Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Aβ42 levels and risk for Alzheimer disease
Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Aβ42 levels and risk for Alzheimer disease
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DOI：
10.1002/humu.20016
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发表时间：
2004-01-01
期刊：
影响因子：
3.9
通讯作者：
Younkin, SG
中科院分区：
文献类型：
--
作者：
Ertekin-Taner, N;Allen, M;Younkin, SG
晚发性阿尔茨海默病（LOAD）和血浆淀粉样蛋白β水平（A β 42;由APP编码）的风险，LOAD的中间表型，显示与染色体10 q相关。几个强候选基因（VR 22，PLAU，IDE）位于1-lod连锁支持区间内。其他人已经独立鉴定了携带IDE的染色体10 q区域中的单倍型，其显示与中间AD表型和AD风险高度显著相关。为了追求这些关联，我们分析了24个扩展LOAD家族中与血浆Abeta 42相关的相同单倍型，以及两个独立病例对照系列中与LOAD相关的相同单倍型。一个系列（MCR，188个年龄匹配的病例对照对）没有显示与276 kb区域中的6个单倍型相关（p = 0.64），这些单倍型跨越了先前显示与LOAD相关的3个基因（IDE、KNSL 1和HHEX）。其他系列（MCJ，109岁，匹配的情况下，控制对）显示出显着的（p = 0.003）与这些单倍型。在MCJ系列中，H4（比值比[OR] = 5.1，p = 0.003）和H2（H7）单倍型（OR = 0.60，p = 0.04）具有与先前报道相同的效应。在这个系列中，H8单倍型（OR = 2.7，p = 0.098）也有类似的效果，在一个以前的病例对照系列，但不是在其他人。在大家族中，H8单倍型与显著升高的血浆A β 42相关（p = 0.02）。此外，在另一项研究中与AD风险降低相关的H5（H10）单倍型与我们家族系列中血浆A β 42降低相关（p = 0.007）。这些结果为携带IDE的276 kb区域中的致病性变体提供了强有力的证据，这些致病性变体影响中间AD表型和AD风险。(C)2004 Wiley-Liss，Inc.
Risk for late onset Alzheimer disease (LOAD) and plasma amyloid beta levels (Abeta42; encoded by APP), an intermediate phenotype for LOAD, show linkage to chromosome 10q. Several strong candidate genes (VR22, PLAU, IDE) lie within the 1-lod support interval for linkage. Others have independently identified haplotypes in the chromosome 10q region harboring IDE that show highly significant association with intermediate AD phenotypes and with risk for AD. To pursue these associations, we analyzed the same haplotypes for association with plasma Abeta42 in 24 extended LOAD families and for association with LOAD in two independent case, control series. One series (MCR, 188 age matched case-control pairs) did not show association (p = 0.64) with the six haplotypes in the 276-kb region spanning three genes (IDE, KNSL1, and HHEX) previously shown to associate with LOAD. The other series (MCJ, 109 age,matched case,control pairs) showed significant (p = 0.003) association with these haplotypes. In the MCJ series, the H4 (odds ratio [OR] = 5.1, p = 0.003) and H2(H7) haplotypes (OR = 0.60, p = 0.04) had the same effects previously reported. In this series, the H8 haplotype (OR = 2.7, p = 0.098) also had an effect similar as in one previous case control series but not in others. In the extended families, the H8 haplotype was associated with significantly elevated plasma Abeta42 (p = 0.02). In addition, the H5 (H10) haplotype, which is associated with reduced risk for AD in the other study is associated with reduced plasma Abeta42 (p = 0.007) in our family series. These results provide strong evidence for pathogenic variant(s) in the 276-kb region harboring IDE that influence intermediate AD phenotypes and risk for AD. (C) 2004 Wiley-Liss, Inc.