when calculated on the basis of the entire T1DGC dataset.…”

Family-based analysis of tumor necrosis factor and lymphotoxin-α tag polymorphisms with type 1 diabetes in the population of South Croatia

“…It has a strong genetic component. The most important genetic factors for determining the risk of developing T1DM reside in the HLA class II loci but also, according to recent findings, in the HLA-B and HLA-A class I genes [2]. Several other gene regions have also been identified: a region 5′ to the INS gene, CTLA4, PTPN22, IL2RA, and the IFIH1 region [3,4].…”

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

“…1,2 However, numerous studies have strongly implicated additional T1D risk loci within the MHC. [3][4][5][6][7][8][9][10][11][12] This complex contains an unusually high density of genes involved in immunological responses, 13 of which many are good candidates for involvement in autoimmune processes. The observation of multiple susceptibility loci in the MHC is shared with a number of other AIDs, including ankylosing spondylitis, celiac disease, Graves' disease, juvenile idiopathic arthritis, multiple sclerosis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus and ulcerative colitis (cf.…”