Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
Department of Health Sciences, OsloMet - Oslo Metropolitan University, Oslo, Norway.
Clin Transl Sci. 2022 Sep;15(9):2135-2145. doi: 10.1111/cts.13347. Epub 2022 Jun 22.
Sertraline is a commonly used SSRI antidepressant drug, metabolized by CYP2C19 and CYP2B6, that exhibits a substantial interindividual variation in clinical response, of which only a part can be attributed to known genetic variants. In the current study we have examined the role of a newly discovered ultrarapid CYP2C:TG haplotype and CYP2B6 variants in order to identify the possible missing heritability for such variation in sertraline response in a large patient population (n = 840). Compared to the reference group (CYP2C191/1, n = 160), sertraline exposure was increased by 128% in CYP2C19 PMs (n = 29, p < 0.001) but decreased by about 20% in CYP2C19 ultrarapid metabolizers (Ums) (homozygous carriers of CYP2C1917 and/or CYP2C:TG haplotype) with the diplotypes CYP2C1917/17, CYP2C:TG/TG, or CYP2C1917/CYP2C:TG (n = 135, p < 0.003, p = 0.022, p < 0.003, respectively). Interestingly, in patients carrying the increased function CYP2B64 allele, and also carrying the CYP2C1917 and CYP2C:TG alleles (n = 10), sertraline exposure was 35.4% lower compared to the reference group, whereas in subjects being poor metabolizers (PM) in both the CYP2C19 and CYP2B6 gene, the sertraline concentrations were raised by 189%. In summary, the CYP2C19 variants including the CYP2C:TG haplotype had a significant impact on sertraline metabolism, as well as the CYP2B6*4, *6, and *9 alleles. Knowing the CYP2B6 and CYP2C19 genotype, including the CYP2C:TG haplotype status, can prospectively be useful to clinicians in making more appropriate sertraline dosing decisions.
舍曲林是一种常用的 SSRI 类抗抑郁药，主要由 CYP2C19 和 CYP2B6 代谢，其临床疗效存在显著的个体间差异，而这种差异只有一部分可以归因于已知的遗传变异。在本研究中，我们研究了新发现的超快 CYP2C：TG 单倍型和 CYP2B6 变异体在一个大的患者群体（n=840）中对舍曲林反应的可能缺失遗传率的作用。与参考组（CYP2C191/1，n=160）相比，CYP2C19 代谢不良者（CYP2C1917 纯合子和/或 CYP2C：TG 单倍型）的舍曲林暴露增加了 128%（n=29，p<0.001），而 CYP2C19 超快代谢者（CYP2C1917/17、CYP2C：TG/TG 或 CYP2C1917/CYP2C：TG 二倍型）的舍曲林暴露减少了约 20%（n=135，p<0.003，p=0.022，p<0.003）。有趣的是，在携带增加功能的 CYP2B64 等位基因的同时还携带 CYP2C1917 和 CYP2C：TG 等位基因的患者（n=10）中，舍曲林的暴露水平比参考组低 35.4%，而在 CYP2C19 和 CYP2B6 基因均为代谢不良者（PM）的患者中，舍曲林的浓度增加了 189%。总之，CYP2C19 变异体包括 CYP2C：TG 单倍型对舍曲林代谢有显著影响，同时 CYP2B6*4、6 和9 等位基因也有影响。了解 CYP2B6 和 CYP2C19 的基因型，包括 CYP2C：TG 单倍型的状态，可能有助于临床医生做出更合适的舍曲林剂量决策。
