Serotonin reuptake inhibitors (SRIs) and the risk of fetal congenital heart anomalies (CHA): An exploratory pharmacogenetics study

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Introduction: Several studies reported the risk of CHA associated with prenatal use of SRIs, but the results have been inconsistent. Objective: To explore whether pharmacogenetics play a role in this teratogenicity using a gene-environment interaction study. Patients and methods: A total of 33 case-mother dyads and 2 mother-only (children deceased) registered in EUROCAT Northern Netherlands were included in a case-only study. Five case-mother dyads and two mothers-only were exposed to SRIs in the first trimester of pregnancy. The remaining 28 case-mother dyads were not exposed to SRIs. Ten genes that encode the enzymes or proteins important in determining fetal exposure to SRIs or its mechanism of action were selected: CYPs (CYP1A2, CYP2C9, CYP2C19, CYP2D6), ABCB1 (placental P-glycoprotein), SLC6A4 (serotonin transporter) and serotonin receptor genes (HTR1A, HTR1B, HTR2A, and HTR3B). All included subjects were genotyped for 58 genetic variations. Logistic regression analyses were performed to determine the interaction odds ratio (OR) between genetic variations and SRIs exposure on the risk of CHA. Results: Due to low phenotype frequencies of CYP450 poor metabolizers among exposed cases, the OR cannot be calculated. For ABCB1, there was no indication of changes in the risk of CHA with any of the ABCB1 SNPs in the children and their mothers. Several genetic variations of the serotonin transporter and receptors (SLC6A4 5-HTTLPR and 5-HTTVNTR, HTR1A rs1364043, HTR1B rs6296 & rs6298, HTR3B rs1176744) were associated with an increased risk of CHA, but with too limited sample size to reach statistical significance. For SLC6A4 genetic variations, the mean genetic scores of the exposed case-mothers tended to be higher than the unexposed mothers (2.5 ± 0.8 and 1.88 ± 0.7, respectively; p=0.061). For SNPs of the serotonin receptors, the mean genetic score for exposed cases (children) tended to be higher than the unexposed cases (3.4 ± 2.2, and 1.9 ± 1.6, respectively; p=0.065). Conclusion: This study was the first to explore the potential gene-environment interaction between pharmacogenetic determinants and SRIs use on the risk of CHA. With small sample sizes, it was not possible to find a significant interaction. However, the role of serotonin receptor polymorphisms in fetuses exposed to SRIs warrants further investigation.
Original languageEnglish
Pages (from-to)S24-100
JournalNaunyn-Schmiedebergs Archives of Pharmacology
Issue numberSuppl. 1
Publication statusPublished - 2017
EventGERMAN PHARM-TOX SUMMIT 2017 - Heidelberg, Germany
Duration: 6-Mar-20179-Mar-2017

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