Rare variants in the FBN1 gene are associated with sporadic dilated cardiomyopathy in a Chinese Han population

Abstract

Introduction: Dilated cardiomyopathy (DCM) represents a diverse set of myocardial diseases characterized by notable genetic heterogeneity. Although over 50 genes have been associated with DCM, these collectively explain 35% of idiopathic DCM cases. Variants in the FBN1 gene encoding fibrillin-1 are primarily linked to connective tissue disorders. Considering the potential of these disorders to impact myocardial tissue, this study probes into the possible association between FBN1 variants and DCM.

Aim: The objective of this study was to investigate the association between FBN1 variants and DCM in a Chinese Han population.

Methods and Results: We performed whole-exome sequencing (WES) to identify rare FBN1 variants among 1,059 DCM cases and 514 controls. Utilizing a case-control strategy and the optimal sequence kernel association test (SKAT-O), we found a significant enrichment of rare deleterious FBN1 variants in DCM patients (19 of 1,059 vs. 0 of 514, P_SKAT-O = 7.49E-04). Clinical characteristics analysis indicated a higher occurrence of atrial fibrillation and a higher rate of implantable cardioverter-defibrillator (ICD) implantation among DCM patients carrying FBN1 variants (FBN1⁺) compared to non-carriers (FBN1^-). However, these FBN1 variants did not significantly affect primary endpoints, defined as cardiac mortality or heart transplantation, yet appeared to increase the risk of secondary endpoints, including all-cause mortality or heart failure recurrence.

Conclusion: The findings suggest an association between rare deleterious variants in the FBN1 gene and DCM in a Chinese Han population. Our findings underline the importance of further research to validate these results and elucidate the role of FBN1 in DCM.

Potential Impact of the findings: This research provides fresh insights into the potential role of FBN1 rare variants in DCM, pointing to new directions for future genetic studies and potential therapeutic strategies in DCM management.

Keywords

Dilated cardiomyopathy / whole-exome sequencing / gene-based association test / case-control study

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