Abstract
Sudden cardiac death is a leading mode of death in adults in the Western world and is largely caused by ventricular fibrillation (VF) during acute myocardial ischemia-infarction (MI). A genetic component in risk of VF in the setting of MI is recognized. However, the underlying genetic factors remain largely unknown. Plasma concentration of C-reactive protein (CRP) is a predictor of sudden cardiac death. Recently, several single nucleotide polymorphisms (SNPs) have been revealed to be associated with CRP levels in genome-wide association studies (GWAS). In this study we investigated the effect of CRP-predicting SNPs in modulation of risk of VF in acute MI. Methods: Patients studied were from the Arrhythmia Genetics in the NEtherlands Study (AGNES), consisting of patients with a first acute MI, with those suffering VF classified as cases (n=515) and those not suffering VF classified as controls (n=457). Twenty independent SNPs (r2<0.75) previously found to be associated with CRP levels at genome-wide significant p-values (P<5e-08) in previous GWAS were identified. Genotypes were obtained by direct genotyping (Illumina 610) or were imputed using HapMap. A Bonferroni-corrected threshold of P<0.002 was used to define statistical significance in testing of individual SNPs. We also generated a genetic risk score based on the number of CRP-increasing alleles. Logistic regression modeling was used to test for association with VF. Results: SNP rs6901250 in GPRC6A was strongly associated with VF in acute MI (OR:1.39;95%CI:1.14,1.69;P=9.6e-04), with the CRP-increasing allele being associated with increased risk for VF. Analysis of SNPs in a 50 Kb region around rs6901250 identified a stronger signal at SNP rs633420 (P=9.7e-05) which was in high linkage disequilibrium (r2=0.73) with rs6901250. The CRP genetic risk score generated based on the number of CRP-increasing alleles was associated with risk of VF after MI (OR: 1.07; 95%CI: 1.01,1.12; P=0.01). Conclusions: CRP-predicting loci in aggregate and rs6901250 individually are associated with risk of VF in MI. Our study highlights the role of inflammatory loci on risk of VF after acute MI.
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