title: Whole-exome sequencing in individuals with multiple cardiovascular risk factors and normal coronary arteries.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: aDepartment 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.
authors.forename: Yigal
authors.initials: Y
authors.lastname: Abramowitz
authors.forename: Arie
authors.initials: A
authors.lastname: Roth
authors.forename: Gad
authors.initials: G
authors.lastname: Keren
authors.forename: Ofer
authors.initials: O
authors.lastname: Isakov
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
authors.forename: Yael
authors.initials: Y
authors.lastname: Laitman
authors.forename: Daphna
authors.initials: D
authors.lastname: Weissglas-Volkov
authors.forename: Yaron
authors.initials: Y
authors.lastname: Arbel
authors.forename: Shmuel
authors.initials: S
authors.lastname: Banai
authors.forename: Ariel
authors.initials: A
authors.lastname: Finkelstein
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D019295:Computational Biology; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000517:prevention & control*; D003331:Coronary Vessels / Q000000981:diagnostic imaging*; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007557:Israel; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D011237:Predictive Value of Tests; D065840:Protective Factors; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D005819:Genetic Markers