Deane Drug Discovery Institute, Duke University, Durham, NC, USA.
Alzheimers Dement. 2010 Mar;6(2):125-31. doi: 10.1016/j.jalz.2010.01.011.
This perspective article provides an opportunity to explain a new genetic finding for late-onset Alzheimer's disease (LOAD). It is specifically written for physicians and scientists who are interested in LOAD, but it may be relevant to those interested in identifying susceptibility variants for other complex diseases. The significant finding discussed here is that a variable-length, deoxythymidine homopolymer (poly-T) within intron 6 of the TOMM40 gene is associated with the age of onset of LOAD [Roses AD, Lutz MW, Amrine-Madsen H, Saunders AM, Crenshaw DG, Sundseth SS, et al. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J 2009 December 22;[Epublication ahead of print]. This result was obtained with a phylogenetic study of the genetic polymorphisms that reside within the linkage disequilibrium (LD) block that contains the TOMM40, APOE, and APOC1 genes from patients with LOAD and age-matched subjects without disease. Although the data will have diagnostic, prognostic, and therapeutic strategy implications, this perspective is meant to place the inheritance pattern for this "complex" human disease into context, and to highlight the potential utility of applying phylogenetic tools to the study of the genetics of complex diseases.
这篇观点文章提供了一个机会，可以解释一个新的迟发性阿尔茨海默病（LOAD）的遗传发现。它是专门为对 LOAD 感兴趣的医生和科学家撰写的，但也可能与那些对鉴定其他复杂疾病易感性变异体感兴趣的人相关。这里讨论的重要发现是 TOMM40 基因内含子 6 中的脱氧胸苷（poly-T）的可变长度与 LOAD 的发病年龄有关[Roses AD、Lutz MW、Amrine-Madsen H、Saunders AM、Crenshaw DG、Sundseth SS 等人。TOMM40 的可变长度多态性预测迟发性阿尔茨海默病的发病年龄。 Pharmacogenomics J 2009 年 12 月 22 日；[Epublication ahead of print]。这一结果是通过对 LOAD 患者和年龄匹配的无疾病对照者的连锁不平衡（LD）块内遗传多态性的系统发育研究获得的，该 LD 块包含 TOMM40、APOE 和 APOC1 基因。尽管这些数据将具有诊断、预后和治疗策略的意义，但本文的观点是将这种“复杂”人类疾病的遗传模式置于背景中，并强调应用系统发育工具研究复杂疾病遗传学的潜在效用。
