An extremes of outcome strategy provides evidence that multiple sclerosis is determined by alleles at the HLA-DRB1 locus
An extremes of outcome strategy provides evidence that multiple sclerosis is determined by alleles at the HLA-DRB1 locus
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DOI：
10.1073/pnas.0707731105
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发表时间：
2007-12-26
影响因子：
11.1
通讯作者：
Ebers, G. C.
中科院分区：
文献类型：
--
作者：
DeLuca, G. C.;Ramagopalan, S. V.;Ebers, G. C.
多发性硬化症（MS）是一种常见的中枢神经系统炎症性疾病，其疾病结局的变异性无与伦比。一组散发MS病例（n = 163），取自长期结果分布的相反极端，用于确定HLA-DRB 1基因座对MS疾病严重程度的作用。良性和恶性MS患者的基因分型集显示，HLA-DRB 1 *01在恶性病例中的代表性明显低于良性病例。从长远来看，该等位基因似乎可以减弱MS的进行性残疾特征。观察结果在（i）撒丁岛良性和恶性患者和（ii）HLA-DRB 1 *01不一致的受影响同胞对队列中双重复制。在后者中，携带HLA-DRB 1 *01等位基因的患者的平均残疾进展指数显著低于不携带HLA-DRB 1 *01等位基因的患者。这些发现还得到了与HLA-DRB 1 *01密切相关的HLA-DRB 1 *04亚型的类似传播失真的支持。HLA-DRB 1 *01在同胞对中的保护作用可能是由于与易感等位基因HLA-DRB 1 *1501的特异性上位性相互作用。在良性和恶性患者的MHC区域的高密度（>700）SNP检查不能识别两组之间显著不同的变体，这表明HLA-DRB 1本身可能是疾病修饰位点。我们的结论是，HLA-DRB 1 *01，以前牵连在疾病抵抗，作为一个独立的疾病进展的修饰符。这些结果将MS的易感性与长期结局密切联系起来，表明共享的基于MHC的定量机制对两者都是共同的，强调了该区域在发病机制中的核心作用。
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases (n = 163), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed that HLA-DRB1*01 was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in (i) Sardinian benign and malignant patients and (ii) a cohort of affected sibling pairs discordant for HLA-DRB1*01. Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1*01 allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion of HLA-DRB1*04 subtypes closely related to HLA-DRB1*01. The protective effect of HLA-DRB1*01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1*1501. A high-density (>700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus. We conclude that HLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis.