title: [Genetic factors in myocardial infarction--Results from a candidate gene and a genome-wide approach between beta blockers].
abstract: BACKGROUND
  Coronary artery disease and myocardial infarction are the most frequent causes of death in the Western societies. Even nowadays, every second myocardial infarction is lethal and hits the patients unexpectedly without previous signs or symptoms. In order to install preventive measures most efficiently, it is necessary to have a detailed knowledge on the pathophysiology of the disease. The identification of patients who are at high risk for suffering from myocardial infarction can be done with epidemiological methods, such as the determination of "traditional" risk factors, like arterial hypertension, hypercholesterolemia, diabetes mellitus or smoking), or eventually in the future using molecular genetic testing. This is of great importance especially for asymptomatic siblings and children from myocardial infarction patients.
  Although traditional risk factors occur frequently in families, they explain only in part the familial accumulation of coronary artery disease. Furthermore, stron genetic effects on the development of coronary artery disease and myocardial infarction have been demonstrated in several studies. These genetic effects can be examined by 1. a candidate gene approach, or 2. a systematic screening of the whole genome. In the first step, several polymorphisms (sequence variations) wee examined in several candidate genes in which a significant influence on a cardiovascular risk factor or intermediate phenotype (such as atherogeneic lipid profile or arterial hypertension) has been shown in the literature. We thus examined in a large population of patients with myocardial infarction and a sample of the general population the effects of the HindIII polymorphism in the lipoproteinlipase gene, of the -344T/C promoter polymorphism in the aldosterone synthase gene and of the 825C/T polymorphism in the gene of the beta3 subunit of the G protein gene (GNB3). In the general population, we could show an association with unfavorable lipid levels in men and in postmenopausal (but not premenopausal) women for the H2H2 genotype of the HindIII lipoproteinlipase polymorphism. However, the theoretical increase in risk for this genotype is not large enough to demonstrate a significant association with myocardial infarction in the population examined. With the promoter polymorphism in the aldosterone synthase gene, anthropometrical and echocardiographical data did not suggest that the polymorphism is a risk factor for myocardial infarction nor for left ventricular remodeling after myocardial infarction, which was observed in earlier studies. Furthermore, we could show an association with arterial hypertension in our general population sample with the polymorphism in the GNB3 gene. However, no association could be demonstrated for this polymorphism with myocardial infarction. AFFECTED SIB-PAIR APPROACH: In a systematic screening of the genome for genes that are relevant in the pathogenesis of coronary artery disease or myocardial infarction, an affected sib-pair approach was followed. 1,261 families were identified in which at least two brothers or sisters were affected with myocardial infarction or severe coronary artery disease, such as percutaneous coronary intervention or coronary after bypass grafting. In a subpopulation of 513 families and 1,407 individuals, we performed a total genome screening. The analyses using the variance component method and the SOLAR program revealed a susceptibility locus for myocardial infarction of chromosome 14q32 with a lod score of 3.89 (genome-wide p < 0.05). This locus comprises a region of about seven centi-Morgan and contains approximately 150 genes. Furthermore, a comprehensive analysis including the cardiovascular risk factors showed that 1. this myocardial infarction locus is unique and does not overlap with chromosomal loci for well-established risk factors, 2. cardiovascular risk factors, such as Lp(a), diabetes mellitus, serum lipids, or arterial hypertension have strong genetic components.
  
  
  CONCLUSIONS
  These findings do not exclude a role of cardiovascular s do not exclude a role of cardiovascular risk factors or candidate genes in the pathogenesis of myocardial infarction, but rather demonstrate that risk factors may act as surrogates of specific underlying disease mechanisms. It is thus necessary to perform a comprehensive analysis of complex polygenic diseases, such as myocardial infarction, including both, established cardiovascular risk factors and genomic data.
authors.affiliation: Klinik und Poliklinik für Innere Medizin II, Universitätsklinik Regensburg, Regensburg, Germany. christian.hengstenberg@klinik.uniregensburg.de
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bröckel
authors.forename: Stephan
authors.initials: S
authors.lastname: Holmer
authors.forename: Björn
authors.initials: B
authors.lastname: Mayer
authors.forename: Marcus
authors.initials: M
authors.lastname: Fischer
authors.forename: Andrea
authors.initials: A
authors.lastname: Baessler
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.forename: Hannelore
authors.initials: H
authors.lastname: Löwel
authors.forename: Günter
authors.initials: G
authors.lastname: Riegger
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000328:Adult; D000367:Age Factors; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001161:Arteriosclerosis / Q000235:genetics; D016009:Chi-Square Distribution; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D003627:Data Interpretation, Statistical; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006306:Health Surveys; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000453:epidemiology; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D010641:Phenotype; D011110:Polymorphism, Genetic; D015995:Prevalence; D012044:Regression Analysis; D012307:Risk Factors; D012737:Sex Factors; D020257:Ventricular Remodeling
chemical_list: D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D000960:Hypolipidemic Agents; D019405:Cytochrome P-450 CYP11B2; D008071:Lipoprotein Lipase; D019204:GTP-Binding Proteins