D. E. L. Wilcken

Circulating transforming growth factor β1 and coronary artery disease

Objective: Transforming growth factor β1 (TGF-β1), a multifunctional cytokine, is involved in many physiological and pathological processes and possibly in atherogenesis. Methods: We explored the association between circulating plasma TGF-β1 measured by ELISA and coronary artery disease (CAD) assessed angiographically in 371 Caucasian patients (269 men and 102 women) aged ≤65 years. Results: While mean±s.e.m. total TGF-β1 was not different among patients with (56.9±1.5 ng/ml) or without (54.6±2.8 ng/ml) angiographically demonstrable CAD, naturally active TGF-β1 was significantly higher in CAD patients (1.74±0.18 vs 0.96±0.17 ng/ml, P <0.01). Active TGF-β1 increased with the number of major coronary arteries with more than 50% luminal obstruction ( P <0.01), and patients with triple vessel disease had twice the level of those with no or mild vessel disease (2.15±0.46 vs 1.12±0.14 ng/ml, P <0.001). We found no relationship between TGF-β1 and Lp(a), but TGF-β1 was significantly correlated with circulating fibrinogen ( r =0.178, P =0.005) and fasting glucose ( r =0.177, P =0.007) levels. Conclusions: Our study identifies an increase in active TGF-β1 levels with both the occurrence and severity of CAD which is independent of standard CAD risk factors. This may reflect a ‘double-edged sword’ effect of TGF-β1 in that it may reduce atherogenesis by inhibiting smooth muscle cell proliferation but, when there is ongoing vessel wall injury, enhance it by promoting excessive extracellular matrix accumulation. The outcome could represent a complex balance between these two competing influences.

Common DNA Polymorphisms at the Lipoprotein Lipase Gene Association With Severity of Coronary Artery Disease and Diabetes

BACKGROUNDnDNA variants of the lipoprotein lipase gene are associated with changes in lipid metabolism similar to those in diabetes and may relate to the development of atherosclerotic lesions, particularly premature lesions.nnnMETHODS AND RESULTSnTo determine whether lipoprotein lipase gene variants are relevant to ongoing atherogenesis, we explored relationships between two common lipoprotein lipase gene polymorphic markers, Pvu II at intron 6 and HindIII at intron 8; the severity of coronary artery disease (CAD); and lipid variables in 475 white patients 65 years of age or younger. We assessed CAD severity as the number of significantly stenosed (> 50% luminal obstruction) major coronary arteries at angiography and by the Green Lane coronary score. We found a significant association between the Pvu II polymorphism and the number of significantly diseased vessels (P = .0099) and coronary score (P = .028), with the Pvu II(-) alleles associated with less severe disease. The HindIII polymorphism was not associated with severity but had an additive effect with the Pvu II polymorphism. There was a close relationship between the Pvu II(+/+) genotype and the presence of diabetes (P = .0025), with an OR of 3.12 (95% CI, 1.30 to 7.49) compared with the Pvu II(-/-) genotype. The interaction between these polymorphisms and CAD severity (rather than occurrence) was independent of the levels of triglycerides and HDL cholesterol and of other lipid variables. There was also a dosage-dependent relationship between the Pvu II polymorphism and levels of triglyceride. The Pvu II(-) allele was associated with low levels and variances of triglycerides.nnnCONCLUSIONSnWe conclude that the lipoprotein lipase Pvu II polymorphism is significantly associated with CAD severity and with type II diabetes in CAD patients, independent of changes in circulating lipid levels. These findings may be relevant to mechanisms mediating atherogenesis.

Polymorphisms of Factor V, Factor VII, and Fibrinogen Genes Relevance to Severity of Coronary Artery Disease

