title: Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.
abstract: BACKGROUND
  Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG).
  
  
  RESULTS
  We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency ≥1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05).
  
  
  CONCLUSIONS
  Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: Charles C
authors.initials: CC
authors.lastname: White
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brody
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.forename: Jireh
authors.initials: J
authors.lastname: Santibanez
authors.forename: Richard
authors.initials: R
authors.lastname: Gibbs
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D050197:Atherosclerosis / Q000453:epidemiology / Q000235:genetics*; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D050609:Sodium-Phosphate Cotransporter Proteins, Type I / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C493550:SLC17A3 protein, human; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human
keywords: atherosclerosis; carotid artery, common; epidemiology; genetics; plaque, atherosclerotic; sequence analysis, DNA