Gray, B;
Baruteau, A-E;
Antolin, AA;
Pittman, A;
Sarganas, G;
Molokhia, M;
Blom, MT;
Bastiaenen, R;
Bardai, A;
Priori, SG;
et al.
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
(2022)
Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome.
Circ Genom Precis Med, 15 (1).
e003391.
ISSN 2574-8300
https://doi.org/10.1161/CIRCGEN.121.003391
SGUL Authors: Behr, Elijah Raphael Camm, Alan John Witney, Adam Austin Chis Ster, Delizia Irina Pittman, Alan Michael
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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.
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Additional Information: | This is a non-final version of an article published in final form in Gray, B; Baruteau, A-E; Antolin, AA; Pittman, A; Sarganas, G; Molokhia, M; Blom, MT; Bastiaenen, R; Bardai, A; Priori, SG; et al. (2022) Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome. Circ Genom Precis Med, 15 (1). | ||||||||||||||||||||||||||||||
Keywords: | allele, drug, exome, long QT syndrome, torsades de pointes | ||||||||||||||||||||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Infection and Immunity Research Institute (INII) Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
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Journal or Publication Title: | Circ Genom Precis Med | ||||||||||||||||||||||||||||||
ISSN: | 2574-8300 | ||||||||||||||||||||||||||||||
Language: | eng | ||||||||||||||||||||||||||||||
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Publisher License: | Creative Commons: Attribution 4.0 | ||||||||||||||||||||||||||||||
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PubMed ID: | 35113648 | ||||||||||||||||||||||||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/114134 | ||||||||||||||||||||||||||||||
Publisher's version: | https://doi.org/10.1161/CIRCGEN.121.003391 |
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