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Prostate cancer is a common malignancy in men worldwide and it is known that oxidative stress is a risk factor for cancer development. A common functional haptoglobin (Hp) polymorphism, originating from a duplication of a gene segment spanning over two exons, results in three distinct phenotypes with different anti-oxidative capacities: Hp1-1, Hp1-2, and Hp2-2. The aim of the study was to investigate the relationship between this Hp polymorphism and prostate cancer mortality. The study was performed on 690 patients with histologically confirmed prostate cancer, recruited between January 2004 and January 2007. Hp genotypes were determined by a TaqMan fluorogenic 5'-exonuclease assay. Hp1-1 was present in 76 (11%), Hp1-2 in 314 (45.5%), and Hp2-2 in 300 (43.5%) patients. During a median follow-up of 149 months, 251 (35.3%) patients died. Hp genotypes were not significantly associated with higher overall mortality (HR 1.10; 95% CI 0.91-1.33; p = 0.34). This remained similar in a multivariate analysis including age at diagnosis, androgen deprivation therapy, and risk group based on PSA level, GS, and T stage (HR 1.11; 95% CI 0.91-1.34; p = 0.30). We conclude that the common Hp polymorphism does not seem to be associated with overall mortality in prostate cancer patients.

Background: Uridine diphosphate glycosyltransferases 1A1 (UGT1A1) plays an essential role in detoxification and excretion of several endogenous and exogenous compounds. A functional polymorphism in the promoter of the UGT1A1 gene (TA repeat insertion, UGT1A1*28, rs3064744) has been associated with reduced UGT1A1 enzyme activity. The purpose of the present study was to investigate the role of UGT1A1 genotypes in mortality., Methods: UGT1A1 genotypes as well as baseline plasma bilirubin levels were analyzed in participants of the Ludwigshafen Risk and Cardiovascular Health study (n=3316). UGT1A1*28 genotypes were determined on an ABI PRISM 3730 genetic analyzer., Results: As expected, UGT1A1 genotypes were associated with baseline bilirubin levels (*1/*1 genotype: 9.1±4.6 µmol/L; *1/*28 genotype: 10.8±5.3; *28/*28: 16.9±9.2; p<0.001). During a median follow-up of 10.4 years, 995 subjects (30.0%) died. In a multivariate regression analysis adjusting for age, sex, smoking, type 2 diabetes, dyslipidemia, alanine aminotransferase (ALT) levels and bilirubin levels, the UGT1A1*28 variant predicted lower overall mortality (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.78-0.95; p=0.003). Contrary to expected, higher baseline bilirubin levels predicted increased mortality (HR, 1.014; 95% CI, 1.002-1.025; p=0.019)., Conclusions: The UGT1A1*28 gene variant is associated with lower mortality rates. The protective effect of the UGT1A1*28 variant likely includes mechanism other than bilirubin metabolism.

Background: Vascular endothelial growth factor (VEGF-A) is a key regulator of tumor-induced angiogenesis and essential for tumor growth and distant tumor spread. The aim of the present study was to evaluate the role of VEGF-A polymorphisms and haplotypes for metastatic progression in breast cancer patients., Material and Methods: We performed a prospective study including 801 breast cancer patients. Occurrence of metastases was examined in regular follow-up investigations. Seven VEGF-A polymorphisms were selected and determined by 5'-nuclease assays (TaqMan). The selection of VEGF-A variants was based upon their location (promoter or UTR) as well as a minor allele frequency of at least 0.10. Haplotypes and linkage disequilibrium were determined using the Haploview program., Results: Within a median follow-up time of 84 months, 165 (21%) patients developed distant metastases. In univariate analysis, carriers of the CCCCC haplotype formed by five polymorphisms upstream the coding region were at decreased risk of distant metastases [hazard ratio (HR)=0.743; 95% CI 0.579-0.953; p=0.019]. Univariate analysis also revealed a decreased risk of distant metastases for postmenopausal patients carrying the -634G>C polymorphism (HR 0.704; 95% CI 0.514-0.965; p=0.029) and the CCCCC haplotype (HR=0.645; 95% CI 0.464-0.898; p=0.009). After adjustment for other co-variates, the HR for distant metastases was 0.651 (95% CI 0.447-0.948) for postmenopausal carriers of the -634G>C polymorphism (p=0.025; corrected p-value=0.262), and 0.586 (95% CI 0.393-0.873) for postmenopausal patients with the CCCCC haplotype (p=0.009, corrected p-value=0.189)., Conclusion: The results from univariate and multivariate analyses suggest an influence of VEGF-A gene variants on the development of distant metastases in breast cancer patients. However, none of the observed associations reached statistical significance after correction for the effects of multiple testing. Additional prospective and sufficiently powered studies are essential before firm conclusions about the role of VEGF-A gene variants for distant progression in breast cancer can be drawn.

Background: DNA repair mechanisms play a major role in cancer risk and progression. Germline variants in DNA repair genes may result in altered gene function and/or activity, thereby causing inter-individual differences in a patient's tumor recurrence capacity. In genes of the DNA repair pathway the gene variants RAD51 rs1801320 G>C, XRCC2 rs3218536 G>A and XPD rs13181 A>C have been previously related to genetic predisposition and prognosis of various cancer entities. In this study we investigated the association between these polymorphisms and time to recurrence (TTR) and overall survival (OS) in soft-tissue sarcoma (STS) patients after curative surgery., Methods: Two hundred sixty STS patients were included in this retrospective study. Germline DNA was genotyped by 5'-exonuclease (TaqMan) technology. Kaplan Meier curves and multivariate Cox proportional models were calculated for TTR and OS., Results: A statistically significant association was observed between tumor grade and adjuvant radiotherapy and TTR and between tumor grade and OS. No association was found between RAD51 rs1801320 G>C, XRCC2 rs3218536 G>A and XPD rs13181 A>C and TTR and OS in univariate and multivariate analysis., Conclusion: Our results underline a prognostic effect of tumor grade and adjuvant radiotherapy in STS patients but indicate no association between RAD51 rs1801320 G>C, XRCC2 rs3218536 G>A and XPD rs13181 A>C and clinical outcome in STS patients after curative surgery., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

