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Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome.

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Date
2022-02-03
ICR Author
Antolin Hernandez, Albert
Author
Gray, B
Baruteau, A-E
Antolin, AA
Pittman, A
Sarganas, G
Molokhia, M
Blom, MT
Bastiaenen, R
Bardai, A
Priori, SG
Napolitano, C
Weeke, PE
Shakir, SA
Haverkamp, W
Mestres, J
Winkel, B
Witney, AA
Chis-Ster, I
Sangaralingam, A
Camm, AJ
Tfelt-Hansen, J
Roden, DM
Tan, HL
Garbe, E
Sturkenboom, M
Behr, ER
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Type
Journal Article
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Abstract
BACKGROUND: Acquired long QT syndrome (aLQTS) is a serious unpredictable adverse drug reaction. Pharmacogenomic markers may predict risk. METHODS: Among 153 aLQTS patients (mean age 58 years [range, 14-88], 98.7% White, 85.6% symptomatic), computational methods identified proteins interacting most significantly with 216 QT-prolonging drugs. All cases underwent sequencing of 31 candidate genes arising from this analysis or associating with congenital LQTS. Variants were filtered using a minor allele frequency <1% and classified for susceptibility for aLQTS. Gene-burden analyses were then performed comparing the primary cohort to control exomes (n=452) and an independent replication aLQTS exome sequencing cohort. RESULTS: In 25.5% of cases, at least one rare variant was identified: 22.2% of cases carried a rare variant in a gene associated with congenital LQTS, and in 4% of cases that variant was known to be pathogenic or likely pathogenic for congenital LQTS; 7.8% cases carried a cytochrome-P450 (CYP) gene variant. Of 12 identified CYP variants, 11 (92%) were in an enzyme known to metabolize at least one culprit drug to which the subject had been exposed. Drug-drug interactions that affected culprit drug metabolism were found in 19% of cases. More than one congenital LQTS variant, CYP gene variant, or drug interaction was present in 7.8% of cases. Gene-burden analyses of the primary cohort compared to control exomes (n=452), and an independent replication aLQTS exome sequencing cohort (n=67) and drug-tolerant controls (n=148) demonstrated an increased burden of rare (minor allele frequency<0.01) variants in CYP genes but not LQTS genes. CONCLUSIONS: Rare susceptibility variants in CYP genes are emerging as potentially important pharmacogenomic risk markers for aLQTS and could form part of personalized medicine approaches in the future.
URI
https://repository.icr.ac.uk/handle/internal/5010
DOI
https://doi.org/10.1161/CIRCGEN.121.003391
https://doi.org/10.1161/CIRCGEN.121.003391
 
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Subject
allele
drug
exome
long QT syndrome
torsades de pointes
Language
eng
Date accepted
2022-02-03
License start date
2022-02-03
Citation
Circ Genom Precis Med, 2022, pp. CIRCGEN121003391 - ?

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