title: Genetic profiling using genome-wide significant coronary artery disease risk variants does not improve the prediction of subclinical atherosclerosis: the Cardiovascular Risk in Young Finns Study, the Bogalusa Heart Study and the Health 2000 Survey--a meta-analysis of three independent studies.
abstract: BACKGROUND
  Genome-wide association studies (GWASs) have identified a large number of variants (SNPs) associating with an increased risk of coronary artery disease (CAD). Recently, the CARDIoGRAM consortium published a GWAS based on the largest study population so far. They successfully replicated twelve already known associations and discovered thirteen new SNPs associating with CAD. We examined whether the genetic profiling of these variants improves prediction of subclinical atherosclerosis--i.e., carotid intima-media thickness (CIMT) and carotid artery elasticity (CAE)--beyond classical risk factors.
  
  
  METHODS
  We genotyped 24 variants found in a population of European ancestry and measured CIMT and CAE in 2001 and 2007 from 2,081, and 2,015 subjects (aged 30-45 years in 2007) respectively, participating in the Cardiovascular Risk in Young Finns Study (YFS). The Bogalusa Heart Study (BHS; n = 1179) was used as a replication cohort (mean age of 37.5). For additional replication, a sub-sample of 5 SNPs was genotyped for 1,291 individuals aged 46-76 years participating in the Health 2000 population survey. We tested the impact of genetic risk score (GRS(24SNP/CAD)) calculated as a weighted (by allelic odds ratios for CAD) sum of CAD risk alleles from the studied 24 variants on CIMT, CAE, the incidence of carotid atherosclerosis and the progression of CIMT and CAE during a 6-year follow-up.
  
  
  RESULTS
  CIMT or CAE did not significantly associate with GRS(24SNP/CAD) before or after adjusting for classical CAD risk factors (p>0.05 for all) in YFS or in the BHS. CIMT and CAE associated with only one SNP each in the YFS. The findings were not replicated in the replication cohorts. In the meta-analysis CIMT or CAE did not associate with any of the SNPs.
  
  
  CONCLUSIONS
  Genetic profiling, by using known CAD risk variants, should not improve risk stratification for subclinical atherosclerosis beyond conventional risk factors among healthy young adults.
authors.affiliation: Department of Clinical Chemistry, University of Tampere, Medical School, and Tampere University Hospital, Tampere, Finland. jussi.hernesniemi@uta.fi
authors.forename: Jussi A
authors.initials: JA
authors.lastname: Hernesniemi
authors.forename: Ilkka
authors.initials: I
authors.lastname: Seppälä
authors.forename: Leo-Pekka
authors.initials: LP
authors.lastname: Lyytikäinen
authors.forename: Nina
authors.initials: N
authors.lastname: Mononen
authors.forename: Niku
authors.initials: N
authors.lastname: Oksala
authors.forename: Nina
authors.initials: N
authors.lastname: Hutri-Kähönen
authors.forename: Markus
authors.initials: M
authors.lastname: Juonala
authors.forename: Leena
authors.initials: L
authors.lastname: Taittonen
authors.forename: Erin N
authors.initials: EN
authors.lastname: Smith
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Sathanur R
authors.initials: SR
authors.lastname: Srinivasan
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Berenson
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Murray
authors.forename: Tomi
authors.initials: T
authors.lastname: Laitinen
authors.forename: Antti
authors.initials: A
authors.lastname: Jula
authors.forename: Johannes
authors.initials: J
authors.lastname: Kettunen
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.forename: Reijo
authors.initials: R
authors.lastname: Laaksonen
authors.forename: Jorma
authors.initials: J
authors.lastname: Viikari
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
mesh_terms: D000328:Adult; D059168:Carotid Intima-Media Thickness; D003324:Coronary Artery Disease / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D003625:Data Collection; D005260:Female; D005387:Finland / Q000453:epidemiology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006262:Health; D006801:Humans; D008145:Louisiana / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors