Impact of the novel CYP2C:TG haplotype and CYP2B6 variants on sertraline exposure in a large patient population. Issue 9 (22nd June 2022)

• Record Type: Journal Article
• Authors: Bråten, Line Skute; Ingelman‐Sundberg, Magnus; Jukic, Marin M.; Molden, Espen; Kringen, Marianne Kristiansen
• Is Part Of: Clinical and translational science. Volume 15:Issue 9(2022)
• Page Start: 2135
• Page End: 2145
• Publication Date: 2022-06-22
• Subjects: Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; 616.027
• DOI: 10.1111/cts.13347
• Languages: English
• ISSNs: 1752-8054

Abstract

Abstract: 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 ( CYP2C19*1/*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 CYP2C19*17 and/or CYP2C:TG haplotype) with the diplotypes CYP2C19*17/*17, CYP2C:TG/TG, or CYP2C19*17/CYP2C:TG ( n = 135, p < 0.003, p = 0.022, p < 0.003, respectively). Interestingly, in patients carrying the increased function CYP2B6*4 allele, and also carrying the CYP2C19*17 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