Andreas Gardemann

The p22 phox A640G gene polymorphism but not the C242T gene variation is associated with coronary heart disease in younger individuals.

BACKGROUNDnMost recently, evidence has been presented that the NADH/NADPH oxidase p22 phox C242T, but not the A640G gene polymorphism is associated with a reduced risk of coronary artery disease (CAD).nnnMETHODS AND RESULTSnWe analysed the relationships of both p22 phox gene polymorphisms to CAD in 2205 male Caucasians whose coronary anatomy was defined by means of coronary angiography. In the total population and in high and low risk groups the relative frequencies of the C242T alleles were essentially the same in patients without or with CAD and in individuals without or with myocardial infarction. In contrast, the G allele of the A640G polymorphism was significantly more frequent in subjects without CAD than in patients with CAD (Odds ratio (OR) 0.74 (0.57-0.98); P = 0.038 in multiple logistic regression (MLR)). Correspondingly, the AA genotype of A640G was preferentially found in patients with CAD. These associations did not disappear when the analyses were corrected for multiple comparisons for other gene polymorphisms (ACE I/D gene variation, angiotensinogen T174M and M235T gene polymorphisms, AT1 receptor gene variation, phox C242T gene polymorphism, paraoxonase PON54 and PON191 gene variations) (2p = 0.01 in MLR for the presence of CAD; 2p = 0.039 in multiple regression for the extent of CAD). The association of the A640G gene variation with the presence and extent of CAD was not only identified in the total sample, but was even stronger in various high risk subpopulations of younger individuals (e.g. with hypertension with or without increased apolipoprotein B plasma levels).nnnCONCLUSIONSnOur observations allow the assumption that the p22 phox A640G gene polymorphism is independently associated with the presence and extent of coronary artery disease.

The T allele of the missense Glu298Asp endothelial nitric oxide synthase gene polymorphism is associated with coronary heart disease in younger individuals with high atherosclerotic risk profile

AIMSnNitric oxide (NO) plays a protective role during atherogenesis. In the endothelium, NO is synthesised by the constitutive NO synthase (ecNOS). We analysed the relation of the ecNOS Glu(298)Asp and 4a/b gene polymorphisms to coronary artery disease (CAD) and myocardial infarction (MI) in a population of 3250 German subjects (533 healthy controls and 2717 individuals who underwent coronary angiography).nnnRESULTSnAlthough in the total sample, the ecNOS T allele was not associated with the risk of CAD (P=0.054) and the extent of this disease (P=0.078), a restriction to younger individuals (age</=61, mean age) revealed an association of the ecNOS T allele with an increased risk of CAD (1.43, 1.05-1.96; P=0.025) and with the severity of this disease (P=0.037). Similar observations were made in various high-risk populations. These associations were even more pronounced when the high-risk subgroups were restricted to younger individuals. For example, an odds ratio of 7.66 for CAD (95% CI, 2.0-29; P=0.003) was detected in diabetic individuals who were younger than 61 years. Also with respect to MI, the most pronounced associations of the ecNOS T allele with the risk of this disease were detected in younger individuals with at least one other cardiovascular risk factor. For example, in diabetics younger than 61 years, the relative risk for ecNOS T allele carriers was 9.73 (95% CI, 1.8-53; P=0.008). In contrast, the allele frequencies of the ecNOS 4a/b gene variation were essentially the same in controls and in CAD and MI patients.nnnCONCLUSIONnThe present data extends earlier observations by the findings that predominantly younger T allele carriers of the ecNOS Glu(298)Asp gene polymorphism with various coronary high-risk profiles had an increased risk to suffer CAD and/or MI. In contrast, no evidence was found for an association of the ecNOS 4a/b gene polymorphism with coronary heart disease.

