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      The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

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          Abstract

          Cardiovascular diseases are leading causes for death worldwide. Genetic disposition jointly with traditional risk factors precipitates their manifestation. Whereas the implications of a positive family history for individual risk have been known for a long time, only in the past few years have genome‐wide association studies ( GWAS) shed light on the underlying genetic variations. Here, we review these studies designed to increase our understanding of the pathophysiology of cardiovascular diseases, particularly coronary artery disease and myocardial infarction. We focus on the newly established pathways to exemplify the translation from the identification of risk‐related genetic variants to new preventive and therapeutic strategies for cardiovascular disease.

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          Most cited references40

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          Genomewide association analysis of coronary artery disease.

          Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P 80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease. Copyright 2007 Massachusetts Medical Society.
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            Cardiovascular disease in Europe 2014: epidemiological update.

            This paper provides an update for 2014 on the burden of cardiovascular disease (CVD), and in particular coronary heart disease (CHD) and stroke, across the countries of Europe. Cardiovascular disease causes more deaths among Europeans than any other condition, and in many countries still causes more than twice as many deaths as cancer. There is clear evidence in most countries with available data that mortality and case-fatality rates from CHD and stroke have decreased substantially over the last 5-10 years but at differing rates. The differing recent trends have therefore led to increasing inequalities in the burden of CVD between countries. For some Eastern European countries, including Russia and Ukraine, the mortality rate for CHD for 55-60 year olds is greater than the equivalent rate in France for people 20 years older.
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              Genetic susceptibility to death from coronary heart disease in a study of twins.

              A family history of premature coronary heart disease has long been thought to be a risk factor for coronary heart disease. Using data from 26 years of follow-up of 21,004 Swedish twins born between 1886 and 1925, we investigated this issue further by assessing the risk of death from coronary heart disease in pairs of monozygotic and dizygotic twins. The study population consisted of 3298 monozygotic and 5964 dizygotic male twins and 4012 monozygotic and 7730 dizygotic female twins. The age at which one twin died of coronary heart disease was used as the primary independent variable to predict the risk of death from coronary heart disease in the other twin. Information about other risk factors was obtained from questionnaires administered in 1961 and 1963. Actuarial life-table analysis was used to estimate the cumulative probability of death from coronary heart disease. Relative-hazard estimates were obtained from a multivariate survival analysis. Among the men, the relative hazard of death from coronary heart disease when one's twin died of coronary heart disease before the age of 55 years, as compared with the hazard when one's twin did not die before 55, was 8.1 (95 percent confidence interval, 2.7 to 24.5) for monozygotic twins and 3.8 (1.4 to 10.5) for dizygotic twins. Among the women, when one's twin died of coronary heart disease before the age of 65 years, the relative hazard was 15.0 (95 percent confidence interval, 7.1 to 31.9) for monozygotic twins and 2.6 (1.0 to 7.1) for dizygotic twins. Among both the men and the women, whether monozygotic or dizygotic twins, the magnitude of the relative hazard decreased as the age at which one's twin died of coronary heart disease increased. The ratio of the relative-hazard estimate for the monozygotic twins to the estimate for the dizygotic twins approached 1 with increasing age. These relative hazards were little influenced by other risk factors for coronary heart disease. Our findings suggest that at younger ages, death from coronary heart disease is influenced by genetic factors in both women and men. The results also imply that the genetic effect decreases at older ages.
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                Author and article information

                Journal
                EMBO Mol Med
                EMBO Mol Med
                10.1002/(ISSN)1757-4684
                EMMM
                embomm
                EMBO Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1757-4676
                1757-4684
                04 May 2016
                July 2016
                : 8
                : 7 ( doiID: 10.1002/emmm.v8.7 )
                : 688-701
                Affiliations
                [ 1 ] Deutsches Herzzentrum München Klinik für Herz‐ und KreislauferkrankungenTechnische Universität München MunichGermany
                [ 2 ]DZHK (German Center for Cardiovascular Research) e.V., partner site Munich Heart Alliance MunichGermany
                Author notes
                [*] [* ]Corresponding author. Tel: +49 89 1218 4073; Fax: +49 89 1218 4013; E‐mail: schunkert@ 123456dhm.mhn.de
                Author information
                http://orcid.org/0000-0001-6428-3001
                Article
                EMMM201506174
                10.15252/emmm.201506174
                4931285
                27189168
                5c147571-11cf-42b9-baae-ce47a2c13036
                © 2016 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 December 2015
                : 08 March 2016
                : 14 April 2016
                Page count
                Pages: 14
                Funding
                Funded by: Fondation Leducq ( CADgenomics: Understanding CAD Genes)
                Award ID: 12CVD02
                Funded by: Bundesministerium für Bildung und Forschung
                Award ID: 01ZX1313A‐2014
                Funded by: European Union Seventh Framework Programme
                Award ID: HEALTH‐F2‐2013‐601456
                Funded by: Deutsche Forschungsgemeinschaft
                Award ID: CRC 1123 (B2)
                Categories
                Review
                Review
                Custom metadata
                2.0
                emmm201506174
                July 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:04.07.2016

                Molecular medicine
                atherosclerosis,coronary artery disease,genome‐wide association studies,myocardial infarction,cardiovascular system,chromatin, epigenetics, genomics & functional genomics

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