Polymorphism in the regulatory region of HLA-DRB genes correlating with haplotype evolution

Abstract

Class II genes of the human major histocompatibility complex (MHC) are polymorphic. Allelic variation of the coding region of these genes is involved in the antigen presentation and is associated with susceptibility to certain autoimmune diseases. The DR region is unique among human class II regions in that multiple DRB genes are expressed. Differential expression of the different DRB loci has been demonstrated, and we sequenced the proximal promoter region of the HLA-DRB genes, known to be involved in the regulation of these genes. We found locus-specific and allele-specific nucleotide variations in their regulatory regions and we determined the relationship between the regulatory regions of HLA-DRB genes. This polymorphism found in the regulatory conserved boxes could be involved in the observed differential expression of DRB loci. In addition, we found a polymorphism between the regulatory regions of DRB1 alleles which might be involved in an allele-specific regulation and therefore could be considered as an additional factor in susceptibility to autoimmune diseases.

Vitamin D Receptor Gene Polymorphisms and HLA DRB1*04 Cosegregation in Saudi Type 2 Diabetes Patients

“…VDREs present a multitude of sequence variations and a spectrum of binding affinities for VDR; this variability enables VDREs to respond optimally to different concentrations of the VDR/ (1,25 [OH]2D) complex (51). Notably, a region almost perfectly overlapping that of VDRE is present in the promoter region of HLA DRB1*04 (52).…”

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

“…Such work was notable for the HLA-DRB genes in which sequence variation involving conserved proximal promoter elements [67][68][69][70] was associated with allelic differences in recruitment of specific-binding factors. [71][72][73] Polymorphism altered gene expression in resting cells [71][72][73][74] but interestingly after cytokine activation, variation in the Y rather than the X1 box was significant.…”

The importance of the back–signal from T cells into antigen–presenting cells in determining susceptibility to parasites

“…These boxes are where transcription factors are known to bind, and where sequence is conserved over long evolutionary distance (Benoist & Mathis 1990;Sultmann et al 1993); indeed this conservation was one of their original de¢ning features. The situation is slightly di¡erent in man, where more alleles have been sequenced, and variation within the X and Y boxes was again found to be high, but not quite as much so as in the intervening sequences (Louis et al 1993). For both man and mouse these generalizations are provisional, as there are many more promoters to sequence; it would be of interest to learn about promoter diversity within the mouse genus, for example.…”