Circulation. Genomic and precision medicine · 2022
Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome.
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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 Gregers, 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
Аннотация
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.
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.