HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging.
HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging.
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DOI：
10.1111/j.1474-9726.2010.00600.x
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发表时间：
2010-10
期刊：
影响因子：
7.8
通讯作者：
Georgia Centenarian Study and the Louisiana Healthy Aging Study
中科院分区：
文献类型：
--
作者：
Jazwinski SM;Kim S;Dai J;Li L;Bi X;Jiang JC;Arnold J;Batzer MA;Walker JA;Welsh DA;Lefante CM;Volaufova J;Myers L;Su LJ;Hausman DB;Miceli MV;Ravussin E;Poon LW;Cherry KE;Welsch MA;Georgia Centenarian Study and the Louisiana Healthy Aging Study
人类长寿基因的研究在很大程度上忽略了遗传相互作用的作用。我们已经确定了三个基因的常见变体的新组合，该基因与人类寿命和健康衰老有显着关联。招募受试者并根据其遗传推断的种族归属进行分层，以解释人口结构。在三个候选基因中进行单倍型分析，并测试单倍型组合与异常长寿的关联。HRAS 1单倍型增强了APOE单倍型对异常生存的影响，LASS 1单倍型进一步增强了其幅度。这些结果在第二个群体中重复。使用赤字累积指数开发了健康老龄化的概况，这表明这种基因变异的组合与健康老龄化相关。LASS 1的变异是功能性的，导致基因表达增强，它有助于健康衰老和在生命的第十个十年中更大的生存。因此，不需要用罕见的基因变异来解释复杂的性状，如衰老;相反，常见基因变异的罕见一致性很容易实现这一作用。这里描述的三个基因之间的相互作用表明了涉及脂毒性的异常生存和健康衰老的细胞和分子机制的新模型。
The search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging. Subjects were recruited and stratified according to their genetically-inferred ethnic affiliation to account for population structure. Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. These results were replicated in a second population. A profile of healthy aging was developed using a deficit accumulation index, which showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role. The interaction between the three genes described here suggests new models for cellular and molecular mechanisms underlying exceptional survival and healthy aging that involve lipotoxicity.
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