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A NOS1AP gene variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin


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.

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Fig. 1: Flow chart of the study population selection.
Fig. 2: Mean QT-interval differences among NOS1AP rs10494366 genotypic groups in digoxin non-users.
Fig. 3: Mean QT-interval differences in digoxin users compared to non-users stratified on NOS1AP rs10494366 genotypic groups.
Fig. 4: Mean QT-interval differences comparing digoxin dose categories in NOS1AP rs10494366 genotyping groups.


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“This Project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 116030. This Joint Understanding receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.”

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BHS, FA, and AJA are responsible for the study concept and design; NS performed the statistical analyses, data interpretation and prepared the manuscript/revision; AJA, MK, JAK, MAI, CN, FA, and BHS critically edited the manuscript for intellectual content. BHS and FA are responsible for the final content, interpretation of the results and contributed to the revision of the manuscript.

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Correspondence to Bruno H. Stricker.

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Soroush, N., Aarnoudse, AJ., Kavousi, M. et al. A NOS1AP gene variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin. Pharmacogenomics J (2021).

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