dc.contributor.author | Gray, B | |
dc.contributor.author | Baruteau, A-E | |
dc.contributor.author | Antolin, AA | |
dc.contributor.author | Pittman, A | |
dc.contributor.author | Sarganas, G | |
dc.contributor.author | Molokhia, M | |
dc.contributor.author | Blom, MT | |
dc.contributor.author | Bastiaenen, R | |
dc.contributor.author | Bardai, A | |
dc.contributor.author | Priori, SG | |
dc.contributor.author | Napolitano, C | |
dc.contributor.author | Weeke, PE | |
dc.contributor.author | Shakir, SA | |
dc.contributor.author | Haverkamp, W | |
dc.contributor.author | Mestres, J | |
dc.contributor.author | Winkel, BG | |
dc.contributor.author | Witney, AA | |
dc.contributor.author | Chis-Ster, I | |
dc.contributor.author | Sangaralingam, A | |
dc.contributor.author | Camm, AJ | |
dc.contributor.author | Tfelt-Hansen, J | |
dc.contributor.author | Roden, DM | |
dc.contributor.author | Tan, HL | |
dc.contributor.author | Garbe, E | |
dc.contributor.author | Sturkenboom, M | |
dc.contributor.author | Behr, ER | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2022-02-11T11:14:05Z | |
dc.date.available | 2022-02-11T11:14:05Z | |
dc.date.issued | 2022-02-03 | |
dc.identifier | https://www.ncbi.nlm.nih.gov/pubmed/35113648 | |
dc.identifier.citation | Circ Genom Precis Med, 2022, pp. CIRCGEN121003391 - ? | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5010 | |
dc.identifier.eissn | 2574-8300 | |
dc.identifier.eissn | 2574-8300 | |
dc.identifier.doi | 10.1161/CIRCGEN.121.003391 | |
dc.identifier.doi | 10.1161/CIRCGEN.121.003391 | |
dc.description.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. | |
dc.format.extent | CIRCGEN121003391 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | LIPPINCOTT WILLIAMS & WILKINS | |
dc.rights.uri | http://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | allele | |
dc.subject | drug | |
dc.subject | exome | |
dc.subject | long QT syndrome | |
dc.subject | torsades de pointes | |
dc.title | Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2022-02-03 | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1161/CIRCGEN.121.003391 | |
rioxxterms.licenseref.startdate | 2022-02-03 | |
dc.relation.isPartOf | Circ Genom Precis Med | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.publication-status | Published online | |
pubs.embargo.terms | No embargo | |
dc.contributor.icrauthor | Antolin Hernandez, Albert | |