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Updated: Jul 15, 2025
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Genetic variants and effect modifiers of QT interval prolongation in patients with sickle cell disease
Mengna Zhang1, William B Hillegass1, Xue Yu1
1Department of Data Science, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Insights
Genetic variants significantly prolong the corrected QT (QTc) interval in sickle cell disease (SCD) patients, increasing sudden cardiac death risk. Serum alanine transaminase (ALT) modifies this genetic effect, highlighting its role in SCD cardiac health.
Area of Science:
- Cardiovascular Genetics
- Hematology
- Pharmacogenomics
Background:
- Sickle cell disease (SCD) is a prevalent inherited blood disorder in African Americans, linked to premature mortality.
- Prolongation of the heart rate-corrected QT interval (QTc) is a known risk factor for sudden cardiac death in SCD patients.
- The impact of genetic variants on QTc prolongation in SCD remains understudied.
Purpose of the Study:
- To validate associations between single nucleotide polymorphisms (SNPs) and QTc interval prolongation in SCD patients using a polygenic risk score (PRS).
- To explore potential interactions between PRS, QTc prolongation, and other factors like serum alanine transaminase (ALT) in African Americans with SCD.
Main Methods:
- Genotyping of candidate genetic variants associated with QTc interval in SCD patients.
- Construction of an unweighted polygenic risk score (PRS) based on risk SNPs identified via linear regression.
- Evaluation of PRS effect on QTc interval using linear regression and stratification analysis for serum ALT levels and QTc subcomponents (QRS, JTc).
Main Results:
- Five risk SNPs were identified for QTc duration under a recessive model.
- Each unit increase in PRS was associated with QTc prolongation (4.0 ms additive, 9.4 ms recessive).
- Serum ALT demonstrated a modifying effect; PRS increased QTc in normal ALT groups but not in elevated ALT groups.
Conclusions:
- Candidate genetic variants are associated with QTc interval prolongation in SCD patients.
- Serum ALT acts as a significant modifying factor in the PRS-QTc relationship.
- Findings suggest the involvement of urea cycle and nitric oxide metabolism in cardiac repolarization in SCD, warranting further investigation.
Background:
Sickle cell disease (SCD) is a common inherited blood disorder among African Americans (AA), with premature mortality which has been associated with prolongation of the heart rate-corrected QT interval (QTc), a known risk factor for sudden cardiac death. Although numerous genetic variants have been identified as contributors to QT interval prolongation in the general population, their impact on SCD patients remains unclear. This study used an unweighted polygenic risk score (PRS) to validate the previously identified associations between SNPs and QTc interval in SCD patients, and to explore possible interactions with other factors that prolong QTc interval in AA individuals with SCD.
Methods:
In SCD patients, candidate genetic variants associated with the QTc interval were genotyped. To identify any risk SNPs that may be correlated with QTc interval prolongation, linear regression was employed, and an unweighted PRS was subsequently constructed. The effect of PRS on the QTc interval was evaluated using linear regression, while stratification analysis was used to assess the influence of serum alanine transaminase (ALT), a biomarker for liver disease, on the PRS effect. We also evaluated the PRS with the two subcomponents of QTc, the QRS and JTc intervals.
Results:
Out of 26 candidate SNPs, five risk SNPs were identified for QTc duration under the recessive model. For every unit increase in PRS, the QTc interval prolonged by 4.0 ms (95% CI: [2.0, 6.1]; p-value: <0.001) in the additive model and 9.4 ms in the recessive model (95% CI: [4.6, 14.1]; p-value: <0.001). Serum ALT showed a modification effect on PRS-QTc prolongation under the recessive model. In the normal ALT group, each PRS unit increased QTc interval by 11.7 ms (95% CI: [6.3, 17.1]; p-value: 2.60E-5), whereas this effect was not observed in the elevated ALT group (0.9 ms; 95% CI: [-7.0, 8.8]; p-value: 0.823).
Conclusion:
Several candidate genetic variants are associated with QTc interval prolongation in SCD patients, and serum ALT acts as a modifying factor. The association of a CPS1 gene variant in both QTc and JTc duration adds to NOS1AP as evidence of involvement of the urea cycle and nitric oxide metabolism in cardiac repolarization in SCD. Larger replication studies are needed to confirm these findings and elucidate the underlying mechanisms.
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