Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk

Circ Cardiovasc Genet. 2012 Dec;5(6):656-65. doi: 10.1161/CIRCGENETICS.112.963660. Epub 2012 Nov 14.

Abstract

Background: Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse.

Methods and results: To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT(mean), IMT(max), and IMT(mean-max)), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11,590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75 × 10(-7) for IMT(max); replication P=7.24×10(-6) for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77-0.90], P=6.53 × 10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83 × 10(-4), n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126-138).

Conclusions: This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Carotid Intima-Media Thickness*
  • Cohort Studies
  • Coronary Artery Disease / genetics*
  • Crk-Associated Substrate Protein / genetics*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genetic Loci / genetics*
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Nuclear Proteins
  • Phenotype
  • Phosphoproteins / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Reproducibility of Results
  • Risk Factors

Substances

  • BCAR1 protein, human
  • CFDP1 protein, human
  • Crk-Associated Substrate Protein
  • Membrane Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • TMEM170A protein, human