Contributions of vitamin D response elements and HLA promoters to multiple sclerosis risk
Nolan D et al. – HLA–DRB1 groups corresponding to serologic HLA–DR profiles as well as promoter polymorphism haplotypes effectively stratified MS risk over an 11–fold range, suggesting functional relationships between risk–modifying HLA–DRB1 alleles. An independent contribution of VDRE motif variation to increase MS risk was not discernible, although vitamin D–dependent regulation of HLA–DR expression may still play an important role given that HLA–DRB1*04/*07/*09 (DR53) alleles that express the “nonresponsive” VDRE motif were associated with significantly reduced risk of MS.Methods
- The authors utilized 32 homozygous HLA cell lines (covering 17 DRB1 alleles) and 53 heterozygote MS samples (20 DRB1 alleles) for HLA-DRB1 promoter sequencing.
- The influence of HLA-DRB1 variation on MS risk was then assessed among 466 MS cases and 498 controls.
- The majority of HLA*DRB1 alleles (including HLA-DRB1*15:01) express the functional VDRE motif, apart from HLA-DRB1*04, *07, and *09 alleles that comprise the HLA-DR53 serologic group.
- Allele-specific variation within functional X-box and Y-box motifs was also associated with serologically defined HLA-DR haplotypes.
- Incorporating these results in an analysis of MS risk, they identified a strong protective effect of HLA-DRB1*04, *07, and *09 (DR53) alleles (p = 10-12-18).