Trade-off in the effects of the apolipoprotein E polymorphism on the ages at onset of CVD and cancer influences human lifespan.
Trade-off in the effects of the apolipoprotein E polymorphism on the ages at onset of CVD and cancer influences human lifespan.
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DOI：
10.1111/j.1474-9726.2011.00689.x
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发表时间：
2011-06
期刊：
影响因子：
7.8
通讯作者：
Yashin AI
中科院分区：
文献类型：
--
作者：
Kulminski AM;Culminskaya I;Ukraintseva SV;Arbeev KG;Arbeeva L;Wu D;Akushevich I;Land KC;Yashin AI
在揭示健康衰老的遗传起源方面取得的进展在一定程度上受到缺乏复制效应的影响，这通常被认为是假阳性发现的标志。我们令人信服地证明，缺乏对衰老相关性状的遗传效应可能是由于基因作用的权衡。我们专注于充分研究的载脂蛋白E（APOE）e2/3/4多态性以及心血管疾病（CVD）和癌症发病时的寿命和年龄，使用了Fracket心脏研究后代队列的3，924名参与者的数据。Kaplan-Meier估计表明，e4等位基因携带者的寿命短于非e4等位基因携带者（对数秩=0.016）。不利影响归因于e4纯合子的存活率差，而常见的e3/4基因型的影响不显著。然而，与非e4等位基因基因型相比，e3/4基因型与这些疾病的发病呈拮抗性相关，这些疾病倾向于CVD的早期发病和癌症的晚期发病。这种权衡解释了e3/4基因型对生存率缺乏显著影响;在考克斯回归模型中对其进行调整使得e4等位基因的不利影响非常显著（p=0.002）。这种权衡可能是由脂质代谢相关（CVD）和非相关（癌症）机制引起的。进化论的基本原理表明，遗传权衡不应该是一个例外，在研究与衰老有关的特征。更深入地了解介导基因作用的生物学机制对于理解健康寿命的遗传调控和个性化医疗护理至关重要。
Progress in unraveling the genetic origins of healthy aging is tempered, in part, by a lack of replication of effects, which is often considered a signature of false positive findings. We convincingly demonstrate that the lack of genetic effects on an aging-related trait can be due to trade-offs in the gene action. We focus on the well-studied apolipoproetin E (APOE) e2/3/4 polymorphism and on lifespan and ages at onset of cardiovascular diseases (CVD) and cancer, using data on 3,924 participants of the Framingham Heart Study Offspring cohort. Kaplan-Meier estimates show that the e4 allele carriers live shorter lives than the non-e4 allele carriers (log rank=0.016). The adverse effect was attributed to the poor survival of the e4 homozygotes, whereas the effect of the common e3/4 genotype was insignificant. The e3/4 genotype, however, was antagonistically associated with onsets of those diseases predisposing to an earlier onset of CVD and a later onset of cancer compared to the non-e4 allele genotypes. This trade-off explains the lack of a significant effect of the e3/4 genotype on survival; adjustment for it in the Cox regression model makes the detrimental effect of the e4 allele highly significant (p=0.002). This trade-off is likely caused by the lipid-metabolism-related (for CVD) and non-related (for cancer) mechanisms. An evolutionary rationale suggests that genetic trade-offs should not be an exception in studies of aging-related traits. Deeper insights into biological mechanisms mediating gene action are critical for understanding the genetic regulation of a healthy lifespan and for personalizing medical care.
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影响因子：
4
作者：
Greer, Eric L.;Brunet, Anne
通讯作者：
Brunet, Anne
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
9.8
作者：
Gorlov, Ivan P.;Gorlova, Olga Y.;Amos, Christopher I.
通讯作者：
Amos, Christopher I.
影响因子：
3.9
作者：
Bonomini, Francesca;Filippini, Francesca;Rezzani, Rita
通讯作者：
Rezzani, Rita
DOI：
10.1073/pnas.0809594106
发表时间：
2009-02-24
影响因子：
11.1
作者：
Flachsbart, Friederike;Caliebeb, Amke;Nebel, Almut
通讯作者：
Nebel, Almut