Histocompatibility & Immunogenetics Laboratory, Stanford Blood Center, Palo Alto, CA, United States.
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, United States.
Front Immunol. 2021 May 25;12:644838. doi: 10.3389/fimmu.2021.644838. eCollection 2021.
Multiple sclerosis (MS) susceptibility shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes in 477 non-Hispanic European MS patients and their 954 unaffected parents using a validated next-generation sequencing (NGS) methodology. HLA haplotypes were assigned unequivocally by tracing HLA allele transmissions. We explored HLA haplotype/allele associations with MS using the genotypic transmission disequilibrium test (gTDT) and multiallelic TDT (mTDT). We also conducted a case-control (CC) study with all patients and 2029 healthy unrelated ethnically matched controls. We performed separate analyses of 54 extended multi-case families by reviewing transmission of haplotype blocks. The haplotype fragment including was significantly associated with predisposition (gTDT: < 2.20e-16; mTDT: =1.61e-07; CC: < 2.22e-16) as reported previously. A second risk allele, (gTDT: = 3.69e-03; mTDT: = 2.99e-03; CC: = 1.00e-02), independent from the haplotype bearing was newly identified. The allele showed significant protection (gTDT: = 8.68e-06; mTDT: = 4.50e-03; CC: = 1.96e-06). Two alleles, (gTDT: = 2.86e-03; mTDT: = 5.56e-02; CC: = 4.08e-05) and (gTDT: = 1.17e-02; mTDT: = 1.16e-02; CC: = 1.21e-02), defined at two-field level also showed protective effects. The HLA class I block, (gTDT: = 5.86e-03; mTDT: = 3.65e-02; CC: = 9.69e-03) and the alleles (gTDT: = 6.28e-04; mTDT: = 2.15e-03; CC: = 1.47e-02) and (gTDT: = 3.20e-03; mTDT: = 6.14e-03; CC: = 1.70e-02) showed moderately protective effects independently from each other and from the class II associated factors. By comparing statistical significance of 11 HLA loci and 19 haplotype segments with both untruncated and two-field allele names, we precisely mapped MS candidate alleles/haplotypes while eliminating false signals resulting from 'hitchhiking' alleles. We assessed genetic burden for the HLA allele/haplotype identified in this study. This family-based study including the highest-resolution of HLA alleles proved to be powerful and efficient for precise identification of HLA genotypes associated with both, susceptibility and protection to development of MS.
多发性硬化症 (MS) 的易感性与 HLA 等位基因和单倍型表现出强烈的遗传关联。我们使用经过验证的下一代测序 (NGS) 方法对 477 名非西班牙裔欧洲 MS 患者及其 954 名未受影响的父母进行了 11 个 HLA 基因的基因分型。通过追踪 HLA 等位基因的传递，明确地分配了 HLA 单倍型。我们使用基因传递不平衡测试 (gTDT) 和多等位基因 TDT (mTDT) 来研究 HLA 单倍型/等位基因与 MS 的关联。我们还对所有患者和 2029 名种族匹配的健康无关对照进行了病例对照 (CC) 研究。我们通过审查单倍型块的传递对 54 个扩展多病例家族进行了单独分析。包括 在内的单倍型片段与易感性显著相关 (gTDT: < 2.20e-16; mTDT: =1.61e-07; CC: < 2.22e-16)，如前所述。第二个风险等位基因 (gTDT: = 3.69e-03; mTDT: = 2.99e-03; CC: = 1.00e-02)，与携带 的单倍型独立，被新发现。等位基因 显示出显著的保护作用 (gTDT: = 8.68e-06; mTDT: = 4.50e-03; CC: = 1.96e-06)。两个 等位基因 (gTDT: = 2.86e-03; mTDT: = 5.56e-02; CC: = 4.08e-05) 和 (gTDT: = 1.17e-02; mTDT: = 1.16e-02; CC: = 1.16e-02)，在双等位基因水平上定义，也显示出保护作用。HLA I 类单倍型块 (gTDT: = 5.86e-03; mTDT: = 3.65e-02; CC: = 9.69e-03) 和等位基因 (gTDT: = 6.28e-04; mTDT: = 2.15e-03; CC: = 1.47e-02) 和 (gTDT: = 3.20e-03; mTDT: = 6.14e-03; CC: = 1.70e-02) 表现出适度的保护作用，彼此独立，与 II 类相关因素独立。通过比较 11 个 HLA 基因座和 19 个单倍型片段与未截断和双等位基因名称的统计学意义，我们在消除了“搭便车”等位基因产生的假信号的同时，精确地定位了 MS 候选等位基因/单倍型。我们评估了本研究中鉴定的 HLA 等位基因/单倍型的遗传负担。这项包括最高分辨率 HLA 等位基因的基于家族的研究被证明是强大和有效的，可用于精确识别与 MS 易感性和保护作用相关的 HLA 基因型。
