A NOS1AP gene variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin.
Adaptor Proteins, Signal Transducing
/ genetics
Aged
Aged, 80 and over
Cardiotonic Agents
/ therapeutic use
Digoxin
/ administration & dosage
Electrocardiography
Female
Follow-Up Studies
Genetic Variation
Genotype
Humans
Linear Models
Long QT Syndrome
/ genetics
Longitudinal Studies
Male
Middle Aged
Prospective Studies
Treatment Outcome
Journal
The pharmacogenomics journal
ISSN: 1473-1150
Titre abrégé: Pharmacogenomics J
Pays: United States
ID NLM: 101083949
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
26
02
2021
accepted:
20
09
2021
pubmed:
8
10
2021
medline:
11
3
2022
entrez:
7
10
2021
Statut:
ppublish
Résumé
Digoxin is characterized by a small therapeutic window and a QT-interval shortening effect. Moreover, it has been shown that the genetic variants of the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. We investigated whether the rs10494366 variant of the NOS1AP gene decreases the QT-interval shortening effect of digoxin in patients using this drug. We included 10,057 individuals from the prospective population-based cohort of the Rotterdam Study during a median of 12.2 (interquartile range (IQR) 6.7-18.1) years of follow-up. At study entry, the mean age was 64 years and almost 59% of participants were women. A total of 23,179 ECGs were longitudinally recorded, of which 334 ECGs were from 249 individuals on digoxin therapy. The linear mixed model analysis was used to estimate the effect of the rs10494366 variant on the association between digoxin use and QT-interval duration, adjusted for age, sex, RR interval, diabetes, heart failure, and history of myocardial infarction. In non-users of digoxin, the GG genotype was associated with a significant 6.5 ms [95% confidence interval (CI) 5.5; 7.5] longer QT-interval duration than the TT variant. In current digoxin users, however, the GG variant was associated with a significantly -23.9 [95%CI -29.5; -18.5] ms shorter mean QT-interval duration than in those with the TT variant with -15.9 [95%CI -18.7; -13.1]. This reduction was strongest in the high digoxin dose category [≥0.250 mg/day] with the GG genotype group, with -40.8 [95%CI -52.5; -29.2] ms changes compared to non-users. Our study suggests that the minor homozygous GG genotype group of the NOS1AP gene rs10494366 variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin in a population of European ancestry.
Identifiants
pubmed: 34616002
doi: 10.1038/s41397-021-00256-2
pii: 10.1038/s41397-021-00256-2
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cardiotonic Agents
0
NOS1AP protein, human
0
Digoxin
73K4184T59
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
55-61Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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