Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism

氯氮平 药物基因组学 单核苷酸多态性 全基因组关联研究 遗传关联 药物遗传学 药理学 生物 遗传学 医学 精神分裂症(面向对象编程) 计算生物学 生物信息学 精神科 基因 基因型
作者
Antonio F. Pardiñas,Mariana Nalmpanti,Andrew Pocklington,Sophie E. Legge,Christopher Medway,Adrian King,John A. Jansen,Marinka Helthuis,Stanley Zammit,James H. MacCabe,Michael J. Owen,Michael O’Donovan,James Walters
出处
期刊:American Journal of Psychiatry [American Psychiatric Association]
卷期号:176 (6): 477-486 被引量:75
标识
DOI:10.1176/appi.ajp.2019.18050589
摘要

Objective: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. Methods: The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics. Results: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data. Conclusions: Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
Lucas应助旅途之人采纳,获得10
刚刚
mkb完成签到,获得积分10
1秒前
lee1992发布了新的文献求助10
1秒前
3秒前
5秒前
无私静白完成签到,获得积分10
5秒前
图图关注了科研通微信公众号
6秒前
神秘骑士发布了新的文献求助10
6秒前
漂亮的忆文完成签到,获得积分10
6秒前
7秒前
qmx发布了新的文献求助10
7秒前
过时的友卉完成签到,获得积分10
7秒前
饱满的百招完成签到 ,获得积分10
8秒前
完美世界应助yzbj采纳,获得10
8秒前
11秒前
风清扬应助研友_8o5V2n采纳,获得10
11秒前
12秒前
共享精神应助qmx采纳,获得10
12秒前
爱笑的万天完成签到,获得积分10
13秒前
RPG完成签到,获得积分10
13秒前
13秒前
14秒前
Wave浪发布了新的文献求助30
15秒前
仿真小学生完成签到,获得积分10
16秒前
昂口3完成签到 ,获得积分10
16秒前
缥缈芷珍发布了新的文献求助10
17秒前
vielate发布了新的文献求助10
17秒前
19秒前
21秒前
21秒前
yzbj完成签到,获得积分10
23秒前
鸣笛应助自然思松采纳,获得20
25秒前
罗罗发布了新的文献求助10
25秒前
大个应助怕黑的盼烟采纳,获得10
25秒前
jz完成签到,获得积分10
26秒前
万能图书馆应助宁缺毋滥采纳,获得10
28秒前
29秒前
30秒前
30秒前
罗罗完成签到,获得积分10
32秒前
高分求助中
【重要!!请各位用户详细阅读此贴】科研通的精品贴汇总(请勿应助) 10000
Semantics for Latin: An Introduction 1055
Plutonium Handbook 1000
Three plays : drama 1000
Robot-supported joining of reinforcement textiles with one-sided sewing heads 600
北师大毕业论文 基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 510
Cochrane Handbook for Systematic Reviews ofInterventions(current version) 500
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4103626
求助须知:如何正确求助?哪些是违规求助? 3641325
关于积分的说明 11538745
捐赠科研通 3349911
什么是DOI,文献DOI怎么找? 1840560
邀请新用户注册赠送积分活动 907604
科研通“疑难数据库(出版商)”最低求助积分说明 824725