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Genetic determinants of atherosclerosis.


Bij bijna 3.000 personen in drie generaties van 100 families in de gemeente Rucphen werd de erfelijkheid van risicofactoren voor hart- vaatziekten bepaald. Diverse bloeddrukparameters en de dikte van de halsslagader blijken voor 40 procent erfelijk te zijn en arteriële stijfheid voor 30 procent. De onderzoekers hebben een aantal genen gevonden die geassocieerd zijn met de boven- en onderbloeddruk. Bij bijna 8.000 mannen en vrouwen boven de 55 jaar in de omgeving van Rotterdam werden genetische typeringen vergeleken met de eigenschappen van hun hart en bloedvaten. Er werden slechts geringe verbanden gevonden met genen die betrokken zijn bij ontsteking, bloedstolling en eigenschappen van de vaatwanden. De conclusie is dat niet alleen atherosclerose, maar ook de stijfheid van de vaatwanden een complexe ziekte is.


Titel: Heritability of the function and structure of the arterial wall: findings of the Erasmus Rucphen Family (ERF) study.
Auteur: Sayed-Tabatabaei FA, van Rijn MJ, Schut AF, Aulchenko YS, Croes EA, Zillikens MC, Pols HA, Witteman JC, Oostra BA, van Duijn CM
Magazine: Stroke
Titel: TGF-b1 Polymorphisms and Arterial Stiffness; the Rotterdam Study.
Auteur: Sie MP, Mattace-Raso FU, Uitterlinden AG, Arp PP, Hofman A, Hoeks AP, Reneman RS, Asmar R, van Duijn CM, Witteman JC
Magazine: Journal of Human Hypertension
Titel: Insertion/Deletion gene polymorphism of the angiotensin-converting enzyme and blood pressure changes in older adults
Auteur: F.U.S. Mattace- Raso, M.P.S. Sie, T.J.M. van der Cammen, M.E. Safar, A. Hofman, C.M. van Duijn, J.C.M. Witteman
Magazine: Journal of Human Hypertension
Titel: ACE polymorphisms.
Auteur: Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JC
Magazine: Circulation Research
Titel: Genetic Variation in the matrix metallo-proteinase 3 gene in relation to arterial stiffness: the Rotterdam Study
Auteur: M.P.S. Sie, F.J.A. van Rooij, M.P.M. de Maat, A. Isaacs, F.U.S. Mattace-Raso, A.G. Uitterlinden, A. Hofman, A.P.G. Hoeks, R.S. Reneman, R. Asmar, C.M. van Duijn, J.C.M. Witteman.
Magazine: European Journal of Cardiovascular Prevention and Rehabilitation
Titel: Genetic variation in the renin-angiotensin system and arterial stiffness; the Rotterdam Study
Auteur: M.P.S. Sie, M. Yazdanpanah, F.U.S. Mattace Raso, A.G. Uitterlinden, A. Hofman, A.P.G. Hoeks, R.S. Reneman, R. Asmar, J.C.M. Witteman, C.M. van Duijn.
Magazine: Journal of Internal Medicine
Titel: Interleukin 6 -174 g/c promoter polymorphism and risk of coronary heart disease: results from the rotterdam study and a meta-analysis.
Auteur: Sie MP, Sayed-Tabatabaei FA, Oei HH, Uitterlinden AG, Pols HA, Hofman A, van Duijn CM, Witteman JC
Magazine: Arteriosclerosis Thrombosis and Vascular Biology
Titel: The interleukin-6 –174 G/C promoter polymorphism and arterial stiffness; the Rotterdam Study
Auteur: M.P.S. Sie, F.U.S. Mattace-Raso, A.G. Uitterlinden, P.P. Arp, A. Hofman, H.A.P. Pols, A.P.G. Hoeks, R.S. Reneman, R. Asmar, C.M. van Duijn, J.C.M. Witteman
Magazine: Vascular Health and Risk Management
Titel: TGF-beta 1 polymorphisms and risk of myocardial infarction and stroke: the Rotterdam Study.
Auteur: Sie MP, Uitterlinden AG, Bos MJ, Arp PP, Breteler MM, Koudstaal PJ, Pols HA, Hofman A, van Duijn CM, Witteman JC
Magazine: Stroke
Titel: Angiotensin converting enzyme gene polymorphism and cardiovascular morbidity and mortality: the Rotterdam Study.
Auteur: Sayed-Tabatabaei FA, Schut AF, Arias A, Bertoli-Avella AM, Hofman A, Witteman JC, van Duijn CM
Magazine: Journal of Medical Genetics
Titel: Genetic variation in the fibrinogen alpha and gamma genes in relation to arterial stiffness: the Rotterdam Study
Auteur: M.P.S. Sie, A. Isaacs, M.P.M. de Maat, F.U.S. Mattace-Raso, A.G. Uitterlinden, I. Kardys, A. Hofman, A.P.G. Hoeks, R.S. Reneman, C.M. van Duijn, J.C.M. Witteman
Magazine: Arteriosclerosis Thrombosis and Vascular Biology
Titel: A study of gene-environment interaction on the gene for angiotensin converting enzyme: a combined functional and population based approach.
Auteur: Sayed-Tabatabaei FA, Schut AF, Hofman A, Bertoli-Avella AM, Vergeer J, Witteman JC, van Duijn CM
Magazine: Journal of Medical Genetics
Titel: Angiotensin-converting enzyme gene polymorphism and carotid artery wall thickness: a meta-analysis.
Auteur: Sayed-Tabatabaei FA, Houwing-Duistermaat JJ, van Duijn CM, Witteman JC
Magazine: Stroke
Titel: ACE and atherosclerosis; pieces of the puzzle
Titel: Genetic Determinants of Arterial Stiffness