The paraoxonase Leu–Met54 and Gln–Arg191 gene polymorphisms are not associated with the risk of coronary heart disease

BACKGROUNDnEvidence has been presented that gene polymorphisms (PON54 L/M, PON191 Q/R) of paraoxonase are risk factors of coronary heart disease.nnnRESULTSnWe determined both PON genotypes in 535 male individuals who were free of vascular disease and in 2249 male subjects who underwent coronary angiography, and analysed the relation of both gene variations to CAD and MI. Both gene polymorphisms were in linkage disequilibrium (P<0.0001). Coronary artery disease: the PON54 gene polymorphism was not associated with an increased risk of CAD. In the total sample and also in younger subjects, an association of the PON191 gene variation with the risk of CAD was not detected when the control group of individuals without coronary heart disease was compared with patients with at least one diseased vessel (verified by coronary angiography). In individuals younger than 62 years, a moderate increase in the relative risk of CAD associated with the PON191 R allele (1.45 (1. 08-1.95); P=0.015) were found, when subjects without vessel disease (verified by coronary angiography) were compared with CAD patients. Myocardial infarction: an association of the PON54 gene variation with MI was not detected when the control group of individuals without coronary heart disease were compared with patients with at least one MI. A marginal increase in the risk of MI associated with the PON54 LL genotype (OR 1.27 (1.05-1.51); P=0.011) were detected when patients without MI but with coronary angiography were compared with MI positive patients. Subgroup analyses of low- and high-risk populations did not reveal any association of both PON gene polymorphisms with CAD or MI.nnnCONCLUSIONnThe present findings do not strengthen the hypothesis that the paraoxonase gene polymorphisms are independently associated with coronary heart disease indicating that these gene variations are of little usefulness as genetic markers of cardiovascular disease.

ACE I:D gene polymorphism: presence of the ACE D allele increases the risk of coronary artery disease in younger individuals

BACKGROUNDnPresence of the D allele or homozygosity for the deletion (D) allele of the ACE insertion/deletion (I/D) polymorphism has been discussed as potent risk factor for coronary artery disease (CAD) and myocardial infarction (MI).nnnMETHODS AND RESULTSnIn 2267 male Caucasians the relation of the ACE I/D gene polymorphism to CAD and MI were investigated. An association of the D allele to CAD was detected in younger subjects (e.g. < 61.7 years, mean value), but not in older patients (e.g. > or = 61.7 years). Additional exclusion of individuals with other cardiovascular risk factors (e.g. high BMI) produced an even stronger association of the D allele to CAD. In contrast, a relation of this polymorphism to non-fatal MI was only observed in older subjects; additional limitation to individuals without cardiovascular risk factors (e.g. BMI and/or diabetes) yielded a further enhancement of this association to MI. In younger subjects (e.g. < 61.7 years) the gene polymorphism was not related to non-fatal MI even after exclusion of additional risk factors.nnnCONCLUSIONSnThe present large case-control study strengthens the assumption of an association of the ACE D allele with the risk of ischemic heart disease.

Angiotensinogen T174M and M235T gene polymorphisms are associated with the extent of coronary atherosclerosis

BACKGROUNDnThe relations of the angiotensinogen (AGT) T174M and M235T gene polymorphisms to the risk of coronary heart disease (CHD) have been investigated in only a few studies with conflicting results.nnnRESULTSnTherefore, we analysed the relationship of the AGT gene polymorphisms to the presence and extent of CHD in 2250 male Caucasians whose coronary anatomy was defined by means of coronary angiography. The relative frequencies of the T and M alleles of the T174M and of the M235T gene variation did not significantly differ between patients without or with single-, double- or triple-vessel disease and between subjects without or with myocardial infarction (MI). In contrast the mean CHD score--defined by Gensini--was higher within MM homozygotes of the T174M gene variation than within TT genotypes; TM subjects had intermediate values. In M235T genotypes, mean CHD scores were similar in the total sample and in older individuals (> or = 62 years), whereas in younger individuals (< 62 years) a higher CHD score was found within AGT 235 T allele carriers than within MM homozygotes. In younger individuals with high apoAI plasma levels, the mean CHD score was clearly higher within TT homozygotes of the M235T gene variation than within MM genotypes; MT subjects had intermediate values. An interaction between both angiotensinogen gene polymorphisms on the extent of CHD or on the risk of non-fatal MI were not observed when the M allele of AGT T174M was combined either with the T allele or the TT genotype of M235T.nnnCONCLUSIONSnThe present study strengthens the hypothesis of an association of both angiotensinogen gene polymorphisms with the extent of coronary heart disease.

