Sequence variation within the major histocompatibility complex subregion centromeric of HLA class II in type 1...

The extended major histocompatibility complex (xMHC) has been studied intensively with regard to type 1 diabetes (T1D) predisposition. So far, little attention has been given to the subregion centromeric of MHC class II. We selected five single nucleotide polymorphisms in genes with potential immune-related functions in the genomic regions of death-domain-associated protein 6 (DAXX, apoptosis associated), TAP-binding protein (TAPBP, human leukocyte antigen class I loading) and retinoic acid receptor beta (RXRB, vitamin D receptor function) that may bear relevance to the pathogenesis of T1D. A total of 277 unrelated individuals with juvenile-onset T1D and 286 control subjects were genotyped using sequence-specific priming-polymerase chain reaction. The genotype and allelic frequencies of the markers tested were not significantly different between patients and control subjects. Subsequent haplotype analysis showed six DAXX-TAPBP-RXRB haplotypic configurations. No difference was observed between patients and control cohorts when stratified for T1D high-risk DQ2-DR17 and DQ8-DR4 haplotypes. However, the distribution of these haplotypes affected T1D susceptibility encoded by the intermediate risk haplotypes DQ5-DR1 and DQ2-DR7 by increasing and decreasing susceptibility, respectively. We propose that studying genetic variants in the xMHC may be particularly rewarding to define disease pathways in patients displaying intermediate risk DQ-DR haplotypes.