Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease
Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease
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DOI：
10.1007/s00439-001-0614-1
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发表时间：
2001-12-01
期刊：
影响因子：
5.3
通讯作者：
Jones, L
中科院分区：
文献类型：
--
作者：
Abraham, R;Myers, A;Jones, L
胰岛素降解酶（IDE，insulysin; EC 3.4.24.56）是一种110-kDa的中性金属肽酶，可降解包括β-淀粉样蛋白在内的许多肽。编码IDE的基因位于10号染色体上，靠近迟发性阿尔茨海默病（LOAD）的连锁区域，因此是这种疾病的功能和位置候选者。我们用变性高效液相色谱和测序方法分析了IDE的所有编码外显子、非翻译区和1000 bp的5 '侧翼序列。我们检测到8个单核苷酸多态性（SNPs）。3个在5 ′侧翼序列中，5个在编码序列中，其中3个以低于5%的频率发现。它们都没有改变氨基酸序列。我们对在英国收集的133例高加索LOAD病例和135例对照以及在美国罗切斯特的马约诊所收集的95例病例和117例对照中等位基因频率超过5%的5个SNP进行了基因分型。在另一个独立的病例对照样本中分析了两个SNP（华盛顿大学，圣路易斯：86例，94例对照）。在任何样本中均未发现与任何单个SNP或与单倍型的显著关联。标记D10 S583，其映射IDE上游36 kb的分析也未能显示来自英国的114例病例和111例匹配对照的相关性（P=0.63）。强连锁不平衡之间的5个SNPs，跨越整个120 kb的基因组区域的IDE和一个主要的和一些次要的单倍型检测到的人口，研究。我们的结论是IDE对LOAD的病因学没有实质性的贡献，因此不能解释LOAD和10 q之间的联系。
Insulin-degrading enzyme (IDE, insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that call degrade a number of peptides including P-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of link-age for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5'-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs). three in the 5' flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with an haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 114 cases and 111 matched controls from the UK (P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the population, Studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.