Cardiology Clinical Academic Group, Molecular & Clinical Sciences Research Institute, St George's, University of London & St George's University Hospitals NHS Foundation Trust, London, United Kingdom (B.G., A.-E.B., R.B., A.S., A.J.C., E.R.B.).
L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France (A.-E.B.).
Circ Genom Precis Med. 2022 Feb;15(1):e003391. doi: 10.1161/CIRCGEN.121.003391. Epub 2022 Feb 3.
Acquired long QT syndrome (aLQTS) is a serious unpredictable adverse drug reaction. Pharmacogenomic markers may predict risk.
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.
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.
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.
获得性长 QT 综合征（aLQTS）是一种严重的不可预测的药物不良反应。药物基因组标记物可能预测风险。
在 153 例 aLQTS 患者（平均年龄 58 岁[范围 14-88]，98.7%为白人，85.6%有症状）中，计算方法确定了与 216 种延长 QT 药物相互作用最显著的蛋白质。所有病例均进行了 31 个候选基因的测序，这些基因来自于该分析或与先天性 LQTS 相关。使用罕见等位基因频率<1%过滤变体，并将其分类为 aLQTS 易感性。然后，对主要队列与对照外显子组（n=452）和独立的复制 aLQTS 外显子组测序队列进行基因负担分析。
在 25.5%的病例中，至少发现了一个罕见变异：22.2%的病例携带与先天性 LQTS 相关的基因中的罕见变异，4%的病例中该变异被认为是先天性 LQTS 的致病性或可能致病性变异；7.8%的病例携带细胞色素 P450（CYP）基因变异。在 12 个确定的 CYP 变异中，有 11 个（92%）在一种已知能代谢至少一种暴露于药物的致病变异药物的酶中。在 19%的病例中发现了影响致病变异药物代谢的药物-药物相互作用。在 7.8%的病例中存在一个以上的先天性 LQTS 变异、CYP 基因变异或药物相互作用。与对照外显子组（n=452）、独立复制的 aLQTS 外显子组测序队列（n=67）和药物耐受对照（n=148）相比，主要队列的基因负担分析显示，CYP 基因中罕见（罕见等位基因频率<0.01）变异的负担增加，但 LQTS 基因中没有。
CYP 基因中的罕见易感性变异正成为 aLQTS 潜在的重要药物基因组风险标志物，并可能成为未来个体化医学方法的一部分。
