Find in Library

The human leukocyte antigen (HLA) region associations account for most of the genetic susceptibility of type 1 diabetes (T1D) and multiple sclerosis (MS), but their involvement in the pathogenesis is unclear. To increase the power of analysis, the current research is focused on the observation that the alleles of the ancestral HLA haplotype (AH) 7.1 (A3-B7-C7-DR15-DQ6) show protective associations with T1D, but risk associations with MS. Functional annotation of common risk markers located in the HLA region was performed to gain insight into the possible mechanisms. None of the common associations pointed towards antigen presentation differences via HLA alleles of AH 7.1 in the differential risk. Around 63 SNPs showed correlation with AH 7.1, and none were the known proxy markers for the HLA alleles of AH 7.1. Twenty common risk markers were on haplotypes different from AH 7.1 with a subset correlating with HLA-B*44:02. On examination of the correlation between SNPs and gene expression levels, all these common risk markers were identified as expression quantitative trait loci (eQTL) in whole blood samplies. One of the most common correlations of risk markers with gene expression is MIR6981. Most of these SNPs are located in histone modification or transcription factor binding sites (TFBS). These transcription factors (TF) have already been implicated in MS and T1D pathogenesis via different pathways affecting immunological balance. The results of this study suggest that the non-HLA content of AH 7.1 and other haplotypes are likely to be instrumental in the pathogenesis of T1D and MS. Markers that show associations in opposite directions in different diseases may be crucial to understand disease biology.