Maria Carmela Latella

Association of polymorphism (Val66Met) of brain-derived neurotrophic factor with suicide attempts in depressed patients

Introduction: Recent post-mortem studies of suicide victims have implicated brain-derived neurotrophic factor (BDNF) in suicide. Therefore, it was decided to examine the possible role of a gene in the regulation of BDNF activity in relation to suicidal behaviour among depressed patients. Method: A series of 170 depressed patients were evaluated for their history of suicide attempts and genotyped for the BDNF Val66Met polymorphism (SNP ID: rs6265). Depressed patients who had (n = 97) or had not (n = 73) attempted suicide were compared. Results: Depressed patients who carried the BDNF Val66Met polymorphism variant (GA + AA) appeared to show a significantly increased risk of suicidal behaviour. The risk of a suicide attempt was also significantly higher among those reporting higher levels of childhood emotional, physical and sexual abuse. Secondary analyses suggested that depression severity was a significant risk factor only in the wild-type BDNF genotype, and that the risk of suicide attempts was more predictable within the wild-type group. Conclusion: These preliminary data suggest that BDNF may play a role in the suicidal behaviour of depressed patients.

Nutrigenomics: a case for the common soil between cardiovascular disease and cancer.

The border between health and disease is often set by a complex equilibrium between two elements, genetics on one hand, lifestyle on the other, To know it better, means to give new weapons, often crucial, in the hands of the doctors and their patients. It also means to adjust therapies, to find out which drug is good for a patient and which prevention strategy will work better for him/her. Nutrigenomics is an approach to individualize or personalize food and nutrition, and ultimately health, by tailoring the food to the individual genotype. In this review, we present the interaction between certain genetic polymorphisms and diet and increased cardiovascular or cancer risk. It is, indeed, now clear that a large number of bioactive food components may provide risk or protection at several stages of both atherosclerosis and cancer formation processes. We are giving here few examples of gene-food interactions relevant for both the risk of cardiovascular disease and cancer, since a common soil could exist in the genesis of cardiovascular disease and of some types of cancer (mainly gastrointestinal tract and hormone-dependent).

Paclitaxel downregulates tissue factor in cancer and host tumour-associated cells

Paclitaxel, a microtubule-stabilising compound with potent anti-tumour activity, has been clinically used in a wide variety of malignancies. Tissue factor (TF) is often expressed by tumour-associated endothelial and inflammatory cells, as well as by cancer cells themselves, and it is considered a hallmark of cancer progression. We investigated whether paclitaxel could modulate TF in human mononuclear (MN) cells, human umbilical vein endothelial cells (HUVEC) and the metastatic breast carcinoma cell line MDA-MB-231. Cells were incubated with or without paclitaxel at 37 degrees C. At the end of incubation, cells were disrupted and tested for procoagulant activity by a one-stage clotting assay, for TF antigen levels by ELISA and TF mRNA by real-time RT-PCR. IL-6 and IL-1beta were tested by ELISA in conditioned medium. Both the strong TF activity and antigen constitutively expressed by MDA-MB-231 and the TF induced by LPS, TNF-alpha and IL-1beta in MN cells and HUVEC were significantly reduced by paclitaxel. In the presence of paclitaxel, lower TF mRNA levels were also detected. Since paclitaxel has been shown to induce the expression of inflammatory genes in monocytes and tumour cells, we tested whether paclitaxel could influence IL-6 and IL-1beta release from the cells used in this paper. Neither the constitutive expression of IL-6 and IL-1beta by MDA-MB-231 nor the basal and LPS-induced release from MN cells and HUVEC was affected. Our data support the hypothesis that the anti-tumour effects of paclitaxel may, at least in part, be mediated by the capacity of this drug to modulate the procoagulant potential of cancer and host cells.

Interleukin 1 Gene Cluster, Myocardial Infarction at Young Age and Inflammatory Response of Human Mononuclear Cells

The objective was to investigate whether genotypes, haplotypes and haplotype-pairs of interleukin (IL) gene cluster are associated with risk of Myocardial Infarction (MI) at young age and with the release of IL-1B and expression of tissue factor pro-coagulant activity (TFPCA), after stimulation in vitro with lipopolysaccharide (LPS) of human peripheral blood mononuclear cells (PBMCs). Patients with MI at young age, frequency-matched for age, sex and recruitment centre, with healthy population-based controls and PBMCs from healthy volunteers were studied. Five single nucleotide polymorphisms (SNPs), identifying two haplotype-blocks, in IL-1B gene and one SNP in IL-1A and IL-RA genes were genotyped. In multivariate analyses, haplotype A2 (122) and A4 (112) were associated with decreased risk of MI [OR = 0.62 (95% CI = 0.40–0.95), p = 0.01; OR = 0.69 (95% CI = 0.51–0.92), p = 0.03, respectively]. Haplotype-pair A2/A2 showed significant reduction in the risk of MI [OR = 0.38 (95% CI = 0.18–0.81); p = 0.01]. Haplotype A2 and A4 were associated with lower levels of IL-1B (respectively p = 0.01; p = 0.04, multivariate analysis) and haplotype-pair A2/A4 showed decreased levels of IL-1beta (p = 0.02). No association was found between block “B” IL-1B haplotypes or IL-1A and IL-RA polymorphisms and risk of MI. IL-1B haplotypes influence the inflammatory response of human mononuclear cells to LPS and affect the risk of MI at young age.

