药物基因组学和药物蛋白质组学杂志

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APOE-TOMM40 in the Pharmacogenomics of Dementia

Ramón Cacabelos, Dmitry Goldgaber, Alexander Vostrov, Hideyuki Matsuki, Clara Torrellas, Dolores Corzo, Juan Carlos Carril and Allen D Roses

Polymorphic variants present in the APOE-TOMM40 region (19q13.2) are implicated in Alzheimer’s disease (AD) and have been shown to modify disease risk, age at onset of symptoms, and the therapeutic response to conventional drugs. We have investigated the structure of the APOE-TOMM40 region and the influence of APOE and TOMM40 poly T variants (rs10524523) in the therapeutic response to a multifactorial treatment in 920 Spanish patients with AD. The frequencies of TOMM40 poly T genotypes were: 18.37% S/S, 7.83% S/L, 38.80% S/VL, 1.52% L/L, 7.17% L/VL, and 26.31% VL/VL. The most frequent APOE-TOMM40 associations were as follows: 82% APOE-3/3 with S/S, 63% with S/VL, and 40% with VL/VL; 90% APOE-3/4 with S/L, 57% with L/VL, and 43% with VL/VL; and 100% APOE-4/4 with L/L. Globally, the response rate was about 59%, with no difference between females and males. APOE-4 carriers were found to be the worst responders (45-56%) whereas APOE-3/3 carriers were the best responders (70%) for a transient period of cognitive improvement (<12 m). Among TOMM40 variants, S/S carriers were the best responders (70%), followed by S/VL (61%), VL/VL (57%), and L/VL carriers (51%). The worst responders were those patients harboring the L/L genotype (35%). Therefore, specific APOE-TOMM40 poly T variants exert a powerful influence on the therapeutic response to conventional treatments in AD.