To elucidate the role of predictive factors on individual's drug response, based on genetic variation, we examined the association between eight germline polymorphisms in genes involved in protection against oxidative stress, apoptosis, oncogenic transformation, proliferation, immune response and DNA repair (TP53, NQO1, IL6, TLR4 and XRCC1) and the pathological response to anthracycline-based neoadjuvant chemotherapy in 70 patients with breast cancer. The DNA was genotyped for eight polymorphisms in five genes (TP53, NQO1, IL6, TLR4 and XRCC1) by 5'-exonuclease (TaqMan™) technology. Fisher's exact test was used to evaluate the association between genotype, clinicopathological parameters and pathological response. A good pathological response, defined as a pathological complete response or residual isolated invasive tumor cells, was found significantly more frequently for estrogen (ER) and progesterone receptor (PR) negative breast carcinomas compared to ER and PR positive and ER or PR positive carcinomas, respectively (43.5 vs. 37.5 and 10.3 %, p = 0.006), and was significantly associated with high tumor grade (G3) (p = 0.002). A non-significant trend towards a good pathological response was shown in patients carrying the Arg/Arg or Arg/Pro TP53 codon 72 gene variant compared to those harboring the Pro/Pro variant (17.6 or 37.9 % vs. 0; p = 0.071). No association was found between NQO1 Pro187Ser, IL6 -174G>C, TLR4 Asp299Gly and Thr399Ile, and XRCC1 Arg194Trp, Arg399Gln and Arg280His and pathological response. The present study shows hormone receptor status and tumor grade as predictors for pathological response to neoadjuvant anthracycline-based chemotherapy. Among various functional germline polymorphisms, a potential predictive value was only found for the TP53 Arg72Pro gene variant.

Recent data suggest that erythropoietin (EPO) plays a substantial role in cancer development and clinical outcome by stimulating cell proliferation, invasion and angiogenesis. A functional polymorphism (rs1617640 G>T) in the promoter region of the EPO gene increases EPO protein expression. In the present study, we investigated the association of EPO rs1617640 G>T with susceptibility and clinical outcome of early-stage breast cancer. Genomic DNA of 539 female patients with histologically confirmed early-stage breast cancer and 804 controls was genotyped for EPO rs1617640 G>T. No association was found between EPO rs1617640 G>T and early-stage breast cancer susceptibility and clinical outcome (hazard ratio=1.24, 95% confidence interval=1.82-1.90, p=0.31). In conclusion, our findings suggest a lack of influence of EPO rs1617640 G>T on early-stage breast carcinogenesis and clinical outcome.

Background and Purpose: Vascular endothelial growth factor (VEGF) is an important determinant of microvascular permeability and angiogenesis and has been shown to be up-regulated during the late phase of radiation injury. The present prospective study was performed to evaluate the role of VEGF gene polymorphisms and haplotypes in the development of radiation-induced late side effects in prostate cancer patients., Patients and Methods: The association of VEGF gene polymorphisms and haplotypes with high-grade late rectal or urinary toxicity (defined as late toxicity EORTC/RTOG ≥ 2) was analyzed using 493 prostate cancer patients from the Austrian PROCAGENE study treated with definitive radiotherapy. Seven candidate polymorphisms in the VEGF gene were selected and determined by 5'-nuclease (TaqMan) assays., Results: Within a median follow-up time of 48 months, 42 patients (8.6%) developed high-grade late rectal and 47 patients (9.6%) urinary toxicity, respectively. In a Kaplan-Meier analysis, carriers of the VEGF -7C > T polymorphism were at increased risk of high-grade late rectal toxicity (p = 0.003) and in a multivariate analysis including clinical and dosimetric parameters as potential confounders the VEGF -7C > T polymorphism remained a significant predictor (HR = 2.8, 95% CI 1.349-5.813; p = 0.006). Furthermore, the ATTGT haplotype formed by five polymorphisms upstream of the coding sequence demonstrated a significant association with late rectal toxicity grade ≥ 2 (p = 0.001). No significant associations were found for the remaining polymorphisms and haplotypes., Conclusion: We conclude that genetic variants in the VEGF gene may influence the risk of high-grade late rectal toxicity after definitive radiotherapy for prostate cancer.

Objective: Central retinal vein occlusion (CRVO) is a vision-threatening disease, primarily occurring among patients aged more than 60 years. Several risk factors, including arterial hypertension and diabetes mellitus, have been identified. Compression of the central retinal vein by an atherosclerotic retinal artery at the lamina cribrosa also has been implicated in the pathogenesis of the disease. Functional gene polymorphisms of cytokines or chemokines previously shown to affect atherogenesis or hemostasis are potential risk factors for CRVO. The present study investigates a hypothesized association between inflammation-related gene polymorphisms and the presence of CRVO in a relatively large cohort of patients., Design: Case-control study., Participants: The study group consisted of 315 patients with CRVO and 335 control subjects., Methods: Determination of genotypes was done by 5' exonuclease assay (TaqMan)., Main Outcome Measures: Genotypes of interleukin (IL)1β -511C>T, IL1 receptor antagonist (IL1RN) 1018T>C, IL4 -584C>T, IL6 -174G>C, IL10 -592C>A, IL18 183A>G, tumor necrosis factor (TNF)-α -308G>A, monocyte chemoattractant protein (MCP)-1/CCL2 -2518A>G, IL8 -251A>T, and RANTES (CCL5) -403G>A polymorphisms., Results: Genotype distributions and allele frequencies of the investigated gene polymorphisms did not significantly differ between both groups (P>0.05). Arterial hypertension, diabetes mellitus, and cigarette smoking were significantly more frequent in patients with CRVO than among control subjects (arterial hypertension: 67.0% vs. 52.2%, P<0.001; diabetes mellitus: 16.8% vs. 6.3%, P<0.001, cigarette smoking: 32.1% vs. 23.6%, P = 0.02). In a logistic regression analysis, the presence of arterial hypertension was associated with an odds ratio (OR) of 1.75 (95% confidence interval [CI], 1.26-2.44) in those with CRVO, whereas an OR of 2.52 (95% CI, 1.46-4.35) was found in those with diabetes mellitus. A history of cigarette smoking was associated with an OR of 1.57 (95% CI, 1.09 - 2.25) for CRVO., Conclusions: Our data suggest that the investigated inflammation-related gene polymorphisms are unlikely major risk factors for CRVO., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: tacrolimus and everolimus are immunosuppressive drugs metabolized by enzymes of the CYP3A subfamily. A common variant of the CYP3A5 gene, CYP3A5*3, results in strongly decreased CYP3A5 activity and has been shown to influence Tacrolimus blood concentrations, but its role for the pharmacogenetics of Everolimus remains unclear. Aim of the study was to examine the role of CYP3A5*3 variant in tacrolimus and everolimus dose and drug levels after heart transplantation., Methods: The present study comprised 15 patients with Tacrolimus and 30 patients with Everolimus-based maintenance therapy after heart transplantation. CYP3A5 genotypes were determined and correlated with clinical data., Results: In the Tacrolimus group, 13 subjects were CYP3A5 non-expressors (*3/*3 genotype) and two were heterozygous expressors (*1/*3 genotype). Average Tacrolimus dose was significantly higher in subjects expressing CYP3A5 compared to non-expressors. Tacrolimus levels were not significantly different at any point of time. In the Everolimus group, 27 subjects were CYP3A5 non-expressors (*3/*3 genotype) and three were heterozygous expressors (*1/*3). Neither Everolimus dose nor levels were significantly different between CYP3A5 expressors and non-expressors at any point of time., Discussion: We conclude that in adult patients after heart transplantation, CYP3A5 genotypes have a strong influence on Tacrolimus, but not Everolimus dose requirement., (© 2009 John Wiley & Sons A/S.)

