Department of Clinical Immunology, Royal Perth Hospital, Perth.
Neurology. 2012 Aug 7;79(6):538-46. doi: 10.1212/WNL.0b013e318263c407. Epub 2012 Jul 11.
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.
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.
The majority of HLADRB1 alleles (including HLA-DRB115:01) 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-DRB104, *07, and 09 (DR53) alleles (p = 10(-12)) and elevated risk associated with DRB115 and *16 (DR51) and *08 (DR8) alleles (p < 10(-18)).
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.
在 HLA-DRB1*15:01 启动子区域内鉴定维生素 D 反应元件 (VDRE) 基序，为 HLA-DR 遗传与维生素 D 暴露对多发性硬化症 (MS) 风险的综合作用提供了一个有吸引力的解释。因此，我们试图将 HLA-DRB1 启动子变异包括 VDRE 基序纳入对 HLA-DRB1 相关 MS 风险的评估中。
我们利用 32 个纯合 HLA 细胞系（涵盖 17 个 DRB1 等位基因）和 53 个杂合 MS 样本（20 个 DRB1 等位基因）进行 HLA-DRB1 启动子测序。然后，在 466 例 MS 病例和 498 例对照中评估 HLA-DRB1 变异对 MS 风险的影响。
除了 HLA-DRB104、07 和09 等位基因组成 HLA-DR53 血清型组外，大多数 HLADRB1 等位基因（包括 HLA-DRB115:01）都表达功能性 VDRE 基序。功能性 X 盒和 Y 盒基序内的等位基因特异性变异也与血清学定义的 HLA-DR 单倍型相关。将这些结果纳入 MS 风险分析中，我们发现 HLA-DRB104、07 和09（DR53）等位基因（p=10(-12)）具有强烈的保护作用，而 DRB115 和16（DR51）和*08（DR8）等位基因（p<10(-18)）与风险相关。
与血清学 HLA-DR 图谱以及启动子多态性单倍型相对应的 HLA-DRB1 组有效地将 MS 风险分层在 11 倍范围内，表明风险修饰 HLA-DRB1 等位基因之间存在功能关系。虽然维生素 D 依赖性 HLA-DR 表达调节可能仍然很重要，但未能发现 VDRE 基序变异对增加 MS 风险的独立贡献，因为表达“非反应性”VDRE 基序的 HLA-DRB1*04/*07/*09（DR53）等位基因与 MS 风险显著降低相关。
