Associations of the beta-fibrinogen Hae III and factor XIII Val34Leu gene variants with venous thrombosis

INTRODUCTION: The factor XIII Val34Leu (100 G-->T) and beta-fibrinogen Hae III (-455 G-->A) gene variants have been associated with reduced risk of venous thrombosis, but not in all studies. METHODS: We investigated the associations of these polymorphisms with risk of venous thrombosis in a prospective, population-based study of 21,680 men and women aged 45-100 years at enrollment. Factor XIII 100 G/T and beta-fibrinogen -455 G/A were analyzed on stored DNA from 511 thrombosis cases and 1028 control subjects without thrombosis during follow up. RESULTS: The beta-fibrinogen A allele was present in 24.4% of cases and 32.3% of controls. Compared to GG subjects, the age, race, and sex adjusted odds ratio (OR) of venous thrombosis was 0.77 (95% CI 0.59-0.99) for GA subjects, and 0.60 (95% CI 0.31-1.16) for AA subjects. The adjusted OR of thrombosis associated with factor XIII 100 G/T was 1.01 (95% CI 0.81-1.26) for GT subjects and 0.45 (95% CI 0.44-1.19) for TT subjects, compared to GG. For both genotypes, ORs of thrombosis were similar in whites and non-whites, although there were no non-white fibrinogen AA cases. beta-fibrinogen -455 GA or AA attenuated the thrombosis risk associated with obesity (from 2.14 to 1.25) and factor V Leiden (from 3.89 to 2.36). CONCLUSIONS: beta-fibrinogen -455 G/A, but not factor XIII 100 G/T, was associated with a lower risk of venous thrombosis in this general population sample. beta-fibrinogen -455 A may attenuate the increased thrombosis risk associated with obesity or factor V Leiden.     

Psychosocial factors and inflammation in the multi-ethnic study of atherosclerosis

BACKGROUND: Psychosocial factors are associated with the development and progress of cardiovascular disease, but the pathological mechanisms remain unclear. We examined the associations of psychosocial risk factors for cardiovascular disease with concentrations of inflammatory markers among healthy adults and assessed the extent to which these associations are mediated by behaviors, body mass index (BMI), and diabetes mellitus. METHODS: This cross-sectional study used data from the baseline examination of the Multi-Ethnic Study of Atherosclerosis, a multisite study of 6814 men and women aged 45 to 84 years. Regression analyses were used to estimate associations of cynical distrust, chronic stress, and depression with serum levels of C-reactive protein, IL-6, and fibrinogen before and after adjustment for socioeconomic position, behaviors, BMI, and diabetes. RESULTS: Higher levels of cynical distrust were associated with higher levels of inflammatory markers. The percentage differences (95% confidence intervals [CIs]) comparing the 80th and 20th percentiles of the scale were 7% (3%-11%) for IL-6; 9% (2%-16%) for C-reactive protein; and 1.3% (0.1%-2.4%) for fibrinogen. Higher levels of chronic stress were associated with higher concentrations of IL-6 and C-reactive protein. The percentage differences (95% CIs) comparing 2 and 0 ongoing stressful circumstances were 4% (1%-8%) for IL-6 and 5% (1%-11%) for C-reactive protein. Depression was positively associated with the level of IL-6 (percentage difference [95% CI] comparing the Center for Epidemiologic Studies-Depression Scale scores of >or=21 vs <21 was 7% [1%-14%]). Associations of psychosocial factors with inflammatory markers were reduced by 20% to 55% after adjustment for behavioral factors and by 45% to 100% after adjustment for BMI and diabetes, mostly owing to the effect of BMI. No associations remained after controlling for socioeconomic position, behaviors, BMI, and diabetes. CONCLUSIONS: Psychosocial factors are associated with higher levels of inflammatory markers, most consistently for cynical distrust. Results are compatible with a mediating role of BMI, behaviors, and diabetes.     

Synthesis and cancer chemopreventive activity of zapotin, a natural product from Casimiroa edulis

An efficient method has been developed to synthesize zapotin (5,6,2',6'-tetramethoxyflavone), a component of the edible fruit Casimiroa edulis, on a multigram scale. The synthesis utilizes a regioselective C-acylation of a dilithium dianion derived from a substituted o-hydroxyactophenone to afford a beta-diketone intermediate that can be cyclized to zapotin in good overall yield, thus avoiding the inefficient Baker-Venkataraman rearrangement pathway. Zapotin was found to induce both cell differentiation and apoptosis with cultured human promyelocytic leukemia cells (HL-60 cells). In addition, the compound inhibits 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity with human bladder carcinoma cells (T24 cells), and TPA-induced nuclear factor-kappa B (NF-kappaB) activity with human hepatocellular liver carcinoma cells (HepG2 cells). These data suggest that zapotin merits further investigation as a potential cancer chemopreventive agent.