Sudden Cardiac Death Susceptibility Research Articles

Novel Indel Variation of NPC1 Gene Associates With Risk of Sudden Cardiac Death

Background and Aims: Sudden cardiac death (SCD) was defined as an unexpected death from cardiac causes during a very short duration. It has been reported that Niemann-Pick type C1 (NPC1) gene mutations might be related to cardiovascular diseases. The purpose of the study is to investigate whether common genetic variants of NPC1 is involved in SCD susceptibility. Methods: Based on a candidate-gene-based approach and systematic screening strategy, this study analyzed an 8-bp insertion/deletion polymorphism (rs150703258) within downstream of NPC1 for the association with SCD risk in Chinese populations using 158 SCD cases and 524 controls. The association of rs150703258 and SCD susceptibility was analyzed using logistic regression. Genotype-phenotype correlation analysis was performed using public database including 1000G, expression quantitative trait loci (eQTL), and further validated by human heart tissues using PCR. Dual-luciferase assay was used to explore the potential regulatory role of rs150703258. Gene expression profiling interactive analysis and transcription factors prediction were performed. Results: Logistic regression analysis exhibited that the deletion allele of rs150703258 significantly increased the risk of SCD [odds ratio (OR) = 1.329; 95% confidence interval (95%CI):1.03–1.72; p = 0.0289]. Genotype-phenotype correlation analysis showed that the risk allele was significantly associated with higher expression of NPC1 at mRNA and protein expressions level in human heart tissues. eQTL analysis showed NPC1 and C18orf8 (an adjacent gene to NPC1) are both related to rs150703258 and have higher expression level in the samples with deletion allele. Dual-luciferase activity assays indicate a significant regulatory role for rs150703258. Gene expression profiling interactive analysis revealed that NPC1 and C18orf8 seemed to be co-regulated in human blood, arteries and heart tissues. In silico analysis showed that the rs150703258 deletion variant may create transcription factor binding sites. In addition, a rare 12-bp allele (4-bp longer than the insertion allele) of rs150703258 was discovered in the current cohort. Conclusion: In summary, our study revealed that rs150703258 might contribute to SCD susceptibility by regulating NPC1 and C18orf8 expression. This indel may be a potential marker for risk stratification and molecular diagnosis of SCD. Validations in different ethnic groups with larger sample size and mechanism explorations are warranted to confirm our findings.

A Functional Indel Polymorphism Within MIR155HG Is Associated With Sudden Cardiac Death Risk in a Chinese Population.

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.

Regulatory variation within 3’UTR of STAT5A correlates with sudden cardiac death in Chinese populations

Definitive diagnosis to sudden cardiac death (SCD) is often challenging since the postmortem examination on SCD victims could hardly demonstrate an adequate cause of death. It is therefore important to uncover the inherited risk component to SCD. Signal transducer and activators of transcription 5 A (STAT5A) is a member of the STAT family and a transcription factor that is activated by many cell ligands and associated with various cardiovascular processes. In this study, we performed a systematic variant screening on the STAT5A to filter potential functional genetic variations. Based on the screening results, an insertion/deletion polymorphism (rs3833144) in 3’UTR of STAT5A was selected as the candidate variant. A total of 159 SCD cases and 668 SCD matched healthy controls was enrolled to perform a case-control study and evaluate the association between rs3833144 and SCD susceptibility in Chinese populations. Logistic regression analysis showed that the deletion allele of rs3833144 had significantly increased the SCD risk (odds ratio (OR) = 1.54; 95% confidence interval (CI) = 1.18–2.01; P = 0.000955). Further genotype-expression eQTL analysis showed that samples with deletion allele appeared to lower expression of STAT5A, and in silico prediction suggested the local 3 D structure changes of STAT5A mRNA caused by the variant. On the other hand, the bioinformatic analysis presented that promoters of RARA and PTGES3L-AARSD1 could interact with rs3833144, and eQTL analysis showed the higher expression of both genes in samples with deletion allele. Dual-luciferase activity assays also suggested the significant regulatory role of rs3833144 in gene transcription. Our current data thus suggested a possible involvement of rs3833144 to SCD predisposition in Chinese populations and rs3833144 with potential function roles may become a candidate marker for SCD diagnosis and prevention.