Background: C-reactive protein is a well established marker of inflammation and has been used to predict future cardiovascular disease. It is still controversial if it plays an active role in the development of cardiovascular disease. Recently, polymorphisms in the gene for HNF1α have been linked to the levels of C-reactive protein and coronary artery disease., Methods: We investigated the association of the rs2259816 polymorphism in the HNF1A gene with the circulating level of C-reactive protein and the hazard of coronary artery disease in the LURIC Study cohort., Results: Compared to CC homozygotes, the level of C-reactive protein was decreased in carriers of at least one A-allele. Each A-allele decreased CRP by approximately 15%. The odds ratio for coronary artery disease was only very slightly increased in carriers of the A-allele and this association did not reach statistical significance., Conclusions: In the LURIC Study cohort the A-allele of rs2259816 is associated with decreased CRP but not with coronary artery disease.

Aims: As data on the cardiovascular risk associated with CYP2C8 and CYP2C9 polymorphisms is controversial, we performed a cross-sectional analysis of subjects enrolled in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study., Materials & Methods: CYP2C8 and CYP2C9 genetic polymorphisms were determined with real-time PCR in 2827 patients. Based on angiography, 1052 of these patients had coronary artery disease (CAD) and 615 did not; 1160 patients had signs or a history of myocardial infarction (MI) in addition to CAD. The association of genotypes with CAD and MI was determined by logistic regression analysis, adjusted for age, sex, dyslipidemia, hypertension, diabetes mellitus and smoking status., Results: Frequencies of CYP2C8 and 2C9 variants were neither significantly different between CAD and control patients, nor between MI and control patients. Men carrying the CYP2C9*3 allele had an increased risk of MI (odds ratio [OR]: 1.67; 95% CI: 1.06-2.63; p = 0.03) and women carrying the CYP2C9*3 allele had a decreased risk of CAD (OR: 0.65; 95%CI: 0.42-0.9; p = 0.05)., Conclusion: Overall, LURIC data confirmed that there is no major cardiovascular risk associated with CYP2C8 and CYP2C9 variants in a cardiovascular risk population of patients having undergone coronary angiography.

Hypoxia-inducible factor 1 (HIF1) is a key regulator of angiogenesis and is involved in inflammation, which are two important features of the pathogenesis of peripheral artery disease (PAD). The gene for the HIF1-alpha subunit (HIF1A) carries two common mis-sense mutations, P582S (C>T, rs11549465) and A588T (G>A, rs11549467), which both have been related to increased trans-activation capacity of HIF1-alpha. The aim of the present study was to analyze the role of these polymorphisms in PAD. The study was designed as a case-control study including 917 patients with documented PAD and 969 control subjects. HIF1A genotypes were determined by exonuclease (TaqMan) assays. HIF1A P582S genotype frequencies were not significantly different between PAD patients (PP 82.2%; PS 16.5%; SS 1.3%) and control subjects (83.2%; 15.3%; 1.5%; p = 0.72). Similarly, HIF1A A588T genotype frequencies did not differ significantly between PAD patients (AA 95.9%; AT 4.1%) and control subjects (AA 96.8%; AT 3.2%; p = 0.28). In a multivariate logistic regression analysis including age, sex, smoking, diabetes, arterial hypertension and hypercholesterolemia, neither the HIF1A P582S polymorphism (odds ratio: 1.26; 95% confidence interval 0.92-1.74; p = 0.16) nor the A588T polymorphism (odds ratio: 1.17; 95% confidence interval 0.59-2.35; p = 0.66) was significantly associated with the presence of PAD. Both polymorphisms were furthermore not associated with age at onset of PAD, Fontaine stage of the disease or the ankle/brachial index of patients. We conclude that functional polymorphisms in the HIF1A gene do not contribute to susceptibility to PAD.

With an incidence of about 300 000 new cases colorectal cancer (CRC) is the second leading cause of cancer-related death in Europe and the United States. Environmental and genetic factors influence CRC risk. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric protein composed of two subunits, HIF-1 alpha and HIF-1 beta, plays a critical role in oxygen homeostasis and is involved in angiogenesis and cell proliferation. The gene for the HIF-1 alpha subunit (HIF1A) carries two common missense mutations-P582S (rs11549465) and A588T (rs11549467)-which both have been related to increased trans-activation capacity of HIF1A. In our case-control study we investigated the association between these polymorphisms and CRC risk. We investigated 381 patients with histologically confirmed CRC and 2156 control subjects. HIF1A genotypes were determined by exonuclease (TaqMan) assays. For determination of microvessel density (MVD) tumor sections were stained using a mouse monoclonal antibody recognizing the pan-endothelial marker CD31. In a multivariate logistic regression analysis including age and sex neither the HIF1A 582S allele (Odds ratio: 1.204; 95% confidence interval 0.911-1.592; P = 0.193) nor the 588T allele was significantly associated with CRC (Odds ratio: 0.851; 95% confidence interval 0.444-1.631; P = 0.626). However, in an exploratory analysis, the HIF1A 588T allele was associated with tumor localization (P = 0.016) and tumor size (P = 0.003). MVD was similar in tumors of patients carrying HIF1A 588T allele and patients without this rare allele. We conclude that functional polymorphisms in the HIF1A gene do not modify CRC risk but maybe associated with clinic-pathological features of the disease., (2010 Wiley-Liss, Inc.)

Coagulation factor XII (FXII) plays a key role in both coagulation and fibrinolysis and has been associated with cardiovascular disease in some studies. Plasma FXIIa levels are strongly determined by a common functional polymorphism in the promoter of the FXII gene (F12-4C>T). To investigate the potential association of this polymorphism with peripheral arterial disease (PAD), we performed a case-control study including 668 patients with PAD and 762 controls participants without cardiovascular disease. F12 genotype frequencies were not significantly different between patients with PAD and control participants. After adjustment for classical risk factors, the odds ratio of carriers of a F12 -4T allele for PAD was 1.06 (95% confidence interval 0.86-1.32). F12 genotypes were associated with a modest increase of the mean-activated partial thromboplastin time but not with PAD stage or severity. We conclude that the functional F124C>T polymorphism is not associated with PAD.

