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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Common candidate gene variants are associated with QT interval duration in the general population
A Marjamaa1, C Newton-Cheh, K Porthan
1Research Program in Molecular Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Journal of Internal Medicine
|November 21, 2008
Summary
Genetic variants in KCNE1, KCNH2, and NOS1AP genes significantly influence QT interval duration. The KCNE1 D85N variant is strongly associated with prolonged QT intervals, potentially increasing arrhythmia risk in the population.
Area of Science:
- Cardiovascular Genetics
- Human Genetics
- Molecular Cardiology
Background:
- QT interval prolongation is a risk factor for sudden cardiac death.
- Heritability accounts for 30-40% of QT interval variability.
- Genetic associations with QT interval prolongation are crucial for understanding arrhythmia susceptibility.
Purpose of the Study:
- To investigate the association of common Long QT Syndrome (LQTS) and NOS1AP gene variants with QT interval duration.
- To analyze these associations in a large, population-based Finnish sample.
Main Methods:
- Genotyping of 12 common LQTS and NOS1AP variants in 5043 Finnish individuals from the Health 2000 study.
- Measurement of QT intervals from digital 12-lead ECGs.
- Adjustment of QT intervals for age, gender, and heart rate using a study-derived nomogram (Nc).
Main Results:
- The KCNE1 D85N minor allele was significantly associated with a 10.5 ms prolongation of the adjusted QT(Nc) interval (P=3.6 x 10(-11)).
- Replicated associations between KCNH2 variants (rs3807375, K897T) and NOS1AP variants (rs2880058) with QT(Nc) interval duration.
- All associations were analyzed under additive genetic models.
Conclusions:
- Each copy of the KCNE1 D85N minor allele significantly prolongs the QT interval by 10.5 ms, potentially impacting arrhythmia susceptibility at a population level.
- Confirmed robust associations between independent KCNH2 and NOS1AP variants and adjusted QT interval duration.
- These findings highlight the role of specific genetic variants in modulating cardiac repolarization.
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