Pérez-Aldana Blanca Estela, Martínez-Magaña José Jaime, Mayén-Lobo Yerye Gibrán, Dávila-Ortiz de Montellano David José, Aviña-Cervantes Carlos Luis, Ortega-Vázquez Alberto, Genis-Mendoza Alma Delia, Sarmiento Emmanuel, Soto-Reyes Ernesto, Juárez-Rojop Isela Esther, Tovilla-Zarate Carlos Alfonso, González-Castro Thelma Beatriz, Nicolini Humberto, López-López Marisol, Monroy-Jaramillo Nancy
Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Mexico City, Mexico.
Laboratorio de Genómica de Enfermedades Psiquiátricas y Neurodegenerativas, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
Front Psychiatry. 2022 May 18;13:870656. doi: 10.3389/fpsyt.2022.870656. eCollection 2022.
Long-term studies have shown significantly lower mortality rates in patients with continuous clozapine (CLZ) treatment than other antipsychotics. We aimed to evaluate epigenetic age and DNA methylome differences between CLZ-treated patients and those without psychopharmacological treatment. The DNA methylome was analyzed using the Infinium MethylationEPIC BeadChip in 31 CLZ-treated patients with psychotic disorders and 56 patients with psychiatric disorders naive to psychopharmacological treatment. Delta age (Δage) was calculated as the difference between predicted epigenetic age and chronological age. CLZ-treated patients were stratified by sex, age, and years of treatment. Differential methylation sites between both groups were determined using linear regression models. The Δage in CLZ-treated patients was on average lower compared with drug-naive patients for the three clocks analyzed; however, after data-stratification, this difference remained only in male patients. Additional differences were observed in Hannum and Horvath clocks when comparing chronological age and years of CLZ treatment. We identified 44,716 differentially methylated sites, of which 87.7% were hypomethylated in CLZ-treated patients, and enriched in the longevity pathway genes. Moreover, by protein-protein interaction, AMPK and insulin signaling pathways were found enriched. CLZ could promote a lower Δage in individuals with long-term treatment and modify the DNA methylome of the longevity-regulating pathways genes.
长期研究表明，与其他抗精神病药物相比，接受氯氮平（CLZ）持续治疗的患者死亡率显著更低。我们旨在评估接受CLZ治疗的患者与未接受精神药物治疗的患者之间的表观遗传年龄和DNA甲基化组差异。使用Infinium MethylationEPIC BeadChip对31名接受CLZ治疗的精神障碍患者和56名未接受过精神药物治疗的精神障碍患者的DNA甲基化组进行了分析。计算Delta年龄（Δage），即预测的表观遗传年龄与实际年龄之间的差异。接受CLZ治疗的患者按性别、年龄和治疗年限进行分层。使用线性回归模型确定两组之间的差异甲基化位点。在所分析的三个时钟中，接受CLZ治疗的患者的Δage平均低于未用药患者；然而，在数据分层后，这种差异仅在男性患者中存在。在比较实际年龄和CLZ治疗年限时，在Hannum和Horvath时钟中观察到了其他差异。我们鉴定出44716个差异甲基化位点，其中87.7%在接受CLZ治疗的患者中发生低甲基化，并在长寿途径基因中富集。此外，通过蛋白质-蛋白质相互作用，发现AMPK和胰岛素信号通路富集。CLZ可以促进长期治疗个体的较低Δage，并改变长寿调节途径基因的DNA甲基化组。
