Interaction of the ACE D Allele and the GNB3 825T Allele in Myocardial Infarction

Abstract

Abstract-In polygenetic disorders, such as ischemic heart disease, the investigation of gene-gene interactions rather than determination of single gene effects is crucial to better understand the contribution of genetic factors. The 825T allele of the G-protein ␤ 3 -subunit gene (GNB3) associated with enhanced G-protein signaling is a candidate to interact with the angiotensin-converting enzyme (ACE) deletion/insertion (D/I) polymorphism to increase the risk for myocardial infarction (MI Key Words: myocardial infarction Ⅲ genetics Ⅲ signal transduction Ⅲ G proteins Ⅲ angiotensin-converting enzyme A lthough coronary artery disease (CAD) and myocardial infarction (MI) are unlikely to be caused by single genetic polymorphisms, few studies have investigated the interaction of susceptibility genes with other genetic or conventional risk factors on MI. Insight into such interactions may result in a significant gain of knowledge about the pathogenesis of MI and may lead to novel risk stratification, prevention, and even therapeutic strategies.The DD genotype of a deletion/insertion (D/I) polymorphism in the angiotensin-converting enzyme (ACE) gene was initially reported to increase the risk for MI, 1 but subsequent studies yielded conflicting results potentially caused by the heterogeneity of the respective genetic background. 2 ACE mediates the conversion of angiotensin I to angiotensin II (AT-II), and, although this has not yet been rigorously proven, it is commonly assumed that the increased serum ACE levels associated with the ACE D allele 3 represent the main mechanism by which the ACE DD genotype increases the risk for MI. AT-II receptors are typical G-protein-coupled receptors 4 ; thus it appears plausible to assume that AT-II mediated effects are further enhanced in the presence of an increased responsiveness of G proteins. Enhanced G-protein reactivity is strictly correlated with the 825T allele of a C825T base exchange in the gene GNB3 encoding the G-protein ␤ 3 -subunit. 5 The 825T allele is also associated with essential hypertension [5][6][7][8] and with an enhancement of diverse cell functions that may play a role in mechanisms ultimately contributing to an increased risk for MI. 9 -12 Therefore, we investigated the hypothesis that the ACE gene D allele and the GNB3 825T allele significantly interact to increase the risk for MI. This analysis was conducted within a sample of thoroughly characterized patients with angiographically documented CAD with or without previous MI. MethodsThis study was conducted in accordance with the Helsinki Declaration, revised in 1983. Study PopulationA total of 585 patients with angiographically confirmed CAD were consecutively enrolled in this study. CAD was defined by a luminal narrowing with Ͼ50% diameter stenosis in at least 1 coronary artery. The following variables were assessed: current age, gender, body mass index, hypercholesterolemia, hypertension, diabetes, smoking, and previous MI. Previous MI was confirmed in 270 patients according to the American College of Car...

Interaction between GNB3 C825T and ACE I/D polymorphisms in essential hypertension in Koreans

“…38,43 This is because complex trait diseases such as EH are not regulated by single-gene effects but are often associated with multiple genetic and environmental factors. In the present study, we examined a significant interaction between the GNB3 and ACE genes.…”

“…In the present study, we examined a significant interaction between the GNB3 and ACE genes. Naber et al 43 reported that a GNB3 C825T polymorphism interacts with the ACE I/D polymorphism in association with MI. They found a significantly increased OR for MI associated with the GNB3 825T genotype in individuals within the ACE DD genotypes.…”

Consensus paper of the WFSBP Task Force on Biological Markers: Biological Markers in Depression

“…As the study was carried out with depressive patients without serious cardiac impairment at the time of the investigation, it was impossible to predict whether this combined action of the ID/DD Á TT genotype is increasing the risk for both disorders. Nevertheless that study reports for the first time that the same allelic combination of two genes that have been shown to increase the risk for myocardial infarction (Naber et al 2000) increase the vulnerability for depressive disorder. The C825T polymorphism was associated with seasonal affective disorder in another study sample (Willeit et al 2003).…”

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

“…NS ¼ nonsignificant. 295 increase the vulnerability for depressive disorder. 296 The reason why most genetic variability within pharmacodynamic elements did not turn out to be highly predictive of favorable antidepressant treatment response might be that most studies focused on short-time effects of antidepressants such as changes in the serotonin-or noradrenaline-pathways.…”