Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Aging Cell. 2010 Oct;9(5):698-708. doi: 10.1111/j.1474-9726.2010.00600.x. Epub 2010 Aug 4.
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.
人类寻找长寿相关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常见变体的新型组合，它们与人类寿命和健康衰老有明显的关联。根据遗传推断的种族归属招募并分层受试者，以解释人口结构。在三个候选基因中进行了单倍型分析，并测试了单倍型组合与异常长寿的相关性。HRAS1 单倍型增强了 APOE 单倍型对异常存活的影响，而 LASS1 单倍型进一步增强了其幅度。这些结果在第二个群体中得到了复制。使用缺陷积累指数开发了健康衰老的特征，表明这种基因变异组合与健康衰老有关。LASS1 的变异是功能性的，导致基因表达增强，它有助于健康衰老，并在生命的第十个十年中增加存活。因此，不需要援引罕见的基因变异来解释衰老等复杂特征；相反，常见基因变异的罕见一致性很容易满足这一角色。这里描述的三个基因之间的相互作用表明，涉及脂毒性的异常存活和健康衰老的细胞和分子机制的新模型。
