A role for CETP TaqIB polymorphism in determining susceptibility to atrial fibrillation: a nested case control study

BACKGROUND: Studies investigating the genetic and environmental characteristics of atrial fibrillation (AF) may provide new insights in the complex development of AF. We aimed to investigate the association between several environmental factors and loci of candidate genes, which might be related to the presence of AF. METHODS: A nested case-control study within the PREVEND cohort was conducted. Standard 12 lead electrocardiograms were recorded and AF was defined according to Minnesota codes. For every case, an age and gender matched control was selected from the same population (n = 194). In addition to logistic regression analyses, the multifactor-dimensionality reduction (MDR) method and interaction entropy graphs were used for the evaluation of gene-gene and gene-environment interactions. Polymorphisms in genes from the Renin-angiotensin, Bradykinin and CETP systems were included. RESULTS: Subjects with AF had a higher prevalence of electrocardiographic left ventricular hypertrophy, ischemic heart disease, hypertension, renal dysfunction, elevated levels of C-reactive protein (CRP) and increased urinary albumin excretion as compared to controls. The polymorphisms of the Renin-angiotensin system and Bradykinin gene did not show a significant association with AF (p > 0.05). The TaqIB polymorphism of the CETP gene was significantly associated with the presence of AF (p < 0.05). Using the MDR method, the best genotype-phenotype models included the combination of micro- or macroalbuminuria and CETP TaqIB polymorphism, CRP >3 mg/L and CETP TaqIB polymorphism, renal dysfunction and the CETP TaqIB polymorphism, and ischemic heart disease and CETP TaqIB polymorphism (1000 fold permutation testing, P < 0.05). Interaction entropy graph showed that the combination of albuminuria and CETP TaqIB polymorphism removed the most entropy. CONCLUSION: CETP TaqIB polymorphism is significantly associated with the presence of AF in the context of micro- or macroalbuminuria, elevated C-reactive protein, renal dysfunction, and ischemic heart disease

Cardiovascular Risk Associated with Interactions among Polymorphisms in Genes from the Renin-Angiotensin, Bradykinin, and Fibrinolytic Systems

Vascular fibrinolytic balance is maintained primarily by interplay of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1). Previous research has shown that polymorphisms in genes from the renin-angiotensin (RA), bradykinin, and fibrinolytic systems affect plasma concentrations of both t-PA and PAI-1 through a set of gene-gene interactions. In the present study, we extend this finding by exploring the effects of polymorphisms in genes from these systems on incident cardiovascular disease, explicitly examining two-way interactions in a large population-based study

Targets of the Entamoeba histolytica Transcription Factor URE3-BP

The Entamoeba histolytica transcription factor Upstream Regulatory Element 3-Binding Protein (URE3-BP) is a calcium-responsive regulator of two E. histolytica virulence genes, hgl5 and fdx1. URE3-BP was previously identified by a yeast one-hybrid screen of E. histolytica proteins capable of binding to the sequence TATTCTATT (Upstream Regulatory Element 3 (URE3)) in the promoter regions of hgl5 and fdx1. In this work, precise definition of the consensus URE3 element was performed by electrophoretic mobility shift assays (EMSA) using base-substituted oligonucleotides, and the consensus motif validated using episomal reporter constructs. Transcriptome profiling of a strain induced to produce a dominant-positive URE3-BP was then used to identify additional genes regulated by URE3-BP. Fifty modulated transcripts were identified, and of these the EMSA defined motif T[atg]T[tc][cg]T[at][tgc][tg] was found in over half of the promoters (54% p<0.0001). Fifteen of the URE3-BP regulated genes were potential membrane proteins, suggesting that one function of URE3-BP is to remodel the surface of E. histolytica in response to a calcium signal. Induction of URE3-BP leads to an increase in tranwell migration, suggesting a possible role in the regulation of cellular motility

Apolipoprotein A-II Influences Apolipoprotein E-Linked Cardiovascular Disease Risk in Women with High Levels of HDL Cholesterol and C-Reactive Protein

Background: In a previous report by our group, high levels of apolipoprotein E (apoE) were demonstrated to be associated with risk of incident cardiovascular disease in women with high levels of C-reactive protein (CRP) in the setting of both low (designated as HR1 subjects) and high (designated as HR2 subjects) levels of high-density lipoprotein cholesterol (HDL-C). To assess whether apolipoprotein A-II (apoA-II) plays a role in apoE-associated risk in the two female groups. Methodology/Principal: Outcome event mapping, a graphical data exploratory tool; Cox proportional hazards multivariable regression; and curve-fitting modeling were used to examine apoA-II influence on apoE-associated risk focusing on HDL particles with apolipoprotein A-I (apoA-I) without apoA-II (LpA-I) and HDL particles with both apoA-I and apoA-II (LpA-I:A-II). Results of outcome mappings as a function of apoE levels and the ratio of apoA-II to apoA-I revealed within each of the two populations, a high-risk subgroup characterized in each situation by high levels of apoE and additionally: in HR1, by a low value of the apoA-II/apoA-I ratio; and in HR2, by a moderate value of the apoA-II/apoA-I ratio. Furthermore, derived estimates of LpA-I and LpA-I:A-II levels revealed for high-risk versus remaining subjects: in HR1, higher levels of LpA-I and lower levels of LpA-I:A-II; and in HR2 the reverse, lower levels of LpA-I and higher levels of LpA-I:A-II. Results of multivariable risk modeling as a function of LpA-I and LpA-I:A-II (dichotomized as highest quartile versus combined three lower quartiles) revealed association of risk only for high levels of LpA-I:A-II in the HR2 subgroup (hazard ratio 5.31, 95% CI 1.12-25.17, p = 0.036). Furthermore, high LpA-I: A-II levels interacted with high apoE levels in establishing subgroup risk. Conclusions/Significance: We conclude that apoA-II plays a significant role in apoE-associated risk of incident CVD in women with high levels of HDL-C and CRP

Dusty Punch Cards and an Eternal Enigma: High-Density Lipoproteins and Atherosclerosis

Epidemiological, clinical, and experimental evidence has accumulated during the last decades suggesting that high-density lipoproteins (HDLs) may protect from atherosclerosis and its clinical consequences. However, more than 55 years after the first description of the link between HDL and heart attacks, many facets of the biochemistry, function, and clinical significance of HDL remain enigmatic. This applies particularly to the completely unexpected results that became available from some recent clinical trials of nicotinic acid and of inhibitors of cholesteryl ester transfer protein (CETP). The concept that raising HDL cholesterol by pharmacological means would decrease the risk of vascular disease has therefore been challenged

Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin : cholesterol acyltransferase and lipid transfer proteins

Insulin resistance and type 2 diabetes mellitus are generally accompanied by low HDL cholesterol and high plasma triglycerides, which are major cardiovascular risk factors. This review describes abnormalities in HDL metabolism and reverse cholesterol transport, i.e. the transport of cholesterol from peripheral cells back to the liver for metabolism and biliary excretion, in insulin resistance and type 2 diabetes mellitus. Several enzymes including lipoprotein lipase (LPL), hepatic lipase (HL) and lecithin: cholesterol acyltransferase (LCAT), as well as cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), participate in HDL metabolism and remodelling. Lipoprotein lipase hydrolyses lipoprotein triglycerides, thus providing lipids for HDL formation. Hepatic lipase reduces HDL particle size by hydrolysing its triglycerides and phospholipids. A decreased