Center for Genetics, Children's Hospital Oakland Research Institute, Oakland, CA, USA.
University of Minnesota Twin Cities, Minneapolis, MN, USA.
Genes Immun. 2019 Apr;20(4):308-326. doi: 10.1038/s41435-017-0006-8. Epub 2018 Jan 8.
We investigated association between HLA class I and class II alleles and haplotypes, and KIR loci and their HLA class I ligands, with multiple sclerosis (MS) in 412 European American MS patients and 419 ethnically matched controls, using next-generation sequencing. The DRB115:01~DQB106:02 haplotype was highly predisposing (odds ratio (OR) = 3.98; 95% confidence interval (CI) = 3-5.31; p-value (p) = 2.22E-16), as was DRB103:01~DQB102:01 (OR = 1.63; CI = 1.19-2.24; p = 1.41E-03). Hardy-Weinberg (HW) analysis in MS patients revealed a significant DRB103:01~DQB102:01 homozyote excess (15 observed; 8.6 expected; p = 0.016). The OR for this genotype (5.27; CI = 1.47-28.52; p = 0.0036) suggests a recessive MS risk model. Controls displayed no HW deviations. The C03:04~B40:01 haplotype (OR = 0.27; CI = 0.14-0.51; p = 6.76E-06) was highly protective for MS, especially in haplotypes with A02:01 (OR = 0.15; CI = 0.04-0.45; p = 6.51E-05). By itself, A02:01 is moderately protective, (OR = 0.69; CI = 0.54-0.87; p = 1.46E-03), and haplotypes of A02:01 with the HLA-B Thr80 Bw4 variant (Bw4T) more so (OR = 0.53; CI = 0.35-0.78; p = 7.55E-04). Protective associations with the Bw4 KIR ligand resulted from linkage disequilibrium (LD) with DRB115:01, but the Bw4T variant was protective (OR = 0.64; CI = 0.49-0.82; p = 3.37-04) independent of LD with DRB115:01. The Bw4I variant was not associated with MS. Overall, we find specific class I HLA polymorphisms to be protective for MS, independent of the strong predisposition conferred by DRB115:01.
我们使用下一代测序技术，在 412 名欧洲裔美国多发性硬化症 (MS) 患者和 419 名具有相同种族背景的对照中，研究了 HLA Ⅰ类和Ⅱ类等位基因和单倍型与 KIR 基因座及其 HLA Ⅰ类配体与 MS 之间的关联。DRB115:01~DQB106:02 单倍型具有高度易感性（比值比 (OR) = 3.98；95%置信区间 (CI) = 3-5.31；p 值 (p) = 2.22E-16），DRB103:01~DQB102:01 也是如此（OR = 1.63；CI = 1.19-2.24；p = 1.41E-03）。在 MS 患者中进行的 Hardy-Weinberg（HW）分析显示，DRB103:01~DQB102:01 纯合子过度存在显著差异（15 例观察到；8.6 例预期；p = 0.016）。该基因型的 OR（5.27；CI = 1.47-28.52；p = 0.0036）表明存在隐性 MS 风险模型。对照者未显示 HW 偏离。C03:04~B40:01 单倍型（OR = 0.27；CI = 0.14-0.51；p = 6.76E-06）对 MS 具有高度保护作用，尤其是在与 A02:01 相关的单倍型中（OR = 0.15；CI = 0.04-0.45；p = 6.51E-05）。A02:01 本身具有中等保护作用（OR = 0.69；CI = 0.54-0.87；p = 1.46E-03），A02:01 与 HLA-B Thr80 Bw4 变体（Bw4T）的单倍型更是如此（OR = 0.53；CI = 0.35-0.78；p = 7.55E-04）。与 Bw4 KIR 配体的保护作用与 DRB115:01 的连锁不平衡（LD）有关，但 Bw4T 变体是独立于与 DRB115:01 的 LD 具有保护作用（OR = 0.64；CI = 0.49-0.82；p = 3.37-04）。Bw4I 变体与 MS 无关。总的来说，我们发现特定的 HLA Ⅰ类多态性对 MS 具有保护作用，独立于 DRB115:01 赋予的强烈易感性。