This study examined the superoxide dismutase 3 (SOD3) R231G polymorphism in relation to the severity of coronary artery disease (CAD) and the risk of myocardial infarction (MI) in 3211 individuals; 94.4% of study participants were homozygous for SOD3 231RR and 5.5% were heterozygous for SOD3 231RG. The odds ratios of the RG and GG genotype (adjusted for age, gender and for conventional cardiovascular risk factors) were 2.02 (95% CI, 1.23-3.33, p=0.005) for the highest vs the lowest Friesinger coronary score and 1.40 (95% CI, 1.02-1.92, p=0.037) for MI, respectively. Further the SOD3 RG and GG genotype was associated with lower alpha-tocopherol levels than the wild type SOD3 RR genotype. It is concluded that the SOD3 231RG and GG genotype is associated with lower alpha-tocopherol levels and the severity of CAD and the risk of MI.

Purpose: Exudative age-related macular degeneration (exudative AMD) is a common vision-threatening disease, with both environmental and genetic factors contributing to its development. Recently, homozygosity for the 72Met variant of the pigment epithelium-derived factor (PEDF) Met72Thr gene polymorphism (rs1136287) was identified as a novel risk factor for exudative AMD in Chinese patients from Taiwan. The role of this polymorphism, however, has not yet been determined in a white European population. In addition, two other PEDF gene polymorphisms, -5736T>C (rs12150053) and -5304C>T (rs12948385), have been associated with increased risk of diabetic retinopathy, but have not yet been studied among patients with exudative AMD. The purpose of the present study was thus to investigate a hypothesized association between these PEDF polymorphisms and the presence of exudative AMD in a white European population., Methods: The present case-control study comprised 269 patients with exudative AMD and 155 control subjects. Genotypes of the PEDF polymorphisms were determined by 5'-exonuclease assays (TaqMan)., Results: PEDF genotype and allele frequencies were not significantly different between AMD patients and control subjects. The two promoter polymorphisms, -5736T>C (rs12150053) and -5304C>T (rs12948385), were in complete association. Presence of the homozygous PEDF 72 Met/Met genotype was associated with a nonsignificant odds ratio of 1.00 (95% confidence interval: 0.67-1.49, p=0.99). Similarly, presence of the homozygous PEDF -5736 TT genotype or -5304 CC genotype was associated with a nonsignificant odds ratio of 0.99 (95% confidence interval: 0.56 - 1.75, p=0.97). Both promoter polymorphisms were in linkage disequilibrium with the Met72Thr (rs1136287) polymorphism (D'=0.83) and formed three common and one rare haplotype. Haplotype frequencies were similar between AMD patients and control subjects (p>0.05)., Conclusions: Our data suggest that none of the investigated PEDF polymorphisms is likely a major risk factor for exudative AMD in a white European population.

Background: There is increasing evidence that lipoprotein-associated phospholipase A2 (LpPLA2) is associated with cardiovascular disease. However, it is still unclear whether LpPLA2 is simply a marker or has a causal role as either a pro- or anti-atherogenic factor., Methods: We analyzed the association of five polymorphisms (-1357G>A, -403T>C, Arg92His, Ile198Thr, Ala379Val) and related haplotypes at the PLA2G7 locus with angiographic coronary artery disease (CAD), plasma LpPLA2 activity, and long-term survival in 3234 patients scheduled for coronary angiography., Results: The promoter variant -403C and His(92) were associated with a decrease and Val(379) with an increase in plasma LpPLA2 activity. Both coding variants revealed a clear gene-dose effect. Interestingly, the rare Thr(198) allele, which was not associated with any change in plasma LpPLA2 activity, was more frequent in subjects without CAD (P = 0.009), with an adjusted odds ratio for CAD of 0.69 (95% CI: 0.49-0.96; P = 0.029). None of the analyzed variants showed any robust association with all-cause or cardiovascular mortality., Conclusion: Irrespective of the significant association between some variants with plasma LpPLA2 activity, it is still unclear whether these polymorphisms or haplotypes are associated with the risk and outcome of cardiovascular disease in Caucasians.

Breast cancer is the most frequently diagnosed cancer among women in western countries and bone metastases of breast cancer cause significant morbidity. G proteins are important components of a multitude of transmembrane receptors and are involved in the regulation of intracellular signaling pathways such as parathormone receptors 1 and 2 (PTH1 and 2), extracellular calcium-sensing receptor, the calcitonin receptor and the OPG/RANKL-system. A common polymorphism in the gene encoding the G protein beta3-subunit, GNB3 825C > T, has been linked to increased G protein activation. To analyse the role of this polymorphism in bone metastasis of breast cancer, we determined GNB3 825C > T genotypes in 500 female breast cancer patients. According to breast cancer staging, patients were divided in three groups, representing patients without metastases (n = 250), those with metastases other than bone (n = 117), and those with bone metastasis (n = 133). Frequency of the GNB3 825 TT genotype was significantly lower among patients with bone metastases (3.1%) than among those with other metastases (12.8%; P = 0.004) or no metastases (13.3%; P < 0.001). In a Cox regression analysis, relative risk of the GNB3 TT genotype for bone metastasis was 0.22 (95% CI 0.08-0.61; P = 0.004) for bone metastasis. We conclude that the homozygous GNB3 825 TT genotype may be protective against development of bone metastasis in breast cancer patients. The precise mechanism for this remains to be determined, but could be due to a direct involvement of G protein-coupled receptors in bone metabolism.

Purpose: Vascular endothelial growth factor (VEGF) is a key regulator of tumor-induced angiogenesis and is required for growth of tumors. We tested the hypothesis that VEGF gene polymorphisms may be associated with breast cancer., Experimental Design: We performed a case-control study including 804 female incident breast cancer patients and 804 female age-matched healthy control subjects. We selected seven VEGF candidate polymorphisms and determined genotypes by 5'-nuclease (TaqMan) assays. Furthermore, VEGF plasma levels and genotypes were analyzed in a group of 81 healthy volunteers (64 men and 17 women)., Results: Haplotype analysis showed two separate blocks of high-linkage disequilibrium, formed by five polymorphisms upstream of the coding sequence (promoter and 5' untranslated region) and two polymorphisms downstream of the coding sequence. None of the single polymorphisms or haplotypes was significantly associated with the presence of breast cancer. After Bonferroni correction for multiple testing, only one statistical signifcant association between VEGF genotypes and haplotypes and tumor characteristics was observed (-634C allele and small tumor size; p < 0.001). In a multivariate regression analysis including sex, age, VEGF genotypes, and haplotypes as covariates and VEGF plasma level as dependent variable, none of the VEGF polymorphism or haplotypes was a significant predictor of VEGF plasma levels., Conclusions: Our findings do not support the hypothesis that VEGF polymorphisms are associated with breast cancer risk. The association of the VEGF -634C allele with small tumor size is in clear contrast to a previous publication and should be interpreted with caution until replicated by additional studies.