Genetic association study of a novel indel polymorphism in HSPA1B with the risk of sudden cardiac death in the Chinese populations

Sudden cardiac death (SCD) has become a global problem due to its high mortality in the general population. Identification of genetic factors predisposed to SCD is significant since it enables genetic testing that would contribute to molecular diagnosis and risk stratification of SCD. It has been reported that HSPA1B gene mutations might be related with SCD. In this study, based on candidate-gene-based approach and systematic screening strategy, a 5-base pair insertion/deletion (Indel) polymorphism (rs3036297) in the 3′UTR of HSPA1B gene was selected to perform a case-control study aiming to investigate its association with SCD susceptibility in Chinese populations. Logistic regression analysis showed that the insertion allele of rs3036297 was correlated with a comparatively lower risk for SCD [OR=0.58, 95%CI=0.43–0.77, P=1.28×10−4] compared with the deletion allele. Luciferase activity assay indicated that HSPA1B expression could be regulated by rs3036297 through interfering binding with miR-134-5p. Furthermore, analysis of database from Haploreg and GTEx revealed that the rs3036297 variant was involved in potential cis-regulatory element with the promoter of HLA-DRB5 through a long-range interaction and the deletion allele of rs3036297 increased HLA-DRB5 expression. In conclusion, the rs3036297 variant may regulate HSPA1B expression via a mechanism of miRNA binding and HLA-DRB5 expression via a long-range promoter interaction through which contributed to SCD susceptibility. Therefore, rs3036297 would be a potential marker for molecular diagnosis and genetic counseling of SCD.

SVAD: A genetic database curates non-ischemic sudden cardiac death-associated variants.

Sudden cardiac death (SCD) is an important cause of mortality worldwide. It accounts for approximately half of all deaths from cardiovascular disease. While coronary artery disease and acute myocardial infarction account for the majority of SCD in the elderly population, inherited cardiac diseases (inherited CDs) comprise a substantial proportion of younger SCD victims with a significant genetic component. Currently, the use of next-generation sequencing enables the rapid analysis to investigate relationships between genetic variants and inherited CDs causing SCD. Genetic contribution to risk has been considered an alternate predictor of SCD. In the past years, large numbers of SCD susceptibility variants were reported, but these results are scattered in numerous publications. Here, we present the SCD-associated Variants Annotation Database (SVAD) to facilitate the interpretation of variants and to meet the needs of data integration. SVAD contains data from a broad screening of scientific literature. It was constructed to provide a comprehensive collection of genetic variants along with integrated information regarding their effects. At present, SVAD has accumulated 2,292 entries within 1,239 variants by manually surveying pertinent literature, and approximately one-third of the collected variants are pathogenic/likely-pathogenic following the ACMG guidelines. To the best of our knowledge, SVAD is the most comprehensive database that can provide integrated information on the associated variants in various types of inherited CDs. SVAD represents a valuable source of variant information based on scientific literature and benefits clinicians and researchers, and it is now available on http://svad.mbc.nctu.edu.tw/.

A common indel polymorphism of the Desmoglein-2 (DSG2) is associated with sudden cardiac death in Chinese populations