Zie Samenvatting Engelstalig

Samenvatting van de aanvraag

Overall aim and key objectives. Althoug it has been recognised for long that genetic factors play a crucial role in the pathogenesis of atherosclerosis, findings of studies aiming to identify the genetic origin have been disappointing. Multiple genes and environmental factors are likely to be involved in the development of atherosclerosis. Genomic screens in classical family or affected sib-pair studies have low power to identify gnes implicated in a such a complex disorder. To unravel the genetics of complex traits such as atherosclerosis requires a different strategy. It has been suggested that a population based approach using genetic association analysis may be a powerful alternative. The statistical power of classical association studies based on linkage disequilibrium for genomic screening, however, is limited. Due to heterogeneity in complex traits such as atherosclerosis, it is unlikely that a substantial number of patients descend from a common ancestor, if patiens are randomly drawn from the general population or clinic based patient series. In recent years much attention has been paid to the possibility of mapping disease gnees through association studies using population-based patient series from genetically isolated populations (Lander E.S, Schork N.J. Science 1994:265, 2037-48). In a genetically isolated population the variety of genetic make-up and therefore may yield findings of limited relevance to other populations such as the Dutch. Sandkuijl and Te Meerman have put forward that theoretically also in small Dutch populaions that have been isolated more recently (5-20 generations), genetic variability will be reduced considerably due to founder effects and genetic drift. A major advantage is that these populations show closer resemblance to the general Dutch population. The method has proven to be successful for complex traits in our previous studies (Nature Gen 1996;12:436-41, N Engl J Med 1996;3354:1941-9). The general objective of the proposed study is to localise genes for atherosclerosis. The specific research aims are: 1. To localise genes implicated in atherosclerosis in a genetically isolated population. 2. To study genes in regions of interest in: 1. A population-based study, The Rotterdam Study. 2. A clinical study of patients with angiographically proven atherosclerosis. Approach. This study is part of a ongoing researcgh program Genetic Research in Isolated Populations (GRIP1) in which several complex genetic disorders are studied in a genetically isolated population of 20,000 subjects in the South Western part of the Netherlands. Extensive data on the genealogy of this population have been collected. At present, a cohort of 2500 subjects from nuclear families is planned to be examined aiming to identify gnes involved in various quantitative traits. For the proposed study, atherosclerosis and its underlying risk factors will be added to the measurements. Atherosclerosis will be measured by ultrasonographic assessment of intima-media thickness of the carotid arteries, which has been shown to be a reliable measure of atherosclerosis (Circulation 1997;96:1432-7). A genome screen will be conducted selecting subjects from the upper 5-10% of the population. Data on possible risk factors underlying atherosclerosis will be ascertained in order to define a more homogeneous phenotype in the analyses. In addition, we will add the measurement of atherosclerosis to our study in patients with hypertension or diabetes mellitus selected from GRIP1. This will provide information on susceptibility genes for atherosclerosis given the presence of a risk factor and will further narrow down the number of genes involved in atherosclerotic disease. In selected subjects, the genome will be screened with a set of highly polymorphic markers that are evenly spread over the genome (distance between markers 5-10 cM). In regions of interest identified, more markers will be tested in order to characterise the risk haplotype. The analysis of the genomic screen will be performed using the computer programs developed by Sandkuijl and Te Meerman. Subsequently, candidate genes in the identified regions of interest will be selected using the results of the Humane Genome Project and bioinformatical data from genetic databases. Testing of candidate genes. Candidate genes in the identified regions of interest, will be subsequently studied in the following populations: 1. The population-based Rotterdam Study, comprising 7983 men and women aged 55 years and older. In 2000-2001, the study will be estende with 4000 subjects in the same age-range and from the same region. Measurements of atherosclerosis in the original and extended Rotterdam Study will be identical. Increase of the numbers of the cohort will facilitate genetic studies on complex disorders. By completion of the extended study, measuremtns of intima-media thickness of the carotid arteries will be available for circa 9000 subjects aged 55 to 75 years. Comparisons will be made in extremes of the distribution (2 * 750). The availability of cardiovascular risk factors data in this study allows for the study of gene-environment interaction. Patients with angiographically proven coronary atherosclerosis aged 45 to 75 years (n=750) and controls selected from the general population. Patients will be recruited from the Academic Hospital Rotterdam. Elements of innovation. Results of genetic studies searching for genes for atherosclerosis have been disappointing. The proposed study of a quantitative train analysis in a genetically isolated population is a novel approach which has not been conducted before. As part of the Human Genome Project, an enormous amount of information on genes and geneic variation in man is bcoming available for population based studies. This will allow sensitive selection of candidate genes for population based and clinical based studies. Relevance for healt care. Knowledge of genes for atherosclerosis may have important implications for the knowledge of the pathogenesis of the disease as it will reveal which proteins (i.e. products of the genes) play a role in the disease etiology. Ultimately, the understanding of the role of genetic factors in atherosclerosis may lead to models for the disease, which can be used for development of therapeutical strategies.



Looptijd: 100%
Looptijd: 100 %
Onderdeel van programma:
Projectleider en penvoerder:
Prof. dr. ir. J.C.M. Witteman
Verantwoordelijke organisatie:
Erasmus MC