Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.

中文翻译：

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APOE、GRN 和 TP53 的遗传变异是额颞叶痴呆的表型修饰符

额颞叶痴呆 (FTD) 是一组临床、遗传和病理异质的神经退行性疾病。在这项研究中，我们研究了 APOƐ4、GRN 中的 rs5848 和 TP53 基因中的 rs1042522 作为疾病风险因素和/或表型修饰剂在 440 名 FTD 患者中的作用，其中包括 175 名 C9orf72 扩增携带者。我们发现 C9orf72 扩张载体显示出较早的发病年龄（p < 0.001）。在临床组中，FTD-MND（运动神经元疾病）的生存率最低（风险比 [HR] = 4.12），进行性非流利性失语症组的发病年龄最高（p = 0.03）。在我们的队列中，TP53 中的 rs1042522 与疾病发作（p = 0.02）和存活率（HR = 1.73）相关，rs5848 GRN 与 CC 纯合子患者的存活率显着缩短（HR = 1.98）相关。APOƐ4 携带者的频率在 C9orf72 非携带者中显着增加（p = 0.022）。尽管对我们的发现进行验证是必要的，但我们的结果表明 TP53、GRN 和 APOE 基因可能在 FTD 中充当表型修饰符，应在未来的临床试验中加以考虑。