Sudden cardiac death (SCD) is referred to as sudden and unexpected death caused by cardiovascular diseases, in which a person preexisted heart disease or not. Compelling evidence indicates that SCD etiology have been predominantly affected by host genetic factors. However, how genetic variants play roles in the inherited risk component of SCD are still largely unknown. It has been reported that Desmoglein-2 (DSG2) mutations might be related to sudden death. In the present study, we used a candidate gene approach to investigate the associations between rs397729601 (a 2-base pair indel polymorphism) mapping to the 3′UTR of DSG2 with the risk of SCD. It is shown by logistic regression analysis that the risk of SCD has been significantly increased by the deletion allele of rs397729601 [odds ratio (OR)=1.51; 95% confidence interval (CI)=1.12–2.05; P=0.00559]. Additional genotype-phenotype analysis was performed to evaluate the mRNA level, revealing that human myocardium tissues with the deletion allele showed higher expression of DSG2. Dual luciferase activity analysis was conducted in an in vitro reporter gene system, suggesting that DSG2 expression could be regulated by rs397729601 which interrupted the binding of miR-933-3p with DSG2. We concluded that rs397729601 may affect the expression of DSG2 through miR-933-3p regulation, contributing to SCD susceptibility. Thus, rs397729601 may be used as a potential marker for molecular diagnosis and genetic counseling of SCD. Our findings need to be validated through replication and further functional studies.

KCNQ1 Polymorphism and Susceptibility to Sudden Cardiac Death in Chinese Population

Background: SCD (Sudden Cardiac Death) occurs commonly in forensic practice and often shows negative anatomy results after a systemic autopsy. In recent years, the importance of genetic background has been emphasized in the examination of SCD. The aim of this study is to establish a feasible method to detect SCD-related mutations located in a SCD-causing gene, potassium voltage-gated channel gene (KCNQ1). This method will meet the requirement of mutation screening for SCD in regular forensic DNA laboratories. Methods: 51 reported single nucleotide polymorphisms (SNPs) from KCNQ1 gene were selected in our study. We examined 60 SCD victims and 60 healthy individuals from the Chinese population residing in Shanxi and Chongqing, China. We performed multiplex PCR for 16 DNA fragments, then using SNaPshot reaction and capillary electrophoresis to obtain the typing results of 51 SNPs. Finding: Four previously reported coding variants were identified in our study: S546S, I145I, P448R and G643S. The allele frequencies of I145I did not differ significantly in the SCD cases compared with Chinese controls (I145I: 10% in SCD cases vs 6% in controls, p=0*301, OR=0*965). The heterozygous mutation of G643S and P448R probably were putative causative mutation for SCD in Chinese population (G643S: 40% in SCD cases vs 10% in controls, p<0*0001, OR=4*000; For P448R: 35% in SCD cases vs 8*3% in controls, p<0*001, OR=4*200). S546S was the 4th mutation found in SCD population resulting in 35% in SCD cases and 18*3% in controls (p=0*049, OR=0*883). Interpretation: The missense mutation of KCNQ1 gene, P448R and G643S, were associated with SCD susceptibility level in Chinese population. The established system would be potentially helpful for investigating the characteristic of SCD-related mutations in KCNQ1 gene. These methods are compatible with current techniques and equipments in forensic DNA laboratory and will help screen mutations in those dead of SCD and their relatives. Funding Statement: This work was supported by the Natural Science Foundation of China (No. 30900593), the Natural Science Foundation of Shanxi Province, China (No. 201601D011091), Scientific Research Foundation for Returned Overseas Chinese Scholars of Shanxi Province (2011-172) and Shanxi Scholarship Council of China (2016-055). Declaration of Interests: The authors have no financial or commercial conflicts of interest. Ethics Approval Statement: The sample collection was approved by the ethics committee of Shanxi Medical University, China. Written informed consent was obtained from participants or their family members, who agreed to use the data for this study.

RETRACTED: Deficiency of a novel gene, Yulink, predisposes to heart failure and ventricular arrhythmia.

