Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome. (3rd February 2022)

• Record Type: Journal Article
• Authors: Gray, Belinda; Baruteau, Alban-Elouen; Antolin, Albert A.; Pittman, Alan; Sarganas, Giselle; Molokhia, Mariam; Blom, Marieke T.; Bastiaenen, Rachel; Bardai, Abdenasser; Priori, Silvia G.; Napolitano, Carlo; Weeke, Peter E.; Shakir, Saad A.; Haverkamp, Wilhelm; Mestres, Jordi; Winkel, Bo; Witney, Adam A.; Chis-Ster, Irina; Sangaralingam, Ajanthah; Camm, A. John; Tfelt-Hansen, Jacob; Roden, Dan M.; Tan, Hanno L.; Garbe, Edeltraut; Sturkenboom, Miriam; Behr, Elijah R.
• Is Part Of: Circulation. Volume 15:Number 1(2022)
• Page Start: e003391
• Publication Date: 2022-02-03
• Subjects: allele -- drug -- exome -- long QT syndrome -- torsades de pointes; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Genetics -- Periodicals; Cardiovascular Diseases -- genetics; Precision Medicine; Periodical; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 616.1042
• DOI: 10.1161/CIRCGEN.121.003391
• Languages: English
• ISSNs: 2574-8300

Abstract

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.