Abstract 640: Common Genetic Variation in the Promotor of the Ankyrin-2 Gene Modifies QT Interval

Abstract

Cardiac QT interval represents both ventricular depolarization and repolarization events. Previous studies suggested significant genetic contribution to the normal QT interval length variation. In a candidate gene approach, we sought to identify novel genetic determinants of the normal QT interval length within the Ankyrin-2 (Ank-2) gene. Population and Methods: The study population consisted of 1492 participants of the WHO MONICA population survey. A standard measurement of the QT interval from the 12-lead ECG was available in 1212 individuals. The QT interval was corrected for covariates using different general and population specific formulas (QTc). Altogether, 22 SNPs within the Ank-2 gene were genotyped using the TaqMan technology. Statistical analyses included ANOVA and linear regression based trend test for comparisons of the QTc means. Results: In the promotor region of the alternative splicing Ank-2 variant, several SNPs and haplotypes were highly significantly associated with the QTc interval length. Specifically, a SNP rs1979086 (minor allele frequency f=0.44) was associated with the QTc length in the whole population (P=0.004 for ANOVA and P<0.001 for the trend test). The QTc difference between the genotype groups was 2.87 ms (95%CI 1.18 – 4.56) and more pronounced in men where the QTc difference between the genotype groups was 4.65 ms (95% CI 2.18 – 7.12; P=0.0006 for ANOVA and P=0.0004 for the trend test). The results remained robust when QTc extreme quartiles and quintiles, respectively, were tested in a case-control pattern. Highly significant association results were obtained for all genetic models used (OR 1.58; P=0.00009; trend test for extreme QTc quartiles). A frequent haplotype (f=0.28) spanning approximately 20 kb in this region was highly significantly associated with the QTc length in the whole study population (QTc difference vs. most prevalent haplotype 3.66 ms, 95%CI 3.14 – 4.17, P<0.0001). Conclusion: A small genomic region in the promotor of the Ank-2 gene contains SNPs and haplotypes that significantly influence the QTc interval in the normal population of German descent. A gender-specific effect with greater influence in male participants requires further evaluation.