Herwig Köppel

INTERLEUKIN-10 PROMOTER POLYMORPHISM IS ASSOCIATED WITH DECREASED BREAST CANCER RISK

Interleukin-10 (IL-10) is an immunosuppressive cytokine which may facilitate development of cancer by supporting tumor escape from the immune response. A [TCATA] haplotype formed by polymorphisms at positions −3575, −2763, −1082, −819 and −592 in the promoter of the IL-10 gene is a strong determinant for IL-10 expression. The presence of this haplotype can be determined by analysis of the −592C > A polymorphism. Aim of the present study was to analyze the role of the IL-10 [TCATA] haplotype for breast cancer. We performed a case–control study including 500 female patients with histologically confirmed breast cancer and 500 female, age-matched, healthy control subjects from population-based screening studies. The −592C > A polymorphism was determined by a 5′-nuclease assay (TaqMan). Frequency of the homozygous −592 AA genotype, indicating homozygosity for the [TCATA] haplotype, was 4.2% among patients and 7.3% among controls (p=0.038; odds ratio 0.56; 95% confidence interval 0.32–0.97). IL-10 genotypes were not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. Therefore we conclude that the IL-10 −592C > A promoter polymorphism may be associated with a reduced breast cancer risk.

Prothrombin G20210A, factor V Leiden, and factor XIII Val34Leu: common mutations of blood coagulation factors and deep vein thrombosis in Austria.

Mutations in the gene for prothrombin (F2 20210A) and factor V (F5 1691A, factor V Leiden) are established risk factors for deep venous thrombosis (DVT). Recently, a mutation in the gene for factor XIII (F13 100T) leading to a Valine-Leucine exchange at amino acid position 34 has been reported to be protective against DVT. To analyze the role of these mutations for DVT in Austria, we analyzed their prevalence in 154 patients with documented DVT and 308 sex- and age-matched control subjects. Allele frequencies of F2 20210A, F5 1691A, and F13 100T were 0.018, 0.039, and 0.274 among controls, and 0.045, 0.120, and 0.211 among patients, respectively. Odds ratios for DVT associated with F2 20210A, F5 1691A, and F13 100T alleles were 2.5 (95% CI: 1.1-5.7), 3.4 (95% CI: 1.9-5.8), and 0.7 (95% CI: 0.5-1.0). We conclude that F2 20210A, F5 1691A, and F13 100T are common mutations in the Austrian population. F2 20210A and F5 1691 increase the risk for DVT, whereas F13 100T is associated with a decreased risk for DVT. Routinely, analysis of these mutations may help to analyze the individual risk for DVT.

The 5A/6A Polymorphism of the Matrix Metalloproteinase 3 Gene Promoter and Breast Cancer

Purpose: The matrix metalloproteinase 3 (MMP3), also known as stromelysin-I, is a key-player for carcinogenesis and tumor growth. A 5A/6A promoter polymorphism is associated with differences in MMP3 activity and has been linked to cancer susceptibility in some studies. In the present study we evaluated the role of this polymorphism for breast cancer risk. Experimental Design: A case–control study was performed including 500 patients with histologically confirmed breast cancer and 500 female, age-matched, healthy control subjects from population-based screening studies. The MMP3 5A/6A polymorphism was determined by a 5′-nuclease (TaqMan) assay. Results: Prevalences of 5A/5A, 5A/6A, and 6A/6A genotypes were similar among patients (20.6, 51.8, and 27.6%, respectively) and controls (23.3, 47.3, and 29.4%, P = 0.34). The odds ratio of carriers of a MMP3 5A allele for breast cancer was 1.09 (95% confidence interval, 0.83–1.44). Patients with the 5A/5A genotype had a higher proportion of lymph-node metastases than those with a 5A/6A or 6A/6A genotype (P = 0.010). Conclusions: The MMP3 5A/6A promoter polymorphism does not appear to influence breast cancer susceptibility but may be linked to a higher risk for metastasizing among breast cancer patients.

G-455A polymorphism of the fibrinogen beta gene and deep vein thrombosis.

Background Elevated fibrinogen levels have been linked to increased risk for deep venous thrombosis, although it is not clear whether fibrinogen is causal or rather a marker for the presence of other risk factors. A common G/A polymorphism in the gene for the fibrinogen beta‐chain (FGB G‐455A) is associated with elevated fibrinogen levels. The present study was designed to analyze the role of this genetic marker for deep venous thrombosis.