Tissue factor gene polymorphisms and haplotypes and the risk of ischemic vascular events: four studies and a meta-analysis.

Summary  Objective: The exposure of tissue factor (TF) to blood flow is the initial step in the coagulation process and plays an important role in thrombogenesis. We investigated the role of genetic polymorphisms and haplotypes of the TF gene in the risk of ischemic vascular disease. Methods: Four hundred and twenty‐two Italian patients with juvenile myocardial infarction (MI) and 434 controls, 808 US cases with MI and 1005 controls, 267 Italian cases with juvenile ischemic stroke and 209 controls and 148 German cases with juvenile ischemic stroke and 191 controls were studied. rs1361600, rs3917629 (rs3354 in the US population), rs1324214 and rs3917639 Tag single nucleotide polymorphisms were genotyped. Additionally, a meta‐analysis of all previous studies on TF loci and the risk of ischemic coronary disease (ICD) was performed. Results: After multivariable analysis none of the SNPs, major SNP haplotypes or haplotype‐pairs showed any consistent association with MI. Pooled meta‐analysis of six studies also suggested that TF polymorphisms are not associated with CHD. A significant, independent association between SNP rs1324214 (C/T) and juvenile stroke was found in Italian and German populations (OR for TT homozygotes = 0.47, 95% CI 0.24–0.92, in combined analysis). Pooled analysis also showed a significant association for haplotype H3 (OR = 0.76, 95% CI 0.57–1.00) and haplotype‐pair H3–H3 (OR = 0.43, 95% CI 0.20–0.92). Conclusions: TF genetic variations were associated with the risk of ischemic stroke at young age, but did not affect ischemic coronary disease.

Leptin upregulates tissue factor expression in human breast cancer MCF-7 cells

INTRODUCTION Obesity is a risk factor for both cardiovascular disease and cancer development. Leptin, a cytokine produced by adipose tissue, controls different processes in peripheral tissues, including cancer development and thrombotic disorders in patients with a variety of clinical disorders. Tissue factor (TF), the trigger of blood clotting, is abundant in the adipose tissue. Since TF, often expressed by cancer cells, is considered a hallmark of cancer progression, we investigated whether leptin could modulate TF in the human metastatic breast carcinoma cell line MCF-7. MATERIALS AND METHODS MCF-7 cells were incubated with or without the different reagents at 37 °C. At the end of incubation, cells were tested for procoagulant activity by a one-stage clotting assay, TF and TNF-α antigen levels and mRNA by ELISA and real-time RT-PCR, respectively. Leptin receptor was studied by FACS. RESULTS Both TF activity and antigen constitutively expressed by MCF-7 were significantly increased by leptin in a dose-dependent fashion. TF mRNA levels were also enhanced indicating that leptin exerts its effect at the transcription level. The effect of leptin was specific and required binding to its receptor (Ob-R), which was found on the surface of the cells, since antibodies against leptin and Ob-R completely prevented TF expression upregulation. In addition, leptin enhanced both TNF-α mRNA synthesis and secretion from MCF7. An anti-TNF-α MoAb completely abolished the leptin-induced TF expression. CONCLUSIONS These data support the hypothesis that leptin, by its upregulation of TF, possibly mediated by TNF-α synthesis, may contribute to processes underlying both cancer and vascular cell disorders.

Genetic variation of alcohol dehydrogenase type 1C (ADH1C), alcohol consumption, and metabolic cardiovascular risk factors: Results from the IMMIDIET study

INTRODUCTION Moderate alcohol consumption is protective against cardiovascular disease (CAD). ADHs are major enzymes of alcohol metabolism. A polymorphism in the alcohol dehydrogenases 1C gene (ADH1C) was reportedly associated with the protective effect of alcohol consumption on CAD risk and risk factor levels. AIMS The aim of our study was to investigate whether the association of alcohol consumption with metabolic risk factors for CAD is related to ADH1C variants. METHODS IMMIDIET is a cross-sectional study of 974 healthy male-female pairs living together, randomly recruited in Belgium, Italy and England. The rs698 ADH1C polymorphism was genotyped. A 1-year recall food frequency questionnaire was used to estimate alcohol intake. RESULTS The intake of alcohol did not vary in relation to ADH1C genotypes. BMI, waist circumference (WC), waist-to-hip ratio, blood pressure, HDL or total cholesterol, triglycerides and FVII:ag levels were positively associated with alcohol intake in men (multivariate ANOVA). Regression coefficient for alcohol and BMI or WC was progressively higher in heterozygotes and gamma 2 homozygotes as compared to gamma 1 homozygotes (p=0.006 and p=0.03 for interaction, respectively). No interaction was found for other risk factors. In women, alcohol intake was positively associated with HDL, LDL and FVII:ag levels but no interaction was found between ADH1C polymorphism and any risk factor. CONCLUSION Regulation of ADH1C genotype on the association between alcohol consumption, BMI and WC was found in men from different European countries. In men homozygous for the gamma 2 alleles, intake of alcohol was positively associated with both BMI and WC values.

Polymorphisms in chromosome 9 and risk of ischemic stroke in two European white populations, and a meta-analysis.

A. D I CASTELNUOVO,* A . PEZZ IN I , M. C . LATELLA ,* C . L ICHY and L . IACOVIELLO* *Laboratory of Genetic and Environmental Epidemiology, Research Laboratories, John Paul II Centre for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso; Dipartimento di Scienze Mediche e Chirurgiche, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italy; and Department of Neurology, University of Heidelberg, Heidelberg, Germany