Ramagopalan Sreeram V, McMahon Roisin, Dyment David A, Sadovnick A Dessa, Ebers George C, Wittkowski Knut M
1Department of Clinical Neurology, University of Oxford, The West Wing, The John Radcliffe Hospital, Oxford, OX3 9DU, UK.
BMC Med Genet. 2009 Feb 4;10:10. doi: 10.1186/1471-2350-10-10.
Multiple sclerosis (MS) is a complex trait in which genes in the MHC class II region exert the single strongest effect on genetic susceptibility. The principal MHC class II haplotype that increases MS risk in individuals of Northern European descent are those that bear HLA-DRB1*15. However, several other HLA-DRB1 alleles have been positively and negatively associated with MS and each of the main allelotypes is composed of many sub-allelotypes with slightly different sequence composition. Given the role of this locus in antigen presentation it has been suggested that variations in the peptide binding site of the allele may underlie allelic variation in disease risk.
In an investigation of 7,333 individuals from 1,352 MS families, we assessed the nucleotide sequence of HLA-DRB1 for any effects on disease susceptibility extending a recently published method of statistical analysis for family-based association studies to the particular challenges of hyper-variable genetic regions.
We found that amino acid 60 of the HLA-DRB1 peptide sequence, which had previously been postulated based on structural features, is unlikely to play a major role. Instead, empirical evidence based on sequence information suggests that MS susceptibility arises primarily from amino acid 13.
Identifying a single amino acid as a major risk factor provides major practical implications for risk and for the exploration of mechanisms, although the mechanism of amino acid 13 in the HLA-DRB1 sequence's involvement in MS as well as the identity of additional variants on MHC haplotypes that influence risk need to be uncovered.
多发性硬化症（MS）是一种复杂性状，其中MHC II类区域的基因对遗传易感性产生最强的单一影响。在北欧血统个体中增加MS风险的主要MHC II类单倍型是那些携带HLA-DRB1*15的单倍型。然而，其他几个HLA-DRB1等位基因与MS呈正相关和负相关，并且每个主要等位基因型由许多序列组成略有不同的亚等位基因型组成。鉴于该基因座在抗原呈递中的作用，有人提出等位基因肽结合位点的变异可能是疾病风险等位基因变异的基础。
在对来自1352个MS家族的7333名个体的调查中，我们评估了HLA-DRB1的核苷酸序列对疾病易感性的任何影响，将最近发表的基于家系关联研究的统计分析方法扩展到高变基因区域的特殊挑战。
我们发现，基于结构特征先前推测的HLA-DRB1肽序列的第60位氨基酸不太可能起主要作用。相反，基于序列信息的经验证据表明，MS易感性主要源于第13位氨基酸。
确定单个氨基酸为主要风险因素对风险评估和机制探索具有重要实际意义，尽管HLA-DRB1序列中第13位氨基酸参与MS的机制以及影响风险的MHC单倍型上其他变异的身份仍有待揭示。