Heart failure is a major cardiovascular disease and is associated with significant morbidity and mortality. Sudden cardiac death (SCD) in heart failure is a disastrous cardiovascular phenomenon. However, few studies have examined the genetic background that determines susceptibility to heart failure and SCD. We found that deficiency of a newly identified gene, Yulink, promoted cardiac alternans in zebrafish cardiomyocytes, and genetic knockdown (KD) resulted in pericardial edema, decreased cardiac output, and premature ventricular contractions. Yulink KD morphants exhibited irregular action potentials, slower Ca2+ reuptake, and alternans of Ca2+ transients and action potential duration, which are hallmarks for SCD susceptibility in heart failure. Similarly, KD of Yulink in mouse cardiomyocytes disrupted Ca2+ reuptake, reduced the expression of cardiac Serca2, and resulted in a reduction in peroxisome proliferator-activated receptor (PPAR)γ activity. Expression of Serca2 was up-regulated by PPARγ agonists and down-regulated by PPARγ-short hairpin RNA KD, suggesting that Yulink regulates Serca2 expression through PPARγ. Finally, Yulink and Serca2 were down-regulated in ventricular samples of hearts from patients with heart failure due to dilated cardiomyopathy. Our results highlight the interaction of Yulink with PPARγ in regulating Serca2 expression and suggest a mechanistic role of the Yulink in the development of human heart failure and SCD.-Tsai, C.-T., Kuo, M.-W., Lin, J.-L., Yu, A. L., Yu, J. Deficiency of a novel gene, Yulink, predisposes to heart failure and ventricular arrhythmia.

Association between an indel polymorphism in the 3'UTR of COL1A2 and the risk of sudden cardiac death in Chinese populations.

Sudden cardiac death (SCD) describes the unexpected natural death from a cardiac cause within a short time period. Compelling evidence suggests the involvement of host genetic factors in SCD etiology. Identification of genetic variations predisposed to SCD enables genetic testing that may contribute to SCD diagnosis and risk stratification. Previous studies have suggested that dysregulation of pro-alpha2 chain of type I collagen, encoded by collagen type I alpha 2 chain (COL1A2) gene, was involved in cardiac disorders such as myocardial infarction, hypertrophic cardiomyopathy and atherosclerosis. By using a candidate-gene-based approach, we evaluated the association of a 7-base pair (7-bp) indel polymorphism (rs3917) in the 3'UTR of COL1A2 with the risk of SCD in a Chinese population (79SCD cases and 328 controls). Logistic regression analysis showed that the deletion allele of rs3917 significantly increased the risk of SCD [odds ratio (OR)=1.82; 95% confidence interval (CI)=1.08-3.06; P=0.0159]. Further genotype-phenotype association analysis revealed that the deletion allele was markedly correlated with lower expression of COL1A2 in human myocardium tissues. The luciferase activity analysis in an in vitro reporter gene system suggested that rs3917 could regulate COL1A2 expression through interrupting the binding of miR-296-3p with COL1A2 in an allele-dependent manner, which in turn confer SCD risk. Our data provided initial evidence that rs3917 was highly relevant to SCD susceptibility, and this indel may become a potential marker for molecular diagnosis and genetic counseling of SCD. The replication of our studies and further functional studies are needed to validate our findings.

Sudden cardiac death is associated both with epilepsy and with use of antiepileptic medications

ObjectiveEpilepsy is associated with increased risk for sudden cardiac death (SCD). We aimed to establish, in a community based study, whether this association is mediated by epilepsy per se, use...

Novel Loci Associated with Increased Risk of Sudden Cardiac Death in the Context of Coronary Artery Disease

BackgroundRecent genome-wide association studies (GWAS) have identified novel loci associated with sudden cardiac death (SCD). Despite this progress, identified DNA variants account for a relatively small portion of overall SCD risk, suggesting that additional loci contributing to SCD susceptibility await discovery. The objective of this study was to identify novel DNA variation associated with SCD in the context of coronary artery disease (CAD).Methods and FindingsUsing the MetaboChip custom array we conducted a case-control association analysis of 119,117 SNPs in 948 SCD cases (with underlying CAD) from the Oregon Sudden Unexpected Death Study (Oregon-SUDS) and 3,050 controls with CAD from the Wellcome Trust Case-Control Consortium (WTCCC). Two newly identified loci were significantly associated with increased risk of SCD after correction for multiple comparisons at: rs6730157 in the RAB3GAP1 gene on chromosome 2 (P = 4.93×10−12, OR = 1.60) and rs2077316 in the ZNF365 gene on chromosome 10 (P = 3.64×10−8, OR = 2.41).ConclusionsOur findings suggest that RAB3GAP1 and ZNF365 are relevant candidate genes for SCD and will contribute to the mechanistic understanding of SCD susceptibility.

