The PR Interval is a Heritable Quantitative Trait with Evidence for Linkage to Chromosome 4 in a Genome-Wide Scan: the Framingham Heart Study
Introduction: Delayed atrioventricular conduction on the electrocardiogram (ECG), manifested by PR interval prolongation, can progress to heart block. Both heart-rate slowing drugs and environmental factors may lead to PR interval prolongation; however, the heritability of the PR interval has not been studied in the general population and genetic variants in the regulation of PR duration have not been characterized. Methods: We examined the heritability of the PR interval and we tested for evidence of linkage of the PR interval to chromosomal regions in a large population-based cohort. 12-lead ECGs were obtained routinely in adult Framingham Heart Study participants as part of the clinic examination. The PR interval was measured using digital calipers. We conducted a 10 cM genome wide scan in 328 extended families (1688 genotyped subjects, 2257 phenotyped subjects, 2028 phenotyped sibling pairs). Variance component methods were used to estimate heritability and to perform linkage analysis. Results: The PR interval (adjusted for age and RR-interval) was heritable [h 2 0.32 (95% confidence interval 0.26-0.37)]. The highest multipoint LOD score for the adjusted PR interval was found on chromosome 4 (LOD score was 2.16 at 123 cM). The next highest LOD score was 1.88 (chromosome 17 at 59 cM). Conclusion: These results suggest there are influential genetic regions contributing to variability in PR interval in the general population. Defining genetic determinants of PR duration may provide insights into the pathophysiology of heart block and may help identify persons with a high susceptibility to drug-induced heart block.