The Brugada Syndrome Susceptibility Gene <i>HEY2</i> Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity
Bibliographic record
Abstract
Rationale: Genome-wide association studies previously identified an association of rs9388451 at chromosome 6q22.3 (near HEY2 ) with Brugada syndrome. The causal gene and underlying mechanism remain unresolved. Objective: We used an integrative approach entailing transcriptomic studies in human hearts and electrophysiological studies in Hey2 +/− ( Hey2 heterozygous knockout) mice to dissect the underpinnings of the 6q22.31 association with Brugada syndrome. Methods and Results: We queried expression quantitative trait locus data acquired in 190 human left ventricular samples from the genotype-tissue expression consortium for cis -expression quantitative trait locus effects of rs9388451, which revealed an association between Brugada syndrome risk allele dosage and HEY2 expression (β=+0.159; P =0.0036). In the same transcriptomic data, we conducted genome-wide coexpression analysis for HEY2 , which uncovered KCNIP2 , encoding the β-subunit of the channel underlying the transient outward current ( I to ), as the transcript most robustly correlating with HEY2 expression (β=+1.47; P =2×10 −34 ). Transcript abundance of Hey2 and the I to subunits Kcnip2 and Kcnd2 , assessed by quantitative reverse transcription–polymerase chain reaction, was higher in subepicardium versus subendocardium in both left and right ventricles, with lower levels in Hey2 +/− mice compared with wild type. Surface ECG measurements showed less prominent J waves in Hey2 +/− mice compared with wild-type. In wild-type mice, patch-clamp electrophysiological studies on cardiomyocytes from right ventricle demonstrated a shorter action potential duration and a lower V max in subepicardium compared with subendocardium cardiomyocytes, which was paralleled by a higher I to and a lower sodium current ( I Na ) density in subepicardium versus subendocardium. These transmural differences were diminished in Hey2 +/− mice because of changes in subepicardial cardiomyocytes. Conclusions: This study uncovers a role of HEY2 in the normal transmural electrophysiological gradient in the ventricle and provides compelling evidence that genetic variation at 6q22.31 (rs9388451) is associated with Brugada syndrome through a HEY2 -dependent alteration of ion channel expression across the cardiac ventricular wall.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".