A common missense variant in the neuregulin 1 gene is associated with both schizophrenia and sudden cardiac death.

Both schizophrenia and epilepsy have been linked to increased risk of sudden cardiac death (SCD). We hypothesized that DNA variants within genes previously associated with schizophrenia and epilepsy may contribute to an increased risk of SCD. To investigate the contribution to SCD susceptibility of DNA variants previously implicated in schizophrenia and epilepsy. From the ongoing Oregon Sudden Unexpected Death Study, comparisons were performed among 340 SCD cases presenting with ventricular fibrillation and 342 controls. We tested for the association between 17 single-nucleotide polymorphisms (SNPs) mapped to 14 loci previously implicated in schizophrenia and epilepsy by using logistic regression and assuming additive, dominant, and recessive genetic models. The minor allele of the nonsynonymous SNP rs10503929 within the neuregulin 1 gene was associated with SCD under all 3 investigated models, with the strongest association for the recessive genetic model (recessive P = 4.01 × 10(-5), odds ratio [OR] 4.04; additive P = 2.84 × 10(-7), OR 1.9; and dominant P = 9.01 × 10(-6), OR 2.06). To validate our findings, we further explored the association of this variant in the Harvard Cohort SCD study. The SNP rs10503929 was associated with an increased risk of SCD under the recessive genetic model (P = .0005, OR 2.7). This missense variation causes a methionine to threonine change and functional effects are currently unknown. The observed association between a schizophrenia-related neuregulin 1 gene variant and SCD may represent the first evidence of coexisting genetic susceptibility between 2 conditions that have an established clinical overlap. Further investigation is warranted to explore the molecular mechanisms of this variant in the pathogenesis of SCD.

Genetic marker of torsades de pointes risk following myocardial infarction

a L i r i s c e c c c g Q Sudden cardiac death (SCD) secondary to ventricular arrhythmia is a common cause of adult mortality especially in the setting of acute myocardial infarction (MI). Epidemiological evidence supports an important contribution of genetic factors to SCD susceptibility as inferred from the robust nature of family history as an independent risk factor for this deadly event. Ventricular fibrillation dominates s the cause for SCD during the acute phase (minutes to ours) following acute MI. Sudden death risk remains subtantially elevated during the subacute (hours to days) and hronic (days to weeks) phases of the recovery period, but he substrate for this predisposition may be different than hat in the acute phase. Infrequently, subjects in the early post-MI period exhibit vidence of abnormal ventricular repolarization, specifically prolonged QT interval, that predisposes to the polymorhic ventricular tachyarrhythmia, torsades de pointes TdP). Although this phenomenon was originally regarded s a form of acquired long-QT syndrome (LQTS), one might have speculated that this idiosyncratic phenotype occurred in genetically predisposed individuals. In this issue of HeartRhythm, Crotti et al report results f a genetic investigation of infarct-related TdP. In this andidate gene, case-control association study, the investiators studied 13 subjects with prolonged QT intervals and dP occurring 2–11 days following acute MI. The subjects ere screened for genetic variants in 5 genes previously inked with congenital LQTS (KCNQ1, KCNH2, SCN5A, CNE1, and KCNE2). Importantly, none of the cases were xposed to QT-prolonging drugs or arrhythmogenic metaolic conditions (eg, hypokalemia). A control group conisting of 133 acute MI survivors without TdP and matched or ethnicity was also genotyped. The investigators discovered 2 types of genetic predisosition. In 2 of the 13 infarct-related TdP cases (15%), utations in either KCNH2 or SCN5A were identified that egregated with prolonged QT intervals in first-degree rel-