Ji Yuan, Schaid Daniel J, Desta Zeruesenay, Kubo Michiaki, Batzler Anthony J, Snyder Karen, Mushiroda Taisei, Kamatani Naoyuki, Ogburn Evan, Hall-Flavin Daniel, Flockhart David, Nakamura Yusuke, Mrazek David A, Weinshilboum Richard M
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
Br J Clin Pharmacol. 2014 Aug;78(2):373-83. doi: 10.1111/bcp.12348.
Citalopram (CT) and escitalopram (S-CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder (MDD). We applied a genome-wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S-CT and their metabolites in MDD patients treated with CT or S-CT.
Our genome-wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within-subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single-nucleotide polymorphisms (SNPs) were modelled as additive allelic effects.
Genome-wide significant associations were observed for S-CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10(-9) ) and with S-didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10(-16) ), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation.
In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome-wide association study performed in MDD patients treated with CT or S-CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors.
西酞普兰（CT）和艾司西酞普兰（S-CT）是用于治疗重度抑郁症（MDD）的处方最广泛的选择性5-羟色胺再摄取抑制剂。我们开展了一项全基因组关联研究，以确定在用CT或S-CT治疗的MDD患者中，导致CT或S-CT及其代谢产物血浆浓度变异的遗传因素。
我们使用来自435例MDD患者的样本进行全基因组关联研究。采用线性混合模型来处理血浆药物/代谢产物浓度纵向测量值（药物治疗开始后4周和8周）的受试者内相关性，单核苷酸多态性（SNP）被建模为加性等位基因效应。
观察到10号染色体上CYP2C19基因内或其附近的SNP与S-CT浓度存在全基因组显著关联（rs1074145，P = 4.1×10⁻⁹），并且22号染色体上CYP2D6基因座附近的SNP与S-去二甲基西酞普兰浓度存在全基因组显著关联（rs1065852，P = 2.0×10⁻¹⁶），这支持了这些细胞色素P45（CYP酶在西酞普兰生物转化中的重要作用。在调整CYP2C19功能等位基因的效应后，分析还确定了新的基因座，这些基因座需要未来进行重复验证和功能验证。
体外和体内研究表明，CT向去甲西酞普兰和二去甲西酞普兰的生物转化由CYP同工酶介导。我们在接受CT或S-CT治疗的MDD患者中进行的全基因组关联研究结果证实了这些观察结果，但也确定了新的基因组位点，这些位点可能在使用这些选择性5-羟色胺再摄取抑制剂治疗MDD患者期间，对CT或其代谢产物血浆水平的变异起作用。
