title: GWAS-identified loci for coronary heart disease are associated with intima-media thickness and plaque presence at the carotid artery bulb.
abstract: BACKGROUND
  Large-scale genome-wide association studies (GWAS) have so far identified 45 loci that are robustly associated with coronary heart disease (CHD) in data from adult men and women of European descent.
  
  
  OBJECTIVE
  To examine whether the CHD-associated loci are associated with measures of atherosclerosis in data from up to 9582 individuals of European ancestry.
  
  
  METHODS
  Forty-five SNPs representing the CHD-associated loci were genotyped in middle-aged to elderly individuals of European descent from four independent population-based studies (IMPROVE, MDC-CC, ULSAM and PIVUS). Intima-media thickness (IMT) was measured by external B-mode ultrasonography at the far wall of the bulb (sinus) and common carotid artery. Plaque presence was defined as a maximal IMT of the bulb >1.5 mm. We meta-analysed single-SNP associations across the four studies, and combined them in a genetic predisposition score. We subsequently examined the association of the genetic predisposition score with prevalent CHD and the three indices of atherosclerosis, adjusting for sex, age and Framingham risk factors.
  
  
  RESULTS
  As anticipated, the genetic predisposition score was associated with prevalent CHD, with each additional risk allele increasing the odds of disease by 5.5% (p = 4.1 × 10(-6)). Moreover, each additional CHD-risk allele across the 45 loci was associated with a 0.24% increase in IMT (p = 4.0 × 10(-3)), and with a 2.8% increased odds of plaque presence (p = 7.4 × 10(-6)) at the far wall of the bulb. The genetic predisposition score was not associated with IMT of the common carotid artery (p = 0.47).
  
  
  CONCLUSIONS
  Our results suggest that the association between the 45 previously identified loci and CHD at least partly acts through atherosclerosis.
authors: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Electronic address: marcel.den_hoed@medsci.uu.se.
authors: Marcel
authors: M
authors: den Hoed
authors: Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors: Rona J
authors: RJ
authors: Strawbridge
authors: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, Malmö, Sweden.
authors: Peter
authors: P
authors: Almgren
authors: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Stefan
authors: S
authors: Gustafsson
authors: Department of Medical Sciences, SNP&SEQ Technology Platform, Uppsala University, Uppsala, Sweden.
authors: Tomas
authors: T
authors: Axelsson
authors: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, Malmö, Sweden.
authors: Gunnar
authors: G
authors: Engström
authors: Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Ulf
authors: U
authors: de Faire
authors: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, Malmö, Sweden.
authors: Bo
authors: B
authors: Hedblad
authors: Centre for Cardiovascular Genetics, University College London, London, UK.
authors: Steve E
authors: SE
authors: Humphries
authors: Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors: Cecilia M
authors: CM
authors: Lindgren
authors: Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Biostatistics, University of Liverpool, Liverpool, UK.
authors: Andrew P
authors: AP
authors: Morris
authors: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, Malmö, Sweden.
authors: Gerd
authors: G
authors: Östling
authors: Department of Medical Sciences, SNP&SEQ Technology Platform, Uppsala University, Uppsala, Sweden; Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden.
authors: Ann-Christine
authors: AC
authors: Syvänen
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano & Centro Cardiologico Monzino, IRCCS, Milan, Italy.
authors: Elena
authors: E
authors: Tremoli
authors: Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors: Anders
authors: A
authors: Hamsten
authors: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Erik
authors: E
authors: Ingelsson
authors: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, Malmö, Sweden.
authors: Olle
authors: O
authors: Melander
authors: Department of Medical Sciences, Cardiovascular Epidemiology and EpiHealth, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden.
authors: Lars
authors: L
authors: Lind
mesh_terms: D000368:Aged; D000483:Alleles; D017536:Carotid Artery, Common / Q000473:pathology*; D059168:Carotid Intima-Media Thickness; D003327:Coronary Disease / Q000235:genetics*; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D058226:Plaque, Atherosclerotic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
keywords: Atherogenic plaque; Atherosclerosis; Carotid artery; Genome-wide association; Intima-media thickness