title: A 45-SNP genetic risk score is increased in early-onset coronary artery disease but independent of familial disease clustering.
abstract: Common genetic risk variants may contribute to the heritability of early-onset coronary artery disease (CAD). We aimed to investigate the association of a genetic risk score (GRS) with age upon CAD-onset and to test the association between the GRS, familial clustering, and CAD severity in early-onset CAD.
  
  
  
  134 early-onset CAD patients (<40 years), 446 late-onset CAD patients (male >55 years/female >65 years), and 89 healthy controls were genotyped for 45 CAD-associated SNPs and a GRS was created. In early-onset CAD patients, family pedigrees with information on 1585 1st and 2nd degree relatives were used to calculate a stratified log-rank family score (SLFS) as a measure of familial clustering.
  
  
  
  Early-onset patients had a higher mean GRS than late-onset CAD patients (p = 0.02) and healthy controls (p < 0.0001). In the adjusted model, a GRS increase of one SD was associated with 1.2 years (95% CI 0.1-2.2) earlier onset. The GRS was not associated with the SLFS in the regression model (p = 0.41) and did not differ between SLFS tertiles (p = 0.98). The SLFS predicted the number of affected coronary vessels (OR [95% CI] per SD increase in SLFS: 2.0 [1.4-3.0]), whereas the association between the GRS and CAD severity was not statistically significant (OR [95% CI] per SD increase in GRS: 1.3 [0.9-1.9]).
  
  
  
  The GRS was increased in early-onset CAD patients, but not associated with the SLFS, suggesting that these common genetic variants are of minor importance in familial clustering of early-onset CAD. Furthermore, family pedigree analysis may predict CAD severity more precisely than common variants.
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Faculty of Health, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address: morten.christiansen@clin.au.dk.
authors.forename: Morten K
authors.initials: MK
authors.lastname: Christiansen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Nyegaard
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Lisbeth N
authors.initials: LN
authors.lastname: Pedersen
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Sanne B
authors.initials: SB
authors.lastname: Larsen
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Würtz
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hjort
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Faculty of Health, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Steen D
authors.initials: SD
authors.lastname: Kristensen
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Faculty of Health, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Henrik K
authors.initials: HK
authors.lastname: Jensen
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D016022:Case-Control Studies; D016000:Cluster Analysis; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D040941:Heredity; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D005819:Genetic Markers
keywords: Age of onset; Coronary artery disease; Genetics; Multifactorial inheritance