抑郁症患者艾司西酞普兰和阿立哌唑治疗结果的基因变异、DNA 甲基化和基因表达综合分析:CAN-BIND-1研究

IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Pharmacopsychiatry Pub Date : 2024-09-01 Epub Date: 2024-06-25 DOI:10.1055/a-2313-9979
Farhana Islam, Amanda Lisoway, Edward S Oh, Laura M Fiori, Leen Magarbeh, Samar S M Elsheikh, Helena K Kim, Stefan Kloiber, James L Kennedy, Benicio N Frey, Roumen Milev, Claudio N Soares, Sagar V Parikh, Franca Placenza, Stefanie Hassel, Valerie H Taylor, Francesco Leri, Pierre Blier, Rudolf Uher, Faranak Farzan, Raymond W Lam, Gustavo Turecki, Jane A Foster, Susan Rotzinger, Sidney H Kennedy, Daniel J Müller
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引用次数: 0

摘要

简介遗传学和表观遗传学对抗抑郁治疗(1)反应和缓解、(2)副作用和(3)血清水平的相互作用知之甚少。本研究探讨了单核苷酸多态性(SNPs)、DNA甲基化(DNAm)和四个药代动力学基因(CYP2C19、CYP2D6、CYP3A4和ABCB1)的mRNA水平之间的关系及其对这些结果的影响:加拿大抑郁症生物标记物整合网络-1数据集由177名重度抑郁症患者组成,这些患者先接受为期8周的艾司西酞普兰(ESC)治疗,然后再接受为期8周的ESC单药治疗或阿立哌唑增效治疗。通过全血中20个SNP与60个CpG位点之间的SNP-CpG关联确定的DNAm定量性状位点(mQTL)与我们的结果进行了关联测试,随后进行了因果推断测试(CIT)以确定甲基化介导的遗传效应:结果:11对顺式-SNP-CpG对(qCYP2C19 rs4244285与治疗相关的体重增加(q=0.027)和血清中ESCadj浓度(qadj浓度)相关。CITs并未表明这些影响是由表观遗传介导的:这些结果阐明了 CYP2C19 rs4244285 与 ESC 药代动力学之间既定关联的功能机制。这一mQTL SNP作为抗抑郁药相关体重增加的标志物还有待进一步探讨。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Integrative Genetic Variation, DNA Methylation, and Gene Expression Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A CAN-BIND-1 Study.

Introduction: Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19, CYP2D6, CYP3A4, and ABCB1, and its effect on these outcomes.

Methods: The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects.

Results: Eleven cis-SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain (q=0.027) and serum concentrations of ESCadj (q<0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESCadj concentrations. CITs did not indicate that these effects were epigenetically mediated.

Discussion: These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored.

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来源期刊
Pharmacopsychiatry
Pharmacopsychiatry 医学-精神病学
CiteScore
7.10
自引率
9.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Covering advances in the fi eld of psychotropic drugs, Pharmaco psychiatry provides psychiatrists, neuroscientists and clinicians with key clinical insights and describes new avenues of research and treatment. The pharmacological and neurobiological bases of psychiatric disorders are discussed by presenting clinical and experimental research.
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