A great first step, but a long way to go

This editorial refers to ‘Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores’†, by R. Tadros et al., on page 3097. In this issue of the European Heart Journal, Tadros et al. report data on the value of polygenic risk scores (PRSs) to predict electrocardiographic (ECG) responses to sodium channel blockade (SCB).1 The authors conclude that genetic factors determine the ECG response to SCB and that a combination of PRSs, some basal ECG features, and a family history of Brugada syndrome (BrS) accurately predict the development of a type I BrS ECG during ajmaline infusion. Similar observations have been previously reported by Strauss et al. in the long QT syndrome.2 PRSs based on common genetic variants (the genetic QT score) predicted QT prolongation and ‘torsade de pointes’ during administration of certain drugs. These findings are important because they bring us one step closer to understanding the very complex genotype–phenotype correlations of cardiac electrical diseases. These investigations support the recent endeavours launched to achieve a form of highly individualized ‘precision medicine’ instead of the ‘one-size-fits-all’ approach.3 Predicting individual responses to drugs, interventions, environmental factors, and others has been and will remain one of the major challenges, if not the real major challenge, in clinical medicine. That individual responses to stimuli are related to their own individual genetic background is simple, straightforward, intuitive reasoning. Proving this hypothesis is not that easy, however. With the major advances made in genome analysis, we can state that we have reached close to 100% understanding of the anatomy of the human genome. In contrast, we have to realize that our understanding of the physiology and pathophysiology of the human genome is very limited. The ‘one gene-one protein-one function’ concept (or variations thereof) has long been abandoned. Genetic switchers, modifiers, even unexpected functions of non-codifying parts have shown us that the road to walk to fully understand genetic mechanisms is still very long. Genotype–phenotype associations do not equate to genotype–phenotype causal relationships. A possible causal relationship may be suspected from controlled randomized studies, as was the case in the analysis of the genetic QT score by Strauss et al.2 However, even then, demonstration of a cause–effect relationship requires a pathophysiological approach: we need to show in the experimental setting that enhancing or suppressing the function of the genetic variant has effects compatible with the pathophysiological mechanisms and phenotype of the disease. Unfortunately, these types of studies are not available for the overwhelming majority of genetic variants discovered, including variants considered definitely pathogenic. Tadros et al. performed a retrospective not controlled observational study of patients undergoing SCB testing because of suspicion of BrS. This major limitation is acknowledged by the authors who stress the need for further validation studies in the general population also using other sodium channel blockers. More important is the problem of interpretation of their results when mutations known to modify sodium channel function are present. As the mutation status for SCN5A was analysed in less than one-third of the study population, the contribution of ‘true mutations’ instead of single nucleotide polymorphisms (SNPs) to the results obtained is not known. Three common variants at the SCN5A, SCN10A, and HEY2 genes were analysed in the PRS for BrS (PRSBrS). At least the HEY2 variant has been previously shown to have clear effects on sodium current; however, it is considered a common variant without pathogenic significance.4 Classification of variants, common or not, and multiple and incidental findings is challenging.5 Reclassification of variants based on new knowledge usually results in ‘downgrading’ (from a possible pathogenic variant to non-pathogenic or uncertain) rather than in ‘upgrading’ (from a non-significant variant to pathogenic) of the variant. Knowledge on cellular pathophysiological effects of the variants is usually lacking. This, however, does not invalidate the contribution by Tadros et al.: the PRSs presented predict ECG changes and development of a type I BrS ECG in this susceptible population. The next question is what does this mean in clinical practice? The PRS may suggest a susceptibility to conduction defects and development of a type I BrS ECG during SCB, but the finding of the genetic variants described cannot be considered equivalent to a diagnosis of BrS. The typical type I BrS ECG will have to be present (spontaneous of after SCB) before a diagnosis of BrS is even considered. Another question, however, and a possible major contribution of this study is to try to understand whether the PRSBrS not only predicts response to SCB but can also help us define the prognosis of these individuals. In this sense, it would have been very interesting to analyse whether PRS combined with results of SCB and other risk factors6 could better define the arrhythmic risk in BrS. In other words, an important study, an important first step that needs further scientific follow-up; an important analysis that, like all significant analyses, gives us some answers but opens up multiple new questions (Figure 1). From genotype to phenotype. From genotype to phenotype. Conflicts of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.