High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy
High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy
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DOI：
10.1093/hmg/ddi361
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发表时间：
2005-11-01
影响因子：
3.5
通讯作者：
Hutton, ML
中科院分区：
文献类型：
--
作者：
Rademakers, R;Melquist, S;Hutton, ML
Tau基因存在两种延伸的单倍型--H1和H2--H1与进行性核上性麻痹(PSP)的风险增加一致相关。我们利用15个单倍型标签SNPs(HtSNPs)捕获了95%的MAPT单倍型多样性，对274例主要经病理证实的PSP患者和424名匹配的对照个体进行了关联分析。我们发现PSP的风险与两种主要的祖先H1单倍型之一H1B有关，从对照组的14%增加到PSP患者的22%(P<；0.001)。在年轻的PSP患者中，H1B风险可定位于内含子0(P<；0.001)的22kb调节区，并可由一个单核苷酸多态性htSNP167完全解释，该SNP创建了一个lbp-1c/lsf/cp2位点，显示出调节其他神经退行性疾病的基因表达。荧光素酶报告数据表明，htSNP167所在的182个碱基保守的调控区在转录上是活跃的，两个等位基因对表达有不同的影响。此外，我们在第二个独立确定的美国PSP患者对照样本中复制了htSNP167相关性。然而，htSNP关联表明，仅有H1风险并不能解释PSP患者和对照组H1和H2频率的总体差异。因此，H1上不同htSNP单倍型上的风险变异和H2上的保护性变异会导致PSP的群体风险。
Two extended haplotypes exist across the tau gene-H1 and H2-with H1 consistently associated with increased risk of progressive supranuclear palsy (PSP). Using 15 haplotype tagging SNPs (htSNPs), capturing > 95% of MAPT haplotype diversity, we performed association analysis in a US sample of 274 predominantly pathologically confirmed PSP patients and 424 matched control individuals. We found that PSP risk is associated with one of two major ancestral H1 haplotypes, H1B, increasing from 14% in control individuals to 22% in PSP patients (P < 0.001). In young PSP patients, the H1B risk could be localized to a 22 kb regulatory region in intron 0 (P < 0.001) and could be fully explained by one SNP, htSNP167, creating a LBP-1c/LSF/CP2 site, shown to regulate the expression of genes in other neurodegenerative disorders. Luciferase reporter data indicated that the 182 bp conserved regulatory region, in which htSNP167 is located, is transcriptionally active with both alleles differentially influencing expression. Further, we replicated the htSNP167 association in a second, independently ascertained US PSP patient-control sample. However, the htSNP association showed that H1 risk alone could not explain the overall differences in H1 and H2 frequencies in PSP patients and control individuals. Thus, risk variants on different H1 htSNP haplotypes and protective variants on H2 contribute to population risk for PSP.