Date Published: January 13, 2017
Publisher: Public Library of Science
Author(s): Reza Jabbari, Charlotte Glinge, Javad Jabbari, Bjarke Risgaard, Bo Gregers Winkel, Christian Juhl Terkelsen, Hans-Henrik Tilsted, Lisette Okkels Jensen, Mikkel Hougaard, Stig Haunsø, Thomas Engstrøm, Christine M. Albert, Jacob Tfelt-Hansen, Chunhua Song.
Several common genetic variants have been associated with either ventricular fibrillation (VF) or sudden cardiac death (SCD). However, replication efforts have been limited. Therefore, we aimed to analyze whether such variants may contribute to VF caused by first ST-elevation myocardial infarction (STEMI).
We analyzed 27 single nucleotide polymorphisms (SNP) previously associated with SCD/VF in other cohorts, and examined whether these SNPs were associated with VF caused by first STEMI in the GEnetic causes of Ventricular Arrhythmias in patients with first ST-elevation Myocardial Infarction (GEVAMI) study on ethnical Danes. The GEVAMI study is a prospective case-control study involving 257 cases (STEMI with VF) and 537 controls (STEMI without VF).
Of the 27 candidate SNPs, one SNP (rs11720524) located in intron 1 of SCN5A which was previously associated with SCD was significantly associated with VF caused by first STEMI. The major C-allele of rs11720524 was present in 64% of the cases and the C/C genotype was significantly associated with VF with an odds ratio (OR) of 1.87 (95% CI: 1.12–3.12; P = 0.017). After controlling for clinical differences between cases and controls such as age, sex, family history of sudden death, alcohol consumption, previous atrial fibrillation, statin use, angina, culprit artery, and thrombolysis in myocardial infarction (TIMI) flow, the C/C genotype of rs11720524 was still significantly associated with VF with an OR of 1.9 (95% CI: 1.05–3.43; P = 0.032). Marginal associations with VF were also found for rs9388451 in HEY2 gene. The CC genotype showed an insignificant risk for VF with OR = 1.50 (95% CI: 0.96–2.40; P = 0.070).
One common intronic variant in SCN5A suggested an association with VF caused by first STEMI. Further studies into the functional abnormalities associated with the noncoding variant in SCN5A may lead to important insights into predisposition to VF during STEMI.
Coronary artery disease and its ultimate consequence, myocardial infarction (MI), are believed to underlie 75% of the deaths of patients who experience sudden cardiac death (SCD).[1–3] It is also estimated that SCD accounts for 30 to 50% of all coronary deaths. SCD is a major challenge for the clinician because most episodes occur in individuals without previously identified cardiac disease.[5,6] The pathophysiology of SCD caused by MI is complex. It is believed to involve an interaction between underlying disease and a transient event, such as acute myocardial ischemia, which results in electrical instability and ventricular fibrillation (VF). VF is a life-threatening complication and occurs in nearly 12% of patients with first ST-segment elevation myocardial infarction (STEMI).[7,8] Therefore, efforts to improve risk stratification for SCD should in part be based on an understanding of the molecular mechanisms and pathways underlying the occurrence of VF. In the GEnetic causes of Ventricular Arrhythmias in patients with first ST-elevation Myocardial Infarction (GEVAMI) study on ethnical Danes and the Dutch AGNES (Arrhythmia Genetics in the NEtherlandS Study) study both suggested a possible genetic component to VF since patients with a family history of sudden death among first-degree relatives had significantly higher odds of experiencing VF before primary percutaneous coronary intervention (PPCI). In the AGNES study, a common genetic variant at 21q21 (rs2824292, odds ratio (OR) = 1.78, 95% CI 1.47–2.13, P = 3.3×10-10) was found to be associated with VF before PPCI in STEMI patients in a genome-wide association study (GWAS). The rs2824292 is located upstream of CXADR gene which encodes the coxsackie and adenovirus receptor (CAR), a transmembrane cell adhesion molecule predominantly located at the intercalated disc between cardiomyocytes. However, this association has yet to be replicated in a larger cohort. There have also been several other variants reported to be associated with SCD, primarily from candidate gene studies with limited replication. Therefore, we aimed to determine whether the 21q21variant, as well as other variants previously associated with SCD, would be associated with underlying susceptibility to VF due to first STEMI in the GEVAMI case-control study.
In this prospective case-control study in Denmark we identified a common variant (rs11720524) located in intron 1 of the SCN5A gene near the promoter region which was associated with VF in patients with STEMI. To our knowledge, this is the first study linking a common variant in SCN5A, the major sodium ion channel in the heart, to VF caused by first STEMI. Genetic studies have been successful in uncovering rare mutations in ion channel genes and these have been associated with rare Mendelian arrhythmic disorders, most notably the long-QT syndrome and to a lesser degree Brugada syndrome,[9,26] and for some of these disorders genetic testing has become a pivotal part of clinical care.[27,28] In contrast, studies aimed at identifying genetic risk factors for VF in the setting of MI affecting the majority and older segment of the population have been sparse and therefore genetic architecture of this complex and multi-factorial disease largely remains unknown.