Mayo Clinic Graduate School of Biomedical Sciences (K.L.T., S.M.D.), Mayo Clinic, Rochester, MN, USA.
Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics (K.L.T., S.M.D., D.J.T., J.M.B., M.J.A.), Mayo Clinic, Rochester, MN, USA.
Circ Genom Precis Med. 2020 Aug;13(4):e002922. doi: 10.1161/CIRCGEN.120.002922. Epub 2020 May 29.
Long-QT syndrome (LQTS) is characterized by a prolonged heart rate-corrected QT interval (QTc). Genome-wide association studies identified common genetic variants that collectively explain ≈8% to 10% of QTc variation in the general population.
Overall, 423 patients with LQT1, LQT2, or LQT3 were genotyped for 61 QTc-associated genetic variants used in a prototype QTc-polygenic risk score (QTc-PRS). A weighted QTc-PRS (range, 0-154.8 ms) was calculated for each patient, and the FHS (Framingham Heart Study) population-based reference cohort (n=853).
The average QTc-PRS in LQTS was 88.0±7.2 and explained only ≈2.0% of the QTc variability. The QTc-PRS in LQTS probands (n=137; 89.3±6.8) was significantly greater than both FHS controls (87.2±7.4, difference-in-means±SE: 2.1±0.7, <0.002) and LQTS genotype-positive family members (87.5±7.4, difference-in-mean, 1.8±.7, <0.009). There was no difference in QTc-PRS between symptomatic (n=156, 88.6±7.3) and asymptomatic patients (n=267; 87.7±7.2, difference-in-mean, 0.9±0.7, P=0.15). LQTS patients with a QTc≥480 ms (n=120) had a significantly higher QTc-PRS (89.3±6.7) than patients with a QTc<480 ms (n=303, 87.6±7.4, difference-in-mean, 1.7±0.8, <0.05). There was no difference in QTc-PRS or QTc between genotypes.
The QTc-PRS explained <2% of the QTc variability in our LQT1, LQT2, and LQT3 cohort, contributing 5× less to their QTc value than in the general population. This prototype QTc-PRS does not distinguish/predict the clinical outcomes of individuals with LQTS.
长 QT 综合征（LQTS）的特征是心率校正 QT 间期（QTc）延长。全基因组关联研究确定了常见的遗传变异，这些变异共同解释了普通人群中约 8%至 10%的 QTc 变异。
总体而言，423 例 LQT1、LQT2 或 LQT3 患者对用于原型 QTc 多基因风险评分（QTc-PRS）的 61 个 QTc 相关遗传变异进行了基因分型。为每位患者计算了加权 QTc-PRS（范围，0-154.8ms），并基于弗雷明汉心脏研究（Framingham Heart Study）人群参考队列（n=853）进行了比较。
LQTS 患者的平均 QTc-PRS 为 88.0±7.2，仅解释了约 2.0%的 QTc 变异性。LQTS 先证者（n=137；89.3±6.8）的 QTc-PRS 明显大于弗雷明汉心脏研究对照（n=137；87.2±7.4）和 LQTS 基因型阳性家族成员（n=137；87.5±7.4），差异分别为 2.1±0.7（<0.002）和 1.8±0.7（<0.009）。有症状（n=156，88.6±7.3）和无症状患者（n=267，87.7±7.2）之间的 QTc-PRS 无差异，差异为 0.9±0.7（P=0.15）。QTc≥480ms（n=120）的 LQTS 患者的 QTc-PRS（89.3±6.7）明显高于 QTc<480ms（n=303，87.6±7.4），差异为 1.7±0.8（<0.05）。基因型之间的 QTc-PRS 或 QTc 无差异。
在我们的 LQT1、LQT2 和 LQT3 队列中，QTc-PRS 仅解释了<2%的 QTc 变异性，对 QTc 值的贡献比普通人群低 5 倍。这种原型 QTc-PRS 无法区分/预测 LQTS 个体的临床结局。
