Identification of Genetic and Environmental Factors Modulating Electrocardiographic Intervals in Korean: The Healthy Twin Study

Abstract

Background

The electrocardiogram (EKG) is a useful and simple tool for evaluating the cardiac condition system. There are many kinds of EKG parameters indicating electrical behavior of the heart. Especially EKG intervals including PR interval, QRS complex, and QT interval are known as clinically significant parameters for assessing abnormal cardiac conditions. Recently, many researchers have noticed the availability of the EKG interval as a clinical parameter to predict a specific cardiovascular disease.

Objective

The purpose of this study is to identify genetic and environmental factors modulating PR interval, QRS complex, and QTc interval. Genetic factors including heritability and genetic loci were suggested for each EKG interval, and compared with the results from former studies. In addition, the effects of environmental factors including cigarette smoking and alcohol consumption were statistically estimated for each EKG interval.

Methods

Individuals from the Healthy Twin Study were selected as the study population. Of the 3,479 attendees at the baseline cohort, 79 individuals were excluded for PR interval, 62 individuals were excluded for QRS complex, and 96 individuals were excluded for QTc interval. Total number of study population was 3,400 for PR interval, 3,417 for QRS complex, and 3,383 for QTc interval.

Every phenotype used in this study was examined according to the standard protocol of the Healthy Twin Study. The EKG results including heart rate and EKG intervals were measured by using standard 12-lead electrocardiography, and recorded at a paper speed of 25mm/s. A single lead (lead II) was used to measure each EKG interval. The results were automatically measured first, and then validated by a trained technician.

Two kinds of single nucleotide polymorphism (SNP) microarray chips were used for genotyping: Affymetrix Genome-wide Human SNP Array 6.0 (Affymetrix SNP microarray), and Illumina HumanCore-12 v1.0 BeadChip (Illumina SNP microarray). The genotyped markers were cleaned through quality control (QC) procedure, and the results were imputed with the Asian reference data from the 1000 Genomes Project by using SHAPEIT2 and IMPUTE2 algorithms. Total 4,174,873 markers were selected as final markers.

Family-based score test for association (FASTA) method was used to decorrelate the familial relationships among study participants. The heritability of each EKG interval and the association between specific locus and EKG intervals were evaluated by using the package GenABEL in R version 3.0.2. Environmental factors including cigarette smoking and alcohol consumption status were statistically analyzed in SAS version 9.3.

Results

Heritability for each EKG interval was evaluated as higher levels: 0.45 to 0.46 for PR interval, 0.35 to 0.37 for QRS complex, and 0.43 to 0.48 for QTc interval. In addition, several loci contributing EKG intervals were identified. For PR interval, four identified loci were significant and the related gene, CAV1 was replicated with several previous studies. For QRS complex and QTc interval, several insignificant (with 5.0x10-8<P) SNPs were identified. Environmental factors including cigarette smoking and alcohol consumption status were significantly verified with P<5.0x10-8.

Conclusion

The results from this study suggest that both genetic and environmental factors affect EKG intervals including PR interval, QRS complex, and QTc interval. In consideration of the potential value of EKG intervals, these findings are significant as reaffirming the result from previous genome-wide association studies in Korean population and suggesting future directions.