Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome
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Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome. / 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.
I: Circulation. Genomic and precision medicine, Bind 15, Nr. 1, e003391, 2022, s. 55-67.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome
AU - Gray, Belinda
AU - Baruteau, Alban-Elouen
AU - Antolin, Albert A
AU - Pittman, Alan
AU - Sarganas, Giselle
AU - Molokhia, Mariam
AU - Blom, Marieke T
AU - Bastiaenen, Rachel
AU - Bardai, Abdenasser
AU - Priori, Silvia G
AU - Napolitano, Carlo
AU - Weeke, Peter E
AU - Shakir, Saad A
AU - Haverkamp, Wilhelm
AU - Mestres, Jordi
AU - Winkel, Bo
AU - Witney, Adam A
AU - Chis-Ster, Irina
AU - Sangaralingam, Ajanthah
AU - Camm, A John
AU - Tfelt-Hansen, Jacob
AU - Roden, Dan M
AU - Tan, Hanno L
AU - Garbe, Edeltraut
AU - Sturkenboom, Miriam
AU - Behr, Elijah R
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1161/CIRCGEN.121.003391
DO - 10.1161/CIRCGEN.121.003391
M3 - Journal article
C2 - 35113648
VL - 15
SP - 55
EP - 67
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
SN - 2574-8300
IS - 1
M1 - e003391
ER -
ID: 291597968