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Abstract
Objective: The identification of a vitamin D–responsive (VDRE) motif within the HLA-DRB1*15:01 promoter region provides an attractive explanation for the combined effects of HLA-DR inheritance and vitamin D exposure on multiple sclerosis (MS) risk. We therefore sought to incorporate HLA-DRB1 promoter variation, including the VDRE motif, in an assessment of HLA-DRB1–associated MS risk.
Methods: We 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.
Results: 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, we identified a strong protective effect of HLA-DRB1*04, *07, and *09 (DR53) alleles (p = 10−12) and elevated risk associated with DRB1*15 and *16 (DR51) and *08 (DR8) alleles (p < 10−18).
Conclusions: 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.
GLOSSARY
- ABMDR=
- Australian Bone Marrow Donor Registry;
- AH=
- ancestral haplotype;
- HARP=
- heterozygous ambiguity resolving primer;
- MS=
- multiple sclerosis;
- OR=
- odds ratio;
- PDDD=
- Perth Demyelinating Disease Database;
- VDR=
- vitamin D receptor;
- VDRE=
- vitamin D–responsive element
Footnotes
Study funding: This study was funded in part by the McCusker Charitable Foundation.
Supplemental data at www.neurology.org.
- Received September 12, 2011.
- Accepted February 1, 2012.
- Copyright © 2012 by AAN Enterprises, Inc.
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