Abstract
AbstractBackgroundThere is a genetic component to the QT-interval. This study investigated whether a polygenic risk score for QTc (PRSQTc) could predict ΔQTc and short-term mortality in first-time users of QT-prolonging medications (QTPM) with a known risk of Torsade de Pointes.MethodsFirst-time users of psychoactive QTPM in the Copenhagen Hospital Biobank and the Danish Blood Donor Study from 2009-2021 were included. ΔQTc was calculated and all-cause 30-day mortality following initiation of treatment was explored. All models were adjusted for conventional QT-prolonging risk factors, and models investigating death were additionally adjusted for potential comorbidity confounders.ResultsThe PRSQTccould predict ΔQTc (2.88 milliseconds (ms) for every increase of standard deviation in PRSQTc(P <0.001)) following treatment initiation. Individuals in the top ≥ 80 % of PRSQTchad a higher risk of ΔQTc of ≥60 ms compared to individuals in <80 % PRSQTc(OR = 4.88 P = 0.019). Furthermore, the study has also shown that the shorter QTc before initiation of QTPM, the higher the risk of greater ΔQTc.A high PRSQTccould also predict short-term mortality following treatment initiation: Individuals in the top PRSQTc≥90 % had an odds ratio of 1.84 (P-value = 0.002) for short-term mortality compared to individuals with PRSQTc<90 %. Individuals in the top PRSQTc≥99 % had an odds ratio of 4.95 (P-value = 0.009) for short-term mortality compared to individuals in the <99 % PRSQTcIt could be replicated that PRSQTc≥90 % was a predictor of short-term mortality with OR 1.52 (P-value = 0.002) compared to PRSQTc<90 % in a bigger cohort (N=15.249).ConclusionPRSQTcseems to be predictive of ΔQTc following initiation of treatment. PRSQTcproves to be a sufficient predictor of 30-day mortality after initiation of QT-prolonging psychoactive drugs with a known risk of Torsade de Pointes.If used in a clinical setting, PRSQTmay help prevent sudden cardiac deaths associated with QTPM.
Publisher
Cold Spring Harbor Laboratory