Vandenbroeck Koen, Fiten Pierre, Heggarty Shirley, Goris An, Cocco Eleonora, Hawkins Stanley A, Graham Colin A, Marrosu Maria G, Opdenakker Ghislain
Rega Institute for Medical Research, University of Leuven, B-3000 Louvain, Belgium.
J Neuroimmunol. 2002 Apr;125(1-2):141-8. doi: 10.1016/s0165-5728(02)00023-1.
Chromosome 7q21-22 and, in particular, the region surrounding D7S554 emerged from the recent American genome screen in multiple sclerosis (MS) as the most promising region genome-wide for harboring a disease susceptibility gene. We tested association between D7S554 and MS in 217 Sardinian trio MS families by the transmission disequilibrium test (TDT), and in a Northern Irish case-control study comprising 542 individuals. In both populations, we found evidence for significant allelic association (P(c)=0.04 and P(c)=0.0002, respectively). In a second stage, we analysed five microsatellite markers in a 4 megabase interval on chromosome 7q21-22 in the same set of Sardinian families. Parental transmission of a single allele of one of these markers, i.e. D7S3126, was significantly distorted (P(c)=0.008). D7S554 and D7S3126 are located at distances of, respectively, 40 and 81 kb 5' from the startcodon of the protachykinin-1 gene (TAC1), and occur in strong linkage disequilibrium (P<10(-7)). Our study indicates that the previous finding of linkage with D7S554 refers possibly to the presence of an MS susceptibility effect in vicinity to TAC1. In addition, a second independent association was uncovered between a microsatellite polymorphism in the plasminogen activator inhibitor-1 gene, i.e. D7S477, and MS. Overall, the analysis presented here may contribute to the increasingly refined genomic map of MS and underscores the requirement for a further high-resolution screening of chromosome 7q21-22.
7号染色体q21 - 22区域，尤其是围绕D7S554的区域，在近期针对多发性硬化症（MS）的美国基因组筛查中脱颖而出，成为全基因组范围内最有希望含有疾病易感基因的区域。我们通过传递不平衡检验（TDT）在217个撒丁岛三联体MS家庭中检测了D7S554与MS之间的关联，并在一项包含542名个体的北爱尔兰病例对照研究中进行了检测。在这两个人群中，我们都发现了显著等位基因关联的证据（分别为P(c)=0.04和P(c)=0.0002）。在第二阶段，我们在同一组撒丁岛家庭中分析了7号染色体q21 - 22上4兆碱基区间内的五个微卫星标记。这些标记之一即D7S3126的单个等位基因的亲本传递存在显著扭曲（P(c)=0.008）。D7S554和D7S3126分别位于速激肽原-1基因（TAC1）起始密码子5'端40和81 kb处，并且处于强连锁不平衡状态（P<10(-7)）。我们的研究表明，先前与D7S554连锁的发现可能是由于TAC1附近存在MS易感效应。此外，还发现纤溶酶原激活物抑制剂-1基因中的一个微卫星多态性即D7S477与MS之间存在第二个独立关联。总体而言，此处呈现的分析可能有助于进一步完善MS的基因组图谱，并强调对7号染色体q21 - 22进行进一步高分辨率筛查的必要性。
