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Published on: June 20, 2020
5 HT(3)-receptor antagonists and cardiac repolarization time in patients expressing a novel genetic target associated
Sadeq A Quraishi1, Gregg H Schuler, Piotr K Janicki
1Department of Anaesthesia, Harvard Medical School, Boston, MA 02115, USA. squraishi@partners.org
Study Objective:
To investigate whether a common single nucleotide polymorphism (SNP), rs10494366, is associated with significant prolongation of the QTc interval following administration of 5-HT(3)-receptor antagonists in the perioperative setting.
Design:
Post-hoc analysis of deoxyribonucleic acid (DNA) samples and electrocardiographic (ECG) data from an established perioperative genomics database.
Setting:
University teaching hospital.
Measurements:
DNA samples of 132 ASA physical status 1, 2, and 3 patients were obtained from an established genomic database of surgical patients who had received either granisetron or dolasetron as part of their general anesthesia plan. ECG recordings were collected on all subjects before administration of antiemetic medication, then 10 minutes after drug injection. DNA analysis was performed using TaqMan real-time PCR genotyping assay. Results from the TaqMan real-time PCR assay were used to calculate relative frequencies of the T (major) and G (minor) alleles, in addition to calculating the genotype frequencies. QTc intervals were calculated according to Bazett's formula.
Results:
Relative frequencies for T and G alleles were 0.63 and 0.37, respectively. The relative frequencies of the pertinent genotypes were TT 39.4%, TG 46.9%, and GG 13.7%. No significant difference was noted in QTc interval pre-antiemetic or post-antiemetic drug administration for the homozygous carriers of the minor allele GG (P = 0.059), but a significant difference was seen in the pre-drug and post-drug QTc intervals in the heterozygous and homozygous carriers of the major allele TG and TT (P = 0.003 and P = 0.017, respectively). Compared with homozygous carriers of the minor allele, absolute risk increase for QTc interval prolongation after antiemetic administration was 0.08 and 0.15 in heterozygous and homozygous carriers of the major allele, respectively.
Conclusion:
Homozygous and heterozygous carrier status for the major SNP, rs10494366 allele (T), in intron 1 of the human NOSA1P gene may be associated with an increased risk of QTc interval prolongation following administration of 5-HT(3)-receptor antagonists in the perioperative setting, when compared with homozygotes for the minor (G) allele.
Insights
A common single nucleotide polymorphism (SNP), rs10494366, is linked to QTc interval prolongation after 5-HT(3)-receptor antagonist use in surgery. Patients with the major T allele face a higher risk of prolonged QTc intervals.
Area of Science:
- Pharmacogenomics
- Cardiology
- Anesthesiology
Background:
- 5-HT(3)-receptor antagonists are widely used for perioperative nausea and vomiting.
- QTc interval prolongation is a potential adverse effect of certain medications.
- Genetic variations may influence drug response and cardiac safety.
Purpose of the Study:
- To examine the association between the single nucleotide polymorphism (SNP) rs10494366 and QTc interval prolongation.
- To assess the impact of this SNP on patients receiving 5-HT(3)-receptor antagonists in the perioperative setting.
Main Methods:
- Post-hoc analysis of DNA and electrocardiographic (ECG) data from 132 surgical patients.
- Genotyping for the rs10494366 SNP using TaqMan real-time PCR.
- QTc intervals were calculated using Bazett's formula before and after antiemetic administration.
Main Results:
- The T allele frequency was 0.63, and the G allele frequency was 0.37.
- Patients with TT (39.4%) and TG (46.9%) genotypes showed significant QTc prolongation (P = 0.017 and P = 0.003, respectively).
- Homozygous carriers of the minor GG allele (13.7%) did not exhibit significant QTc prolongation (P = 0.059).
Conclusions:
- Carrier status for the major allele (T) of SNP rs10494366 is associated with an increased risk of QTc interval prolongation.
- This risk is elevated in heterozygous (TG) and homozygous (TT) carriers compared to homozygous minor allele (GG) carriers.
- Genetic screening for rs10494366 may aid in identifying patients at higher risk for QTc prolongation from 5-HT(3)-receptor antagonists.
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