Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores

Tadros, Rafik; Tan, Hanno L.; Mathari, Sulayman El; Kors, Jan A.; Postema, Pieter G.; Lahrouchi, Najim; Beekman, Leander; Radivojkov-Blagojevic, Milena; Amin, Ahmad S.; Meitinger, Thomas; Tanck, Michael W.T.; Wilde, Arthur A.M.; Bezzina, Connie R.

doi:10.1093/eurheartj/ehz435

Cited by 60 publications

(44 citation statements)

References 32 publications

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“…These results are in line with the previous reporting of better efficacy of statins in high-risk samples, for example, due to diabetes, hypertension, or high CRP concentrations [68]. A recent study demonstrated a potential role of PRS for electrocardiogram parameters in predicting the cardiac electrical response to sodium channel blockade [69].…”

Section: Prs In Treatment Choicesupporting

confidence: 91%

Polygenic risk scores: from research tools to clinical instruments

2020

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Genome-wide association studies have shown unequivocally that common complex disorders have a polygenic genetic architecture and have enabled researchers to identify genetic variants associated with diseases. These variants can be combined into a polygenic risk score that captures part of an individual's susceptibility to diseases. Polygenic risk scores have been widely applied in research studies, confirming the association between the scores and disease status, but their clinical utility has yet to be established. Polygenic risk scores may be used to estimate an individual's lifetime genetic risk of disease, but the current discriminative ability is low in the general population. Clinical implementation of polygenic risk score (PRS) may be useful in cohorts where there is a higher prior probability of disease, for example, in early stages of diseases to assist in diagnosis or to inform treatment choices. Important considerations are the weaker evidence base in application to non-European ancestry and the challenges in translating an individual's PRS from a percentile of a normal distribution to a lifetime disease risk. In this review, we consider how PRS may be informative at different points in the disease trajectory giving examples of progress in the field and discussing obstacles that need to be addressed before clinical implementation.

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Section: Prs In Treatment Choicesupporting

confidence: 91%

Polygenic risk scores: from research tools to clinical instruments

2020

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“…This demonstrates that predisposition to BrS can occur because of the presence of common genetic variants in sodium channel genes or the transcriptional regulator HEY2. Furthermore, association data from genome-wide association studies used to calculate weighted polygenic risk scores have been explored as predictive tools to anticipate the results of ajmaline challenges, with a study by Tadros and colleagues [78] describing the association between polygenic risk scores and the slowing of cardiac conduction with ajmaline. Thus, the role of common variants in disease susceptibility must be considered, and is much more important than previously recognized.…”

Section: Sodium Channel Mutationsmentioning

confidence: 99%

Brugada Syndrome: Oligogenic or Mendelian Disease?

Monasky

Micaglio

Ciconte

et al. 2020

IJMS

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Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70-85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant's frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype-phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.

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“…More recently, it has been shown that a BrS PRS could potentially be of clinical utility in the diagnostic strategy of BrS. 25 …”

Section: Identification Of Genetic Risk Variants In Rare Cardiac Disementioning

confidence: 99%

When genetic burden reaches threshold

Walsh

Tadros

Bezzina

2020

European Heart Journal

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Rare cardiac genetic diseases have generally been considered to be broadly Mendelian in nature, with clinical genetic testing for these conditions predicated on the detection of a primary causative rare pathogenic variant that will enable cascade genetic screening in families. However, substantial variability in penetrance and disease severity among carriers of pathogenic variants, as well as the inability to detect rare Mendelian variants in considerable proportions of patients, indicates that more complex aetiologies are likely to underlie these diseases. Recent findings have suggested genetic variants across a range of population frequencies and effect sizes may combine, along with non-genetic factors, to determine whether the threshold for expression of disease is reached and the severity of the phenotype. The availability of increasingly large genetically characterized cohorts of patients with rare cardiac diseases is enabling the discovery of common genetic variation that may underlie both variable penetrance in Mendelian diseases and the genetic aetiology of apparently non-Mendelian rare cardiac conditions. It is likely that the genetic architecture of rare cardiac diseases will vary considerably between different conditions as well as between patients with similar phenotypes, ranging from near-Mendelian disease to models more akin to common, complex disease. Uncovering the broad range of genetic factors that predispose patients to rare cardiac diseases offers the promise of improved risk prediction and more focused clinical management in patients and their families.

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Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores

Cited by 60 publications

References 32 publications

Polygenic risk scores: from research tools to clinical instruments

Polygenic risk scores: from research tools to clinical instruments

Brugada Syndrome: Oligogenic or Mendelian Disease?

When genetic burden reaches threshold

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