Leveraging a genetic proxy to investigate the effects of lifelong cardiac sodium channel blockade

Abstract Atrial fibrillation (AFib) and other cardiac arrhythmias pose a major public health burden but prevention remains difficult. Here, we investigated a genetic variant which we found to act like a natural lifelong cardiac sodium channel blockade. We studied the impact of the Finnish-enriched SCN5A missense variant (rs45620037 [T220I]) on cardiac arrhythmias, associated mortality and electrocardiographic (ECG) phenotypes in > 1M individuals across three cohorts (FinnGen, UK biobank, Health 2000). We identified protective effects of T220I on multiple common cardiac arrhythmias, most notably atrial fibrillation (AFib) (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.55 – 0.66, p = 3.13×10-25), but also ventricular premature depolarization or ventricular tachycardia, yet increasing susceptibility to conduction-slowing conditions such as sick sinus syndrome (mostly in older age groups). Overall, T220I conveyed a protection from mortality due to cardiac arrhythmia (HR = 0.65, 0.47 – 0.98, p = 0.015) without a significant effect on overall mortality (HR=0.98, p = 0.78). T220I heterozygotes had similar electrophysiological effects as sodium channel blockers such as significantly shortening QT intervals (−7.49 ms 95% CI −10.07 – [−4.91] ms, p = 0.0037, n=6,048) in the H2000 cohort, which we replicated in the UK Biobank (n=81,195). In addition, T220I protected from (left) heart failure and dilated cardiomyopathy. Early post–myocardial infarction, we found that T220I increased mortality in agreement with known sodium channel blocker effects which however continuously normalised to baseline 10-15 years post myocardial infarction. Finally, we found that T220I could lower a high genetic burden (a high polygenic score) for AFib to population average. The SCN5A T220I variant, consistent with a previously described weak loss-of-function effect, acted like a genetic proxy for 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. Our findings may also inspire redesign of cardiac sodium channel blockers. Competing Interest Statement 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. Funding Statement The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sàrl), Genentech Inc., Merck Sharp & Dohme LCC, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis AG, and Boehringer Ingelheim International GmbH. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study complies with all relevant ethical regulations. We obtained approval for the FinnGen study protocol from the Ethics Committee of the Hospital District of Helsinki and Uusimaa (approval number: HUS/990/2017). In the UKBB, the analyses were conducted under application numbers 77717 and 17488, 17488 was approved by the local Massachusetts General Hospital Institutional Review Board. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Based on National and European regulations (GDPR) access to individual-level sensitive health data must be approved by national authorities for specific research projects and for specifically listed and approved researchers. The FinnGen data may be accessed through Finnish Biobanks? FinBB portal (www.finbb.fi; email: info.fingenious{at}finbb.fi). For access to the UK Biobank data, the procedures are described at https://www.ukbiobank.ac.uk/enable-your-research