The angiotensin-converting-enzyme insertion/deletion polymorphism is not related to venous thrombosis

The insertion/deletion (I/D) polymorphism of the gene for angiotensin-converting-enzyme (ACE) is associated with ACE plasma levels and activity. Conflicting results have been reported about the relevance of this polymorphism for venous thrombosis. The aim of the present study was to analyze the role of this polymorphism for deep venous thrombosis. The study was designed as a case-control study, including 330 patients with documented deep venous thrombosis and 354 controls. ACE genotype was determined by size-analysis of polymerase chain reaction products. Results showed that, ACE genotype frequencies were similar between patients (II: 24.8%; ID: 43.3%; DD: 31.8%) and controls (II: 22.9%; ID: 50.6%; DD: 26.6%, P = 0.15). The adjusted odds ratio of carriers of the DD geno-type for venous thrombosis was 1.24 (95% confidence interval 0.90-1.80). The polymorphism was furthermore not associated with age at first thromboembolic event or the occurrence of pulmonary embolism. From these results, we can conclude that the ACE I/D polymorphism is not a significant risk factor for deep venous thrombosis.

The functional -4C>T polymorphism of the coagulation factor XII gene is not associated with deep venous thrombosis

4 and heparin. Glycobiology 1993; 3: 271–7. 10 Savi P, Chong BH, Greinacher A, Gruel Y, Kelton JG,Warkentin TE, Eichler P,MeulemenD, PetitouM,Herault JP, CariouR, Herbert JM. Effect of fondaparinux on platelet activation in the presence of heparindependent antibodies: a blinded comparative multicenter study with unfractionated heparin. Blood 2005; 105: 139–44. 11 Harenberg J, Jorg I, Fenyvesi T. Treatment of heparin-induced thrombocytopenia with fondaparinux.Haematologica 2004; 89: 1017– 8. 12 Haase M, Bellomo R, Rocktaeschel J, Ziemer S, Kiesewetter H, Morgera S, Neumayer HH. Use of fondaparinux (ARIXTRA ) in a dialysis patient with symptomatic heparin-induced thrombocytopaenia type II. Nephrol Dial Transplant 2005; 20: 444–6.

Vascular Endothelial Growth Factor in Predicting Outcome in Breast Cancer

To the editor: We have read with great interest the work by Konecny et al. about HER-2/neu and vascular endothelial growth factor (VEGF) expression and breast cancer outcome [(1)][1] . As we reported recently, a polymorphism downstream of the VEGF gene, 936C>T, was associated with VEGF expression

Minimal Effects of Levosimendan on Coronary Artery Smooth Muscle Tone

Sir, Levosimendan is a novel calcium-sensitising drug which was designed for the treatment of severe heart failure [1,2,3,4]. Beside sensitising the myocardial contractile apparatus for intracellular calcium, it shows additional properties like activation of ATP sensitive potassium channels (KATP channels) in ventricular myocytes [5] and arterial vascular smooth muscle cells [6]. The effect of levosimendan in isolated coronary arteries has not been looked at in detail, especially under the aspect of KATP channel opening. Here we use isolated bovine coroanary arteries and show that the effect of Levosimendan on coronary arteries is minimal both at rest as well as under 5-fold increased calcium in the solution.

KATP channel opening does not contribute significantly to the vasodilatory effect of SH-group-containing ACE inhibitors

SummaryAngiotensin-converting enzyme (ACE) inhibitors are widely used in the management of hypertension, heart failure, and nephropathy. It has been suggested that ACE inhibitors containing the sulfhydryl group (SH) have an additional effect on KATP channels. To prove this hypothesis, we studied the effects of the SH-containing ACE inhibitors, captopril and zofenopril, on KATP channel opening of bovine coronary arteries and guinea pig thoracic aortas. Bovine coronary arteries were precontracted with the thromboxane A2 analogue, U46619, and guinea pig thoracic aortas were precontracted with phenylephrine and then relaxed with either captopril or zofenopril (n=8). Inhibition of KATP channel opening with glibenclamide moderately attenuated the zofenopril-induced relaxation of guinea pig thoracic aorta. However, in the bovine coronary arteries, the relaxing effect of both captopril and zofenopril remained uneffected by glibenclamide. In experiments with enalapril (a non SH-containing ACE inhibitor:n=6) on guinea pig thoracic aortas, no effect on KATP channels could be seen. From our experiments, we conclude that the postulated opening of KATP channels by SH-group-containing ACE inhibitors contributes little to the vasodilation of guinea pig thoracic aortas caused by ACE inhibitors, and that SH groups have no influence upon KATP channels of bovine coronary arteries.

Cellular Mechanisms of Myocardial Hibernation, Stunning, and Ischemic Preconditioning

Myocardial hibernation, stunning, and ischemic preconditioning are different pathological entities related to reduced blood supply to the myocardium.