The inheritance of resistance alleles in multiple sclerosis
The inheritance of resistance alleles in multiple sclerosis
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DOI：
10.1371/journal.pgen.0030150
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发表时间：
2007-09-01
期刊：
影响因子：
4.5
通讯作者：
Ebers, George C.
中科院分区：
文献类型：
--
作者：
Ramagopalan, Sreeram V.;Morris, Andrew P.;Ebers, George C.
多发性硬化症（MS）是一种复杂的性状，II类基因座HLA-DRB1和HLA-DQB1或其附近的等位基因与遗传风险有显著关系。携带HLA-DRB1*15和HLA-DRB1*17的单倍型和HLA-DRB1位点的相互作用增加了MS的风险，但鉴定耐药HLA-DRB1等位基因需要大量样本。在这项来自1432个MS家族的7093个人的调查中，我们评估了HLA-DRB1抗性等位基因的有效性、遗传方式、相关基因型和相互作用。HLA-DRB1*14-、HLA-DRB1*11-、HLA-DRB1*01-和HLA-DRB1*10单倍型总体上具有保护作用，但它们的作用机制似乎不同。第一种抗性等位基因为HLA-DRB1*14和HLA-DRB1*11。每一种都显示出一种倍增的遗传模式，表明了对风险的广泛抑制，但保护程度不同。相反，第二种类型以HLA-DRB1*10和HLA-DRB1*01为例。当这些等位基因与HLA-DRB1*15单倍型特异性反式相互作用时，它们具有显著的保护作用。HLA-DRB1*01和HLA-DRB1*10不与HLADRB1*17相互作用，这意味着在主要组织相容性复合体相关的MS易感性中可能有几种机制起作用，可能类似于抗性等位基因。这对风险和动物模型机制的探索具有重要的实际意义。HLA-DRB1*15限制抗原呈递似乎是主要组织相容性复合体相关易感性的一个不太可能的简单机制。
Multiple sclerosis ( MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk. HLA-DRB1*15 and HLA-DRB1*17-bearing haplotypes and interactions at the HLA-DRB1 locus increase risk of MS but it has taken large samples to identify resistance HLA-DRB1 alleles. In this investigation of 7,093 individuals from 1,432 MS families, we have assessed the validity, mode of inheritance, associated genotypes, and the interactions of HLA-DRB1 resistance alleles. HLA-DRB1*14-, HLA-DRB1*11-, HLA-DRB1*01-, and HLA-DRB1*10-bearing haplotypes are protective overall but they appear to operate by different mechanisms. The first type of resistance allele is characterised by HLA-DRB1*14 and HLA-DRB1*11. Each shows a multiplicative mode of inheritance indicating a broadly acting suppression of risk, but a different degree of protection. In contrast, a second type is exemplified by HLA-DRB1*10 and HLA-DRB1*01. These alleles are significantly protective when they interact specifically in trans with HLA-DRB1*15-bearing haplotypes. HLA-DRB1*01 and HLA-DRB1*10 do not interact with HLADRB1*17, implying that several mechanisms may be operative in major histocompatibility complex-associated MS susceptibility, perhaps analogous to the resistance alleles. There are major practical implications for risk and for the exploration of mechanisms in animal models. Restriction of antigen presentation by HLA-DRB1*15 seems an improbably simple mechanism of major histocompatibility complex-associated susceptibility.