Marcel den Hoed1, Rona J Strawbridge2, Peter Almgren3, Stefan Gustafsson4, Tomas Axelsson5, Gunnar Engström3, Ulf de Faire6, Bo Hedblad3, Steve E Humphries7, Cecilia M Lindgren8, Andrew P Morris9, Gerd Östling3, Ann-Christine Syvänen10, Elena Tremoli11, Anders Hamsten2, Erik Ingelsson4, Olle Melander3, Lars Lind12. 1. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Electronic address: marcel.den_hoed@medsci.uu.se. 2. Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. 3. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, Malmö, Sweden. 4. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. 5. Department of Medical Sciences, SNP&SEQ Technology Platform, Uppsala University, Uppsala, Sweden. 6. Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 7. Centre for Cardiovascular Genetics, University College London, London, UK. 8. Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. 9. Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Biostatistics, University of Liverpool, Liverpool, UK. 10. Department of Medical Sciences, SNP&SEQ Technology Platform, Uppsala University, Uppsala, Sweden; Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden. 11. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano & Centro Cardiologico Monzino, IRCCS, Milan, Italy. 12. Department of Medical Sciences, Cardiovascular Epidemiology and EpiHealth, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden.
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. OBJECTIVES: 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.
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. OBJECTIVES: 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.
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