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Whole-exome sequencing in individuals with multiple cardiovascular risk factors and normal coronary arteries
Yigal Abramowitz1, Arie Roth, Gad Keren
1aDepartment of Cardiology, Tel-Aviv Medical Center, Sackler Faculty of Medicine bSusanne Levy Gertner Oncogenetics Unit, Danek Gertner Institute of Genetics, Chaim Sheba Medical Center, Sackler Faculty of Medicine cSackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Insights
Researchers identified 19 gene variants potentially protecting against coronary artery disease (CAD) by studying high-risk individuals with normal coronary arteries. These findings offer new insights into CAD pathogenesis.
Area of Science:
- Genetics
- Cardiovascular Disease Research
- Molecular Biology
Background:
- Most coronary artery disease (CAD) genetic studies focus on diagnosed patients.
- Investigating high-risk individuals with normal coronary arteries (NCA) may reveal protective genetic factors.
- Understanding these protective mechanisms is crucial for novel therapeutic strategies.
Purpose of the Study:
- To identify genes and sequence variants that may confer protection against the development of coronary artery disease (CAD).
- To explore the genetic basis of protection in individuals with cardiovascular risk factors but without diagnosed CAD.
Main Methods:
- Pooled whole-exome sequencing (WES) was employed on individuals with cardiovascular risk factors and NCA, compared to controls with CAD.
- Rare, NCA-unique sequence variants were identified and individually validated.
- Genotyping was performed on selected variants in additional control groups.
Main Results:
- Whole-exome sequencing detected numerous variants, with a focus on rare, nonsynonymous variants for validation.
- Nineteen protective variants in 16 genes were identified in the NCA group and absent in CAD controls.
- Genes SPTBN5, NID2, and ADAMTSL4 showed variants in multiple protected individuals, suggesting a potential protective role.
Conclusions:
- Whole-exome sequencing successfully identified 19 potential CAD-protective variants in high-risk individuals with NCA.
- These variants may offer protection through currently unknown mechanisms.
- Studying the genetics of protected high-risk individuals provides novel insights into CAD pathogenesis.
Objectives:
Most studies on the genes involved in coronary artery disease (CAD) targeted individuals with angiographically or clinically proven CAD. Focusing on high-risk individuals with normal coronary arteries (NCA) may offer novel insights into the pathogenesis of CAD. We aimed to identify genes putatively protective for development of CAD.
Methods:
Pooled whole-exome sequencing (WES) was performed on 17 patients with multiple cardiovascular risk factors and NCA and on 17 controls with multivessel CAD. Rare NCA-unique sequence variants were subsequently individually validated using the Fluidigm platform in 100 additional CAD controls and 100 general population controls.
Results:
In total, 555 100 variants were detected in at least one WES pool in the study group and in none of the control WES pools. For second phase validation, we focused on rare, nonsynonymous variants, resulting in a total of 144 variants in 40 genes, of which 96 were selected for subsequent genotyping. Validation phase genotyping resulted in 19 variants in 16 genes that were found in the NCA group and in none of the CAD controls. The SPTBN5, NID2, and ADAMTSL4 genes harbored sequence variants in more than one CAD-protected patient and none of the 117 CAD controls.
Conclusion:
Applying WES technology and focusing on individuals seemingly protected from developing CAD successfully identified 19 variants that may offer protection from CAD by undetermined mechanisms. Studying the genetics of high-risk individuals apparently protected from CAD may provide novel insights into the pathogenesis of CAD.
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