We explored the associations between G-->A mutations of factor V and factor VII genes and the Hae III polymorphism of the fibrinogen gene and the severity of coronary artery disease (CAD), as assessed angiographically in 545 white Australian patients (388 male and 157 female) aged < or = 65 years. We also assessed the relations with other potentially atherogenic variables. Elevated fibrinogen levels were associated with more severe CAD (P < .05), but none of the factor V, factor VII, and fibrinogen DNA variants were predictive of CAD severity, as assessed by the number of significantly diseased vessels (> 50% luminal obstruction). The rare allele frequencies of factor V (A allele), factor VII (M2 allele), and fibrinogen (H2 allele) were .025, .114, and .201 for men and .022, .077, and .169 for women, respectively, and were not different from those in healthy whites. In the patient population, there was a strong, positive association between lifetime smoking dose (in pack-years) and circulating fibrinogen levels (r = .184, P = .001). This association was stronger than that between current smoking habit and fibrinogen and is consistent with a dosage effect. However, there was no significant contribution of fibrinogen genotype to fibrinogen levels in this patient population. We conclude that elevated fibrinogen levels are associated not only with the occurrence of CAD but also with more severe CAD and that measurement of DNA variants of the factor V, factor VII, and fibrinogen genes that we assessed may not provide information in predicting CAD severity in addition to that obtained by measuring circulating levels of the relevant clotting factors. There is, moreover, a positive dosage effect (in pack-years) of smoking on circulating fibrinogen levels.

Genotype Distribution of Angiotensin-Converting Enzyme Polymorphism in Australian Healthy and Coronary Populations and Relevance to Myocardial Infarction and Coronary Artery Disease

Angiotensin-converting enzyme is a key component of the renin-angiotensin system that plays an important role in cardiovascular regulation. An association between the angiotensin-converting enzyme insertion/deletion (I/D) polymorphism and increased coronary risk has been found in some studies but not in others. To explore this further in an Australian white population, we compared the ACE genotype distribution in 550 patients aged 37 to 65 years with coronary artery disease documented by angiography with the genotype distribution in 404 healthy school children aged 6 to 13 years. We also explored associations in the patients between the angiotensin-converting enzyme I/D polymorphism and a history of myocardial infarction and coronary artery disease severity assessed by the number of major coronary arteries with more than 50% luminal obstructions and by the Green Lane coronary score. The frequencies of the angiotensin-converting enzyme genotype in the coronary artery disease patients were 0.236 for I/I, 0.395 for I/D, and 0.369 for D/D genotypes. This distribution with an excess of the D/D genotype was significantly different (chi 2 = 23.69, P < .0001) from that in the school children, in whom the genotype distribution was in Hardy-Weinberg equilibrium (I/I, 0.21; I/D, 0.54; D/D, 0.25). There was also a significant excess of D/D genotype among patients with a history of myocardial infarction (chi 2 = 9.42, P = .009), and there was the same D/D excess in the subgroup of children (n = 60) with two or more grandparents who had had coronary artery disease. We found no associations between the angiotensin-converting enzyme polymorphism and the number of significantly stenosed coronary arteries (chi 2 = 2.069, P = .91). We conclude that the D/D genotype is a significant predictor for coronary artery disease events in the Australian white population but is not a marker for angiographically assessed coronary artery disease severity. The angiotensin-converting enzyme genotype-associated increased risk for coronary events may be mediated more by angiotensin II-induced coronary vasoconstriction than by an increase in injury-related smooth muscle cell proliferation in the coronary vasculature.

Interactive effect of the p53 gene and cigarette smoking on coronary artery disease

OBJECTIVEnp53 is a tumour suppressor protein involved in the control of cell growth and has an established role in carcinogenesis, particularly in relation to smoking. It may also be related to arteriosclerosis by affecting smooth muscle cell proliferation, a feature of atherogenesis.nnnMETHODSnWe explored a role for p53 in atherogenesis by assessing the association between two DNA polymorphisms of the p53 gene (MspI at intron 6 and HaeIII at intron 1) and angiographically documented coronary artery disease (CAD) in 654 Australian Caucasian patients.nnnRESULTSnThere was a significant interactive effect of the two polymorphisms and cigarette smoking on CAD in a logistic regression analysis (P = 0.0039) but no association between CAD and either individual p53 polymorphic marker. CAD occurrence was more frequent in non-smoking patients with rare alleles at both sites (85.0%) compared to those homozygous for common alleles at both sites (70.4%). However, this was not seen in smokers (85.7 vs 82.8%). In all 654 patients cigarette smoking remained a significant predictor of CAD irrespective of p53 genotypes (P = 0.0065).nnnCONCLUSIONSnOur findings identify an interactive effect of both p53 polymorphisms and cigarette smoking on the occurrence of coronary artery disease in that non-smoking patients with rare alleles at both sites had increased incidence of CAD. They illustrate the relevance of genotype-specific and environment-dependent enhanced cardiovascular risk and foreshadow a need for further studies to establish functional changes.