The expression of angiotensin-I converting enzyme in human atherosclerotic plaques is not related to the deletion/insertion polymorphism but to the risk of restenosis after coronary interventions

Plasma and tissue concentrations of the angiotensin-I converting enzyme (ACE) have been shown to be associated with the ACE insertion/deletion (I/D) polymorphism. The purpose of this study was to examine the relation of ACE levels in atherosclerotic plaques to the ACE I/D polymorphism and to restenosis after balloon angioplasty and directional atherectomy (DCA). The study included 104 patients who underwent DCA and received angiographic follow-up at 12 to 18 months. The amount of ACE protein in various morphologically defined plaque components (fibrous, atheromatous, and complicated lesions) of the atherectomy specimens was determined by qualitative and semiquantitative immunohistochemistry. ACE levels were related to the ACE genotype, to plaque morphology and to the risk of restenosis. Sequential staining revealed that pathologic ACE overexpression of the atherosclerotic lesions occurred in intimal smooth muscle cells, fibrocytes/fibroblasts and macrophage/foam cells. The ACE content of the whole plaques and of the single plaque components was not associated with the I/D polymorphism, but with restenosis after coronary interventions. In addition, ACE levels in the atherosclerotic lesions correlated with the severity of vessel wall damage. The ACE phenotype might serve as an indicator for the risk of restenosis after coronary interventions.

Association of the insertion/deletion gene polymorphism of the apolipoprotein B signal peptide with myocardial infarction.

The Del allele of the apolipoprotein B (apoB) signal peptide (SP) insertion/deletion (Ins/Del) polymorphism has been shown to be associated with elevated plasma levels of apoB, cholesterol and low density lipoprotein. It was the aim of the present study to analyse the relation of this gene variation to the risk of coronary artery disease (CAD) and of myocardial infarction (MI) in a population of 2259 male Caucasians, whose coronary anatomy was defined by means of coronary angiography. ApoB SP DelDel genotypes had significantly higher apoB plasma concentrations than InsIns homozygotes (P = 0.0001) and InsDel heterozygotes (P = 0.002); however, the apoB plasma levels of InsIns and InsDel genotypes were essentially the same (P = 0.54). Similar observations were made with respect to ApoB SP genotype-dependent cholesterol plasma concentrations. Since the apoB plasma level was not only associated with the apoB SP Ins/Del gene variation but also to the extent of coronary artery disease (P <0.0001), individuals with an InsIns genotype and without CAD had the lowest and subjects with a DelDel genotype and triple vessel disease the highest apoB plasma levels (P <0.0001). An association of the apoB SP Ins/Del gene variation with CAD was not detected, neither in the total population nor in low risk groups. In contrast, the gene variation was associated with MI (P <0.05). An Odds ratio of 1.18 (95% CI, 1.01-1.39) associated with the Del allele was detected in the total sample (P <0.02). In a subpopulation of individuals with low plasma triglyceride levels ( <154 mg/dl; mean value) and an DD genotype of the angiotensin I-converting enzyme insertion/deletion gene polymorphism an Odds ratio of 2.01 (1.42-3.05) was calculated (P <0.001). The present study presents evidence for a statistically significant difference in the development of MI between genotype classes of the apoB SP Ins/Del gene polymorphism.

Antibody Response to the 60-kDa Heat-Shock Protein of Chlamydia pneumoniae in Patients with Coronary Artery Disease

Serum specimens from 752 individuals undergoing coronary arteriography were examined for antibodies to Chlamydia pneumoniae. Patients with coronary artery disease (CAD) were more likely to have IgG antibodies to C. pneumoniae than were individuals without CAD (60% vs. 52%; P=.007; odds ratio, 1.8; 95% confidence interval, 1. 17-2.77). Antibodies to recombinant hsp60 of C. pneumoniae were found with nearly the same frequency in patients with CAD and individuals without CAD (29% vs. 30%; P=.751). There was no association between chlamydial hsp60 antibodies and the severity of CAD or a previous myocardial infarction. Patient sera reacted most frequently to C. pneumoniae proteins of 17, 38, 40, 58, and 60/62 kDa. Reactivity to these proteins was not different between patients with and without CAD. Study results indicate that neither antibodies to chlamydial hsp60 nor antibodies to other C. pneumoniae proteins are useful for discriminating between seropositive patients with and without CAD.