In the biology of complex disorders, such as breast cancer, interactions among genetic factors may play an important role and theoretical considerations suggest that gene-gene interactions are quite common in such diseases. In this case-control study with 500 breast cancer patients and 500 population-based healthy sex- and age-matched control subjects, we applied a multigenic approach to examine the associations with breast cancer risk of a comprehensive panel of 16 selected polymorphisms in a variety of pathways using classification tree analysis (CART). Overall, 79.6% of all breast cancer patients and 80.6% of all control subjects were correctly classified on the basis of their individual genetic profile by the classification procedure. CART analysis of the data identified the heterozygous vascular endothelial growth factor (VEGF) and matrix metalloproteinase 3 (MMP3) genotype and homozygous cyclooxygenase-2 (PTGS2) mutant as the initial splits, indicating that these genotypes exert the greatest impact on the classification process. Breast cancer patients were primarily indicated by 30 distinct genetic profiles. The odds ratio of these genetic risk profiles for breast cancer was 16.12 (95% confidence interval 11.09-23.49). Five genetic profiles formed homogenous breast cancer subgroups and represented highest risk genetic profiles. This is the first comprehensive study to use a multigenic analysis for breast cancer and the data suggest that individuals with distinct genetic profiles are at an increased risk for breast cancer, confirming the importance of taking a multigenic approach for risk assessment.

Background: Disorders of calcium homeostasis have been implicated in atherosclerosis. The calcium-sensing receptor (CASR) is crucial to the regulation of calcium metabolism. An alanine (A) to serine (S) polymorphism at codon 986 (A986S) of the CASR gene has been associated with higher calcium and osteoporosis; the association with coronary artery disease (CAD) has not been studied., Methods and Results: We investigated this polymorphism in individuals with CAD (n = 2561), including survivors of myocardial infarction (MI) (n = 1358) compared to 698 controls without angiographic CAD. Compared to AA homozygotes, the prevalence of CAD [multivariate odds ratio 1.25; 95% confidence interval (CI) 1.02-1.54] and previous MI (multivariate odds ratio 1.33; 95% CI 1.06-1.68) was increased in carriers of at least one S-allele. With each S-allele, the prevalence of CAD and MI increased 1.22-fold (95% CI 1.02-1.47) and 1.30-fold (95% CI 1.06-1.60), respectively. Fully adjusted hazard ratios for total and cardiovascular mortality per one S-allele were 1.24 (95% CI 1.05-1.46) and 1.38 (95% CI 1.13-1.67), respectively. In carriers of at least one S-allele, the adjusted hazard ratios for all-cause and cardiovascular death were 1.25 (95% CI 1.04-1.51) and 1.48 (95% CI 1.18-1.86), respectively. These associations were independent of cardiovascular risk factors, calcium and phosphate. The S-allele was associated with higher calcium (P < 0.001) and PTH (P < 0.02), and lower phosphate (P < 0.003) in CAD patients and controls., Conclusion: Serine at position 986 of CASR may be an independent genetic predictor of angiographic CAD, previous MI, and cardiovascular mortality.

Purpose: Pro- and anti-inflammatory cytokines, including interleukin 10 (IL-10), play an essential role in atherogenesis. Increased IL-10 production has been found among carriers of the IL10 [TCATA] haplotype, which is formed by five polymorphisms at position -3575, -2763, -1082, -819, and -592 in the promoter region of the IL10 gene. Due to linkage disequilibrium, the presence of the [TCATA] haplotype can be unequivocally determined by analysis of the IL10-592C>A polymorphism. The purpose of the present study was to investigate a hypothesized association between the haplotype-tagging IL10 -592C>A polymorphism and the presence of retinal artery occlusion (RAO)., Methods: The present case-control study was comprised of 194 patients with RAO and 257 normal control subjects. Genotypes of the IL10 -592C>A polymorphism were determined by fluorogenic exonuclease (TaqMan) assay., Results: Carriers of the IL10 -592A-allele, indicating the presence of the IL10 [TCATA] haplotype, were found significantly more often in controls than among patients with RAO (48.6% versus 36.1%; p=0.008). In a logistic regression analysis after adjusting for age, sex, arterial hypertension, diabetes mellitus, hypercholesterolemia, and smoking habits, carriage of the IL10 -592A-allele was associated with an odds ratio of 0.65 (95% CI: 0.44-0.97) for RAO., Conclusions: Our data suggest that the IL10 [TCATA] haplotype, identified by the presence of the IL10 -592A-allele, may exert a protective effect against RAO.

Nicotine increases serotonin release in the brain and symptoms of nicotine withdrawal may be modulated by diminished serotonergic neurotransmission. The promoter region of the serotonin transporter gene, solute carrier family neurotransmitter transporter member 4 (SLC6A4), contains a functional tandem repeat polymorphism. The long (L) variant is more actively transcribed than the short (S) variant and is associated with a higher serotonin uptake. To investigate the potential role of this polymorphism for smoking behavior, SLC6A4 genotypes were determined in two different studies, the SMOKING GENES case-control study (470 current smokers and 419 subjects who had never smoked) and the cross-sectional Ludwigshafen risk and cardiovascular health (LURIC) study (777 current smokers and 1178 subjects who had never smoked). In the SMOKING GENES case-control study, SLC6A4 genotype frequencies were not statistically different between smokers (LL: 30.9%; LS: 46.8%; SS: 16.4%) and non-smokers (LL: 36.3%; LS: 41.8%; SS: 14.3%; P=0.13). Similar results were obtained in the cross-sectional LURIC study (smokers: LL, 36.5%, LS, 45.6%, SS, 17.9%; non-smokers: LL, 33.6%, LS, 48.9%, SS, 17.6%; P=0.33). SLC6A4 genotypes were furthermore not associated with Fagerstrom Tolerance Questionnaire score, packyears, number of cigarettes smoked per day or previous attempts to quit smoking. We conclude that the SLC6A4 promoter polymorphism is not a major determinant of smoking behavior in Caucasian.

Purpose: Primary open-angle glaucoma (POAG) is a multifactorial optic neuropathy with a strong hereditary component. Recent studies suggested a role for tumour necrosis factor-alpha(TNF-alpha) in the pathogenesis of POAG. The purpose of the present study was to investigate a hypothesized association between the TNF-alpha-308G>A and -238G>A gene polymorphisms and the presence of POAG in a Caucasian population., Methods: The present case-control study comprised 114 unrelated patients with POAG and 228 healthy control subjects, matched for age and gender. Genotyping of the TNF-alpha-308G>A and -238G>A polymorphisms was performed using polymerase chain reaction., Results: Allelic frequencies and genotype distributions of both the TNF-alpha-308G>A and -238G>A gene polymorphisms did not significantly differ between patients with POAG and control subjects. Presence of the TNF-alpha-308A-allele was associated with an odds ratio (OR) of 0.96 for POAG, whereas an OR of 0.52 was found among carriers of the TNF-alpha-238A-allele., Conclusion: Our data suggest that none of the investigated TNF-alphagene polymorphisms is a major risk factor among Caucasian patients with POAG.

Background: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear., Objective: To evaluate the relation between VDR polymorphisms, BMD, and fractures., Design: Prospective multicenter large-scale association study., Setting: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams., Participants: 26,242 participants (18,405 women)., Measurements: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures., Results: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model)., Limitations: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis., Conclusions: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.

The deletion (D) allele of the angiotensin-I converting enzyme (ACE) is associated with higher ACE activity and has been implicated only recently in the pathogenesis of type 2 diabetes in Caucasian subjects. We have studied the ACE I/D polymorphism in 1054 patients with type 2 diabetes and in 2251 individuals without type 2 diabetes in Caucasians persons undergoing coronary angiography. Further parameters of glucose metabolism (fasting glucose, HbA1c, insulin, C-peptide, pro-insulin, and pancreatic beta-cell function) were analyzed according to the ACE I/D genotype in a subgroup of 2000 individuals in whom an oral glucose challenge was performed. The genotypes ACE II, ID, DD occurred at similar frequencies in patients with type 2 diabetes mellitus (21.0, 50.8, and 28.3%, respectively) compared to non-diabetic individuals (23.3, 49.2, and 27.5%, respectively). There was no association of the ACE D allele with all type 2 diabetes mellitus (OR 1.16, 95%CI, 0.94-1.43), nor with known (OR 1.28, 95% CI, 0.99-1.68) or newly diagnosed diabetes (OR 1.00, 95% CI, 0.75-1.32). These findings were not materially altered when we adjusted for age and gender, cardiovascular risk factors and anti-diabetic or cardiovascular medication. Further the ACE D-allele was not associated with angiographic coronary heart disease or myocardial infarction. The ACE I/D genotype is not associated with type 2 diabetes mellitus, glucose metabolism, coronary heart disease, or myocardial infarction.

Purpose: An insertion/deletion (I/D) polymorphism of the gene for angiotensin-converting enzyme (ACE) is associated with higher ACE plasma levels and activity. This enzyme is known to play an important role in blood pressure regulation and the ACE I/D gene polymorphism has been suggested as a risk factor for atherosclerotic vascular diseases. The purpose of the present study was to investigate a hypothesized association between the ACE I/D polymorphism and retinal artery occlusion (RAO)., Methods: A total of 159 patients with RAO and 304 control subjects were enrolled in the present retrospective case-control study. ACE I/D genotypes were determined by polymerase chain reaction., Results: Allelic frequencies and genotype distribution of the ACE I/D polymorphism did not significantly differ between patients and control subjects (ACE DD 25.8% versus 28.0%; p = 0.36). A logistic regression analysis predicted the presence of RAO by arterial hypertension and current smoking status, but not by ACE I/D genotypes., Conclusion: Our data suggest that the ACE I/D polymorphism is not a major risk factor for RAO.

Integrins are cell surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Some of them, e.g. alpha(V)beta(3), alpha(IIb)beta(3) and alpha(2)beta(1), have been suggested as key players for cancer development and tumor metastasis. Two polymorphisms in the gene for the alpha(2) component, ITGA2 807C>T and 1648G>A, have been associated with the cell-surface density of integrin alpha(2)beta(1). The 176T>C polymorphism in the ITGB3 gene, encoding the beta(3) subunit of integrins alpha(IIb)beta(3) and alpha(V)beta(3), modifies a variety of traits of beta(3) expressing cells. To analyze the role of ITGA2 and ITGB3 polymorphisms for breast cancer risk and prognosis, we performed a case-control study including 500 female breast cancer patients and 500 healthy female age-matched control subjects. All study participants were of Caucasian origin (Austria, Middle-Europe). The ITGA2 1648&#95;AA genotype was significantly associated with breast cancer (odds ratio 3.12; 95% confidence interval 1.11-8.77). Carriers of the most common ITGA2 haplotype (807C&#95;1648G, 'wildtype') were at decreased risk for breast cancer (odds ratio 0.72; 95% confidence interval 0.53-0.98). A histological grade of 3 or 4 was found more often in ITGA2 807TT subjects (p=0.039 compared to CC+CT genotypes) and carriers of an ITGA2 1648A allele (p=0.017 compared to GG genotype). Carriers of the ITGA2 807C&#95;1648G haplotype were less likely to have a histological grade 3 or 4 compared to non-carriers (p=0.003). The ITGB3 176T>C polymorphisms was not associated with breast cancer susceptibility. In a Cox-regression analysis, carriers of the homozygous ITGB3 176-CC genotype had a higher risk for metastasis (relative risk 2.3; 95% CI 1.3-4.2; p=0.005). We conclude that functional polymorphisms in integrin genes ITGA2 and ITGB3 influence the development and progression of breast cancer, respectively. The precise mechanism remains to be determined, but likely involves dysregulated signaling pathways.

Purpose: Increased plasma homocysteine levels have been found in patients with primary open angle glaucoma (POAG) and glaucoma secondary to pseudoexfoliation syndrome (PEXG). A common polymorphism of the methylenetetrahydrofolatereductase (MTHFR 677C>T) leads to moderately elevated plasma homocysteine levels particularly under conditions of impaired folate status. It was the aim of this study to investigate a hypothesized association between this polymorphism and the presence of either POAG or PEXG., Methods: The present retrospective case-control study included a total of 553 participants comprising 204 patients with POAG, 138 patients with PEXG, and 211 control subjects. Genotyping for the MTHFR 677C>T polymorphism was performed by polymerase chain reaction (PCR)., Results: No significant difference in the genotype distribution of the MTHFR 677C>T polymorphism was found between control subjects and patients with POAG or PEXG. The prevalence of the MTHFR 677TT genotype was 6.9% in patients with POAG, 11.6% in patients with PEXG, and 9.5% in control subjects., Conclusions: The present data suggest that the MTHFR 677C>T polymorphism itself is not a major genetic risk factor for POAG and PEXG in a central European population.

An association between susceptibility to rheumatoid arthritis (RA) and a common -168A>G polymorphism in the MHC2TA gene with differential major histocompatibility complex (MHC) II molecule expression was recently reported in a Swedish population. The objective of the present study was to replicate this finding by examining the -168A>G polymorphism in an Austrian case-control study. Three hundred and sixty-two unrelated RA cases and 351 sex-matched and age-matched controls as well as 1,709 Austrian healthy individuals were genotyped. All participants were from the same ethnic background. Genotyping was performed using 5' allelic discrimination assays. The association between susceptibility to RA and the -168A>G single nucleotide polymorphism was examined by chi-square test. Comparison was made assuming a dominant effect (AG + GG genotypes versus AA genotype). In contrast to the primary report, the frequency of MHC2TA -168G allele carriers was not significantly different between patients and controls in the Austrian cohort. The homozygous MHC2TA -168 GG genotype was more frequent in matched controls than in Austrian RA patients. There was no association between the presence of RA-specific autoantibodies and the MHC2TA -168 GG genotype. In this cohort of Austrian patients, no association between the MHC2TA polymorphism and RA was found.

Objective: Branch retinal vein occlusion (BRVO) is a common cause of severe visual loss. Numerous risk factors, including arterial hypertension, diabetes mellitus, and arteriosclerosis, have been identified. Gene polymorphisms affecting hemostasis may also play a role in the pathogenesis of BRVO. The present study was therefore done to determine the prevalence of genetic polymorphisms in factors implicated in hypercoagulability among patients with BRVO., Design: Retrospective case-control study., Participants: The study cohort consisted of 294 patients with BRVO and 294 control subjects, matched for age and gender., Methods: Determination of genotypes was done by allele-specific digestion of polymerase chain reaction products, or by 5' exonuclease assay (TaqMan)., Main Outcome Parameters: Genotypes of factor V R506Q (factor V Leiden), prothrombin 20210G>A, fibrinogen beta -455G> A, factor XII (FXII) 46C>T, and ITGA2 807C>T (platelet glycoprotein Ia [GPIa] 807C>T) and ITGB3 L59P (platelet GPIIIa PlA1/PlA2) polymorphisms., Results: Genotype distributions of the investigated gene polymorphisms did not differ significantly between patients and control subjects. In contrast, significantly increased prevalences of arterial hypertension and hypercholesterolemia were found among patients with BRVO. In a logistic regression analysis, the presence of arterial hypertension was associated with an odds ratio (OR) of 2.32 (95% confidence interval [CI], 1.62-3.32), whereas hypercholesterolemia yielded an OR of 2.54 (95% CI, 1.74-3.70) for BRVO., Conclusion: Our data indicate that the prevalences of the investigated gene polymorphisms do not differ significantly in patients with BRVO and control subjects. This suggests that these polymorphisms are not major risk factors for BRVO.

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.

Background and Purpose: Proinflammatory cytokines including interleukin-6 (IL-6) are supposed to play a pivotal role in the development of atherosclerosis. A common polymorphism in the promoter of the IL-6 gene (IL-6 -174G>C) affects plasma IL-6 concentrations and has been suggested as a risk factor for cardiovascular disease. The aim of the present case-control study was to investigate the role of this polymorphism for retinal artery occlusion (RAO)., Methods: One hundred eighty-two patients with RAO and 307 control subjects were genotyped for the IL-6 -174G>C polymorphism. Genotypes were determined by fluorogenic exonuclease (TaqMan) assay., Results: The prevalence of the CC genotype was significantly lower in patients with RAO than in control subjects (10.4% versus 19.9%; P=0.006). Homozygosity for the C allele was associated with an odds ratio of 0.50 (95% CI, 0.28 to 0.89) for RAO., Conclusions: The CC genotype of the IL-6 -174G>C polymorphism may be associated with a protective effect against RAO.

Sulfotransferase 1A1 (SULT1A1), also designated as phenol-preferring sulfotransferase, is involved in the bioactivation and detoxification of a variety of potential carcinogens, including iodothyronines, hydroxylated aromatic amines, and phenolic xenobiotics. A common arginine (R) to histidine (H) polymorphism at amino acid position 213 influences SULT1A1 activity and has been suggested as risk factor for a different types of cancers. To investigate the role of this polymorphism for breast cancer risk, SULT1A1 genotype was determined in 500 women with clinically verified breast cancer and 500 female age-matched healthy control subjects. Frequencies of heterozygous (controls: 42.5% patients: 50.2%) or homozygous (controls: 12.6%; patients: 9.4%) carriers of the 213H variant were not significantly different between groups. The SULT1A1 genotype was furthermore not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. The SULT1A1 213H variant was associated with the presence of lymph node metastases (p = 0.002). We conclude that the SULT1A1 R213H polymorphism is not a general risk factor for breast cancer, but may be involved in lymph node metastazing in breast cancer patients.

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.

The 825C>T polymorphism in the gene for the G-protein beta3 subunit (GNB3) has been linked to the occurrence of a splice variant of GNB3 and distinct cellular and metabolic features and may be associated with malignant disease. 500 patients with histologically confirmed breast cancer and 500 female age-matched healthy control subjects were genotyped for the GNB3 polymorphism to analyze its role for breast cancer. Prevalences of GNB3 CC, CT and TT genotypes were similar among patients (49.7, 39.8, 10.5%) and controls (50.1, 42.4, 7.5%, P = 0.25). The GNB3 genotype was furthermore not linked to tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. In an exploratory analysis, carriage of a 825-T allele was associated with a longer metastasis-free period in patients with primary low-grade breast cancer, but not in those with primary high-grade breast cancer (Cox regression, P = 0.025). We conclude that the GNB3 825C>T polymorphism does not appear to be associated with breast cancer risk, but may influence development of metastasis in low-grade tumors.

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.

Transforming growth factor-beta 1 (TGF-beta1) is a potent inhibitor of proliferation of epithelial, endothelial and hematopoietic cells and acts as a tumor suppressor. The gene for TGF-beta1, TGFB1, carries a common T/C variation of nucleotide 29, resulting in a leucine (L) to proline (P) polymorphism at codon 10 (TGFB1 L10P). The less common 10P allele has repeatedly been linked to higher TGF-beta1 levels and in at least one study to a lower incidence of breast cancer. To further analyze the role of this polymorphism for breast cancer risk, 500 patients with histologically confirmed breast cancer and 500 sex-and age-matched healthy control subjects were genotyped for the TGFB1 L10P polymorphism by an allele-specific polymerase chain reaction assay. TGFB1 LL, LP and PP genotype frequencies were not significantly different for patients (39.6, 44.2, 16.2%) and controls (36.5, 45.9, 17.6%). We conclude that the TGFB1 L10P polymorphism is not associated with breast cancer risk.

Background and Aim of the Study: Genetic variants of the angiotensin-converting enzyme (ACE) cascade may influence left ventricular myocardial mass (LVMM) regression after aortic valve surgery. Postoperative long-term changes in LV indices were investigated in patients with asymptomatic aortic regurgitation (AR) and symptomatic aortic stenosis (AS) and related to alleles of ACE polymorphisms., Methods: A total of 96 patients was included in the study, 21 with class IIa AR (22%) and 75 with class I AS (78%) recommendations for surgery. Patients were evaluated for demographic risk factors and underwent a thorough clinical examination including 3-D cardiac imaging by ultrafast-computed tomography. Genomic DNA was isolated for genotyping., Results: AR patients were younger (55.8 +/- 8.9 versus 64 +/- 9.1 years, p = 0.0014), had a larger body surface area (1.92 +/- 0.21 versus 1.82 +/- 0.19 m2, p = 0.039), and were more likely to be asymptomatic (myocardial infarction, p = 0.04; syncope, p = 0.0099; thromboembolism, p = 0.03; NYHA class IV, p = 0.04). Postoperatively, the reduction in absolute LVMM (from 297.1 +/- 52.6 to 190.1 +/- 57.1 g versus 214.4 +/- 55.7 to 143.8 +/- 40.0 g; pT = 0.0000001) and indexed LVMM (from 156.0 +/- 31.7 to 99.3 +/- 28.4 g/m2 versus 118.7 +/- 28.3 to 79.3 +/- 20.6 g/m; pT = 0.0000001) over time was more significant in AR patients, but never reached normal values. Enforced ACE inhibitor medication resulted in significantly higher postoperative indexed LVMM differences in homozygote DD patients compared to AR patients with II/ID alleles of ACE 16 ins/del polymorphism., Conclusion: AR patients showed a statistically significant decrease in absolute/indexed LVMM during follow up, but never achieved LV mass recovery compared to standard values or to values in patients undergoing aortic valve replacement for AS. The benefits of ACE inhibitors were observed among AR patients with homozygote DD alleles of ACE 16 ins/del polymorphism.

A common 936 C/T polymorphism in the gene for the vascular endothelial growth factor (VEGF) has been associated with VEGF plasma levels. In our case-control study, we investigated the role of this polymorphism for breast cancer risk. VEGF genotype was determined in 500 women with breast cancer and 500 sex- and age-matched healthy control subjects. Carriers of a 936T-allele were more frequent among controls (29.4%) than among patients (17.6%; p = 0.000014). The odds ratio for carriers of a 936T-allele for breast cancer was 0.51 (95% confidence interval 0.38-0.70). Additionally, VEGF plasma levels were determined in 21 nonsmoking post-menopausal controls; carriers of a 936T allele had significantly lower levels (median 23 pg/ml; range 6-50 pg/ml) than noncarriers (37; 21-387; p = 0.034). We conclude that carriers of a VEGF 936T-allele are at decreased risk for breast cancer, this, however, requiring further confirmation in a larger study., (Copyright 2003 Wiley-Liss, Inc.)

Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and plays a role in DNA biosynthesis, methylation, and repair in actively dividing cells. A common 677C>T polymorphism in the gene for MTHFR, leading to a thermolabile enzyme with decreased activity, has been associated with reduced plasma folate levels and elevated homocysteine levels and could be a risk factor for breast cancer. In the present case-control study, MTHFR genotype was determined in 500 women with clinically verified breast cancer and 500 female age-matched healthy control subjects. The homozygous TT genotype was found in 13.0% patients and 13.1% controls (P = n.s.). The odds ratio of TT homozygotes for breast cancer was 0.99 (95% confidence interval 0.68-1.43). The MTHFR genotype was furthermore not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. In a subgroup of 116 premenopausal patients, no increased frequency of the homozygous 677T genotype was found (13.8%). Therefore, we conclude that the MTHFR 677C>T polymorphism is not associated with individual susceptibility to breast cancer.

Background and Purpose: The C825T dimorphism of the gene encoding the human G protein beta3 subunit (GNB3) is associated with hypertension and obesity. Although these findings suggest an association with insulin resistance and atherosclerosis, this hypothesis has yet been tested only partially., Methods: To investigate this hypothesis, the C825T dimorphism was determined in a population of 932 middle-aged white subjects of middle European (Austrian) origin. Insulin sensitivity was measured with the short insulin tolerance test; intima-media thickness of the carotid artery and morphological plaque burden were measured by ultrasound., Results: Insulin sensitivity was found to be significantly lower in carriers of the T allele (3.55+/-1.27 versus 3.92+/-1.30%/min, P=0.012) in the group of male subjects with abdominal body fat distribution (waist-to-hip ratio >0.9). No effect was observed in women or men with a waist-to-hip ratio <0.9. Advanced carotid artery plaques were more frequent (odds ratio, 1.606; 95% confidence interval, 1.002 to 2.575; P=0.04) in carriers of the T allele regardless of sex. No effect was observed with regard to carotid artery intima-media thickness., Conclusions: In summary, our results demonstrate that the GNB3 825T allele is associated with reduced insulin sensitivity in men with abdominal fat distribution and with more advanced carotid atherosclerosis in middle-aged white men and women.

Objective: CX(3)CR1 is a novel chemokine receptor located on monocytes. Recently, two polymorphisms were linked to coronary artery disease (CAD), V249I and T280M. Carriers of at least one I-allele or one M-allele were found less frequently among patients with CAD compared to controls. The aim of the present study was to investigate the influence of these polymorphisms on the development of peripheral arterial disease (PAD)., Methods: 522 human subjects with documented PAD and 522 age and sex matched controls were genotyped by polymerase chain reaction followed by restriction digestion., Results: Adjusted odds ratio (OR) of carriers of the I-allele for PAD was 1.34 (95% confidential interval (CI) from 0.86 to 2.09; P=0.19). The OR associated with the M-allele for PAD was 0.65 (95% CI from 0.41 to 1.04; P=0.07), when tested in the same regression analysis with the V249I genotypes. The genotypes were not linked to age at onset or severity of the disease. A subgroup of 137 CAD patients of whom 131 could be genotyped and who did not differ in baseline parameters from the remaining PAD patients, showed VV-genotype in 52.0%, VI in 42.7% and II in 5.3% CAD (OR associated with the I-allele for CAD: 1.29; 95% CI: 0.66-2.51; P=0.46). The distribution of the T280M genotypes was 67.1, 29.8, 3.1% (TT, TM, MM) also showing no association with CAD (OR=0.77; 95% CI 0.36-1.46; P=0.37)., Conclusion: In this study we could not detect a difference in genotype frequencies of the V249I and T280M polymorphisms in CX(3)CR1 between PAD patients and controls. CAD concomitant with PAD was also not affected by the I- or the M-allele.

Background: An 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 atherosclerotic vascular disease. The aim of the present study was to analyze the role of this polymorphism for peripheral arterial disease (PAD)., Methods: The study was designed as a case-control study including 522 patients with documented PAD and 522 sex- and age-matched controls. ACE genotype was determined by size-analysis of polymerase chain reaction products., Results: ACE genotype frequencies were similar between patients (II: 23.4%; ID: 44.8%; DD: 31.8%) and controls (II: 23.8%; ID: 48.3%; DD: 27.9%, P=0.37). The adjusted odds ratio of carriers of the DD genotype for PAD was 1.29 (95% confidence interval 0.95-1.75). The polymorphism was furthermore not associated with age at onset of PAD (P=0.56), Fontaine stage of the disease (P=0.68) or ankle/brachial index of patients (P=0.86)., Conclusion: The ACE I/D polymorphism is not a significant risk factor for PAD.