# TBX5 genetic variants and SCD-CAD susceptibility: insights from Chinese Han cohorts

## TL;DR

This study explores how a genetic variant in the TBX5 gene influences the risk of sudden cardiac death linked to coronary artery disease in Chinese Han populations.

## Contribution

The study identifies rs11278315 as a novel genetic risk marker for SCD-CAD and explores its functional impact on TBX5 expression and splicing.

## Key findings

- The deletion allele of rs11278315 is associated with a significantly reduced risk of SCD-CAD.
- The deletion allele shows lower transcriptional activity and reduced TBX5 expression in human cardiac tissue.
- rs11278315 influences TBX5 alternative splicing, potentially altering its functional effects.

## Abstract

The prevention and prediction of sudden cardiac death (SCD) present persistent challenges, prompting exploration into common genetic variations for potential insights. T-box 5 (TBX5), a critical cardiac transcription factor, plays a pivotal role in cardiovascular development and function. This study systematically examined variants within the 500-bp region downstream of the TBX5 gene, focusing on their potential impact on susceptibility to SCD associated with coronary artery disease (SCD-CAD) in four different Chinese Han populations.

In a comprehensive case-control analysis, we explored the association between rs11278315 and SCD-CAD susceptibility using a cohort of 553 controls and 201 SCD-CAD cases. Dual luciferase reporter assays and genotype-phenotype correlation studies using human cardiac tissue samples as well as integrated in silicon analysis were applied to explore the underlining mechanism.

Binary logistic regression results underscored a significantly reduced risk of SCD-CAD in individuals harboring the deletion allele (odds ratio = 0.70, 95% CI [0.55–0.88], p = 0.0019). Consistent with the lower transcriptional activity of the deletion allele observed in dual luciferase reporter assays, genotype-phenotype correlation studies on human cardiac tissue samples affirmed lower expression levels associated with the deletion allele at both mRNA and protein levels. Furthermore, our investigation revealed intriguing insights into the role of rs11278315 in TBX5 alternative splicing, which may contribute to alterations in its ultimate functional effects, as suggested by sQTL analysis. Gene ontology analysis and functional annotation further underscored the potential involvement of TBX5 in alternative splicing and cardiac-related transcriptional regulation.

In summary, our current dataset points to a plausible correlation between rs11278315 and susceptibility to SCD-CAD, emphasizing the potential of rs11278315 as a genetic risk marker for aiding in molecular diagnosis and risk stratification of SCD-CAD.