Pleiotropy in the presence of allelic heterogeneity: alternative genetic models for the influence of APOE on serum LDL, CSF amyloid-β42, and dementia.
Pleiotropy in the presence of allelic heterogeneity: alternative genetic models for the influence of APOE on serum LDL, CSF amyloid-β42, and dementia.
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DOI：
10.3233/jad-2010-100864
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发表时间：
2010
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影响因子：
--
通讯作者：
Prince JA
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文献类型：
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作者：
Bennet AM;Reynolds CA;Gatz M;Blennow K;Pedersen NL;Prince JA
两种遗传多态性rs7412和rs429358共同构成载脂蛋白E （APOE）的ε2、ε3和ε4等位基因，是基因组中研究最广泛的序列变异之一。测试APOE的主要模型涉及ε2、ε3和ε4的单倍型组合，并已成为与痴呆、动脉粥样硬化和血脂水平相关的基础。在这里，我们证明了这两个组成位点的功能独立性，rs7412贡献了血清LDL的大部分方差（p = 10−20），而rs429358单独影响CSF a - β42的方差（p = 10−17）。后一种关系也反映在APOE与痴呆的关联中，其中rs429358强烈影响疾病（p = 10−67），而rs7412则没有。与单独rs429358相比，基于ε2、ε3和ε4的模型解释痴呆风险和CSF Aβ42的差异较小。当调整CSF Aβ42时，rs429358与痴呆的相关性大大降低，但仍然显著表明APOE多态性通过与Aβ42代谢不同的其他机制影响疾病。本研究得出四个主要结论：1)单独rs429358负责APOE与痴呆的关联2)APOE与痴呆的关联在很大程度上是由其对中枢神经系统Aβ42水平的影响介导的3)APOE与痴呆的关联不是由其对外周脂质代谢的影响介导的4)rs429358和rs7412的双重作用代表了已知复杂性状遗传多效性的最好例子之一，说明了APOE等位基因异质性的重要性。
The two genetic polymorphisms, rs7412 and rs429358, that collectively form the ε2, ε3, and ε4 alleles of apolipoprotein E (APOE)are among the most widely studied sequence variants in the genome. The predominant model for testing APOE involves the haplotype combinations of ε2, ε3, and ε4 and has been basis of associations with dementia, atherosclerosis, and serum lipid levels. Here, we demonstrate the functional independence of these two component sites, with rs7412 contributing to the majority of variance in serum LDL (p = 10−20), whereas rs429358 alone influences variance in CSF Aβ42(p = 10 −17). This latter relationship is also reflected in the association of APOE with dementia, where rs429358 strongly influences disease (p = 10−67), but rs7412 does not. Models based upon ε2, ε3, and ε4 explained less variance for both dementia risk and CSF Aβ42 than did rs429358 alone. When adjusted for CSF Aβ42, the association of rs429358 with dementia is greatly reduced but remains significant indicating that APOE polymorphism influences disease by additional mechanisms distinct from Aβ42 metabolism. We reach four principal conclusion from this study; 1) rs429358 alone is responsible for the association of APOE with dementia 2) The association of APOE with dementia is substantially mediated by its effect on CNS Aβ42 levels 3) The association of APOE with dementia is not mediated by its impact on peripheral lipid metabolism 4) The dichotomy of effects of rs429358 and rs7412 represents one of the best examples of genetic pleiotropy for complex traits known and illustrates the importance of allelic heterogeneity in APOE.