Dataset Information

Verification of Single Nucleotide Polymorphisms rs34554140, rs6670279, and rs6874185 as Novel Molecular Genetic Markers of Sudden Cardiac Death.

ABSTRACT: The aim of the study was to explore the association between sudden cardiac death (SCD) and single nucleotide polymorphisms (SNPs) rs34554140, rs6670279, and rs6874185 from the list of potential molecular genetic markers of SCD, obtained in our earlier genome-wide allelotyping on pooled DNA samples.

Materials and methods

The study is based on the case-control principle. The SCD group included 438 deceased residents of Novosibirsk (average age - 53.2±9.1 years; men - 72.7%, women - 28.3%) with the main postmortem diagnoses of acute circulatory failure or acute coronary failure, which met the criteria of SCD established by the European Society of Cardiology. The control group included 435 live subjects enrolled in the international projects HAPIEE and MONICA (average age - 53.2±8.9 years; men - 70.0%, women - 30.0%). DNA was isolated by phenol-chloroform extraction from the myocardial tissue in the SCD group and from the venous blood in the control group. Genotyping was performed by polymerase chain reaction with subsequent analysis of restriction fragment length polymorphism in a polyacrylamide gel.

Results

The frequencies of the genotypes of SNPs rs34554140, rs6670279, and rs6874185 in the control group correspond to those predicted by the Hardy-Weinberg equilibrium (c²=0.98, 0.009, 3.39, respectively). The AA genotype of rs34554140 is associated with an increased risk of SCD (p=0.002; OR=1.85; 95% CI 1.26-2.71). The AT genotype has a protective effect against SCD (p=0.001; OR=0.53; 95% CI 0.36-0.78). In subgroups separated by gender and age, the differences persist in the subgroups of men, women, and individuals under 50 years old (p<0.05). The AA genotype of rs6670279 is associated with an increased risk of SCD (p=0.005; OR=1.54; 95% CI 1.15-2.06). The AT genotype has a protective effect against SCD (p=0.047; OR=0.73; 95% CI 0.54-0.98). When distributed by sex and age, the differences persist in the subgroups of men, individuals above 50 years old, and men above 50 years old (p<0.05). There were no significant differences in the frequencies of genotypes and alleles of rs6874185 between the SCD and control groups, even after the subgroups specified by gender and age were compared (p>0.05).

Conclusion

The association of single nucleotide polymorphisms rs34554140 and rs6670279 with SCD was confirmed. In contrast, no association of rs6874185 with SCD was detected.

SUBMITTER: Ivanova AA

PROVIDER: S-EPMC8353714 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Sudden cardiac death occurs in ?220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. OBJECTIVES:This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population. METHODS:The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death. RESULTS:Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02). CONCLUSIONS:Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ?1% of asymptomatic adults.