Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland.
J Alzheimers Dis. 2012;28(2):309-22. doi: 10.3233/JAD-2011-110743.
Recently, it has been reported that TOMM40 variable-length poly-T sequence polymorphism (rs10524523) in combination with APOE alleles (E2, E3, E4) significantly influences late-onset Alzheimer's disease (LOAD) age of onset. In a group of 414 LOAD patients, 173 centenarians and 305 neurologically healthy individuals, we investigated the impact of TOMM40 poly-T tracts on LOAD incidence, age of onset, and longevity. TOMM40 allelic variants were classified into four categories: short (S; 14-16T), long a (La; 20-22T), long b (Lb; 26-30T), and very long (VL; 31-39T). Our results demonstrate that La and Lb share similar characteristics in affecting LOAD risk, thus for some analyses they were combined into L category. We observed significantly lower frequency of VL allele (p < 0.0001) and significantly higher frequency of L alleles in the LOAD patients compared to the control individuals (p < 0.0001). S/S, S/VL, and VL/VL genotypes and VL-E2, S-E3, VL-E3 haplotypes are significantly associated with lower LOAD risk. VL-E3 haplotype carriers significantly more frequently developed LOAD when they were ≥79 years old. Additionally, S/L genotype is associated with a significantly increased LOAD risk (p < 0.0001). We conclude that in the carriers of TOMM40-APOE haplotypes comprising E4 allele, the TOMM40 rs10524523 allele does not play substantial role in establishing LOAD risk. Nevertheless, TOMM40 L allele increases the risk when E4 is absent. Finally, L allele, as well as genotypes (S/L, V/L) and haplotypes (L-E3, L-E4) comprising L significantly reduce the likelihood of living up to 100 years.
最近有报道称，TOMM40 可变长度多态性（rs10524523）与 APOE 等位基因（E2、E3、E4）的组合显著影响迟发性阿尔茨海默病（LOAD）的发病年龄。在一组 414 名 LOAD 患者、173 名百岁老人和 305 名神经健康个体中，我们研究了 TOMM40 多态性对 LOAD 发病率、发病年龄和寿命的影响。TOMM40 等位基因变体分为四类：短（S；14-16T）、长 a（La；20-22T）、长 b（Lb；26-30T）和非常长（VL；31-39T）。我们的结果表明，La 和 Lb 在影响 LOAD 风险方面具有相似的特征，因此在某些分析中，它们被合并为 L 类。我们观察到 VL 等位基因的频率明显降低（p < 0.0001），LOAD 患者的 L 等位基因频率明显高于对照组（p < 0.0001）。与 S/S、S/VL 和 VL/VL 基因型和 VL-E2、S-E3、VL-E3 单倍型相比，S/S、S/VL 和 VL/VL 基因型和 VL-E2、S-E3、VL-E3 单倍型与 LOAD 风险降低显著相关。VL-E3 单倍型携带者在≥79 岁时发生 LOAD 的频率明显更高。此外，S/L 基因型与 LOAD 风险显著增加相关（p < 0.0001）。我们得出结论，在包含 E4 等位基因的 TOMM40-APOE 单倍型携带者中，TOMM40 rs10524523 等位基因在确定 LOAD 风险方面没有发挥重要作用。然而，当 E4 不存在时，L 等位基因会增加风险。最后，L 等位基因以及包含 L 的基因型（S/L、V/L）和单倍型（L-E3、L-E4）显著降低了活到 100 岁的可能性。
