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

Circ Genom Precis Med. 2022 Feb;15(1):e003391.doi: 10.1161/CIRCGEN.121.003391. Epub 2022 Feb 3.

Belinda Gray# 1 Alban-Elouen Baruteau# 1 2 Albert A Antolin 3 Alan Pittman 4 Giselle Sarganas 5 Mariam Molokhia 6 Marieke T Blom 7 Rachel Bastiaenen 1 Abdenasser Bardai 7 Silvia G Priori 8 9 Carlo Napolitano 8 9 Peter E Weeke 2 10 Saad A Shakir 11 12 Wilhelm Haverkamp 13 Jordi Mestres 3 Bo Gregers Winkel 14 15 Adam A Witney 16 Irina Chis-Ster 16 Ajanthah Sangaralingam 1 A John Camm 1 Jacob Tfelt-Hansen 15 14 Dan M Roden 10 Hanno L Tan 7 Edeltraut Garbe 17 Miriam Sturkenboom 18 Elijah R Behr 1

PMID: 35113648 DOI: 10.1161/CIRCGEN.121.003391


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.

Keywords: allele; drug; exome; long QT syndrome; torsades de pointes.

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