¹Hasso-Plattner-Institut, Universitaet Potsdam, Potsdam, Germany
²Finnish Institute for Health and Welfare, Helsinki, Finland
³Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
⁴Broad Institute of MIT and Harvard, Boston, United States
⁵The Hasso Plattner Institute for Digital Health at Mount Sinai, New York, United States

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Introduction: Cardiac arrhythmias, most notably atrial fibrillation (AFib), pose a significant global health burden with limited preventive strategies. The SCN5A gene, encoding the cardiac sodium channel Nav1.5, is crucial for heart rhythm, with variants linked to various arrhythmias. The Finnish-enriched SCN5A missense variant T220I (rs45620037) was previously associated with AFib protection and higher risk of sick sinus syndrome in smaller studies [1], but its overall clinical impact remained unclear, with conflicting reports, mostly limited to family-studies. Based on prior electrophysiological data suggesting a mild loss-of-function effect, we hypothesized that T220I acts as a natural genetic proxy for a lifelong mild cardiac sodium channel blockade, influencing cardiac conduction and disease risk.

Methods: We investigated the association of T220I by analyzing genotyping, electronic health record, and electrocardiogram (ECG) data from over one million individuals across three cohorts: FinnGen, UK Biobank, and Health 2000. Specifically, we tested the hypotheses that T220I carrier status confers protection against tachyarrhythmias (like AFib) while increasing risk for bradyarrhythmias and conduction-slowing conditions, consistent with its role as a genetic proxy for sodium channel blockade. We tested associations between carrier status of T220I and cardiac arrhythmias, heart failures and cardiomyopathies (ICD codes I40-I50) as well as mortality outcomes using PheWASs and Cox proportional hazard models. Further, we tested how carrier status of T220I influences ECG parameters such as QT time, PR time within H2000 and the UK Biobank. We examined mortality outcomes post-myocardial infarction (MI) to replicate the cast trial [2] and investigated the interaction between T220I and a polygenic score (PGS) for AFib [3].

Results: We found that heterozygous T220I carriers are protected against multiple tachyarrhythmias across lifetime, most notably AFib (Hazard Ratio [HR] 0.60, 95% CI 0.55-0.66, p=3.13x10^-25), ventricular premature depolarization, and ventricular tachycardia with smaller protective assocations against dilated cardiomyopathy (HR 0.66, p=0.021) and (left) heart failure (HR 0.84, p=1.24x10^-3). However, T220I increased the risk for bradyarrhythmias such as sick sinus syndrome (Odds Ratio [OR] 2.36, p=4.32x10^-22) and AV block, particularly in homozygotes, consistent with sodium channel blockade side effects. Overall, T220I conferred protection against mortality due to cardiac arrhythmia (HR 0.65, p=0.015) without significantly affecting all-cause mortality. Post-MI, T220I carriers showed an increased short-term all-cause mortality, mirroring pharmacological sodium channel blocker effects [2], with a normalized risk after 10-15 years. T220I significantly shortened the QTc interval (-7.49ms, p=0.0037 in H2000) and acted mostly independent with an AFib PGS, counterbalancing a high genetic burden for AFib to average levels.

Conclusion: The T220I variant, consistent with a weak loss-of-function effect, acts as a genetic proxy for a lifelong cardiac sodium channel blockade. This enabled us to gain new potentially clinically relevant insights for pharmacological sodium channel blockade such as after myocardial infarction which would be too risky to investigate with clinical trials and potential therapeutic benefits against cardiac arrhythmia related mortality [4].

P.T.E. has received sponsored research support from Bayer AG, IBM Health, Bristol Myers Squibb, and Pfizer; he has consulted for Bayer AG, Novartis and MyoKardia.

The authors declare that a positive ethics committee vote has been obtained.

Literatur

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