Common Genetic Variants, QT Interval, and Sudden Cardiac Death in a Finnish Population-Based Study

Abstract

Although sudden cardiac death (SCD) is heritable, its genetic underpinnings are poorly characterized. The QT interval appears to have a graded relationship to SCD, and 35% to 45% of its variation is heritable. We examined the relationship among recently reported common genetic variants, QT interval, and SCD. We genotyped 15 common (minor allele frequency >1%) candidate single nucleotide polymorphisms (SNPs), based on association with the QT interval in prior studies, in individuals in 2 cohort studies (Health 2000, n=6597; Mini-Finland, n=801). After exclusions, we identified 116 incident SCDs from the remaining sample (n=6808). We constructed a QT genotype score (QT _score ) using the allele copy number and previously reported effect estimates for each SNP. Cox proportional hazards models adjusting for age, sex, and geographical area were used for time to SCD analyses. The QT _score was a continuous independent predictor of the heart rate–corrected QT interval ( P −107 ). Comparing the top with the bottom quintile of QT _score , there was a 15.6-ms higher group mean QT interval ( P −84 ). A 10-ms increase in the observed QT interval was associated with an increased risk of SCD (hazard ratio, 1.19; 95% confidence interval, 1.07 to 1.32; P =0.002). There was no linear relationship between QT _score and SCD risk; although in post hoc secondary analysis there was increased risk in the top compared with the middle QT _score quintile (hazard ratio, 1.92; 95% confidence interval, 1.05 to 3.58; P =0.04). Our study strongly replicates the relationship between common genetic variants and the QT interval and confirms the relationship between the QT interval and SCD but does not show evidence for a linear relationship between QT _score and SCD risk.