Abstract
Sudden cardiac death (SCD) is a devastating complication of multiple disease processes and has gradually became a major public health issue. miR-155 is one of the best characterized miRNAs and plays a critical role in several physiological and pathological process, including cardiovascular diseases. In this study, we systematically screened the whole region of miR-155 host gene (MIR155HG) and identified a 4-bp insertion/deletion variant (rs72014506) residing in the intron region of MIR155HG as the candidate polymorphism. The association of rs72014506 with SCD susceptibility was evaluated using 166 SCD cases and 830 healthy controls in a Chinese population. Logistic regression analysis suggested that the homozygote del/del genotype significantly decreased the risk of SCD [odds ratio (OR) = 0.29; 95% confidence interval (CI) = 0.12–0.74; Ptrend = 0.0004]. Further genotype–expression association study using human myocardium tissue samples suggested that the deletion allele was intimately linked to lower the expression of both MIR155HG and mature miR155. Luciferase activity assay also revealed that the deletion allele of rs72014506 inhibited gene transcriptional activity. Finally, we performed electrophoretic mobility shift assay and verified the preferential binding affinity of the deletion allele with POU2F1 (POU domain class 2 transcription factor 1). Collectively, we have successfully identified a SCD risk conferring polymorphism in the MIR155HG gene and a likely biological mechanism for the decreased risk of SCD associated with the deletion allele. This novel variant may thus serve as a potential genetic marker for SCD diagnosis and prevention in natural populations, if validated by further studies with a larger sample size.
Highlights
Sudden cardiac death (SCD) is a devastating complication of multiple disease processes and has gradually become a major public health issue [1, 2]
Considering the wide application of capillary gel electrophoresis (CE) combined with PCR-based assays in forensic genetics, genetic marker selection priority was given to those length polymorphisms such as indels
We initially identified that one 4-bp indel polymorphism in the intron region of MIR155HG was functionally relevant to SCD susceptibility in a Chinese population
Summary
Sudden cardiac death (SCD) is a devastating complication of multiple disease processes and has gradually become a major public health issue [1, 2]. A single common variant may contain limited effect size, but a combination of these significant variants would present a clear clinical picture of SCD For these reasons, much progress has been made in illuminating the genetic underpinning of predisposition to SCD. Genome-wide association studies have revealed robust correlations of common genetic variants with SCD or SCD-related cardiac electric traits [8,9,10]. MicroRNAs represent a class of small non-protein-coding molecules involved in post-transcriptional gene regulation [13]. Emerging studies revealed the crucial role of miR-155 in several physiological and pathological process, including inflammation, immunity, and cardiovascular diseases [15, 16]. Considering that miR155 emerges as a key effector in cardiovascular biology, we hypothesized that MIR155HG variants may be associated with SCD occurrence. Additional experiments were conducted to uncover the potential mechanisms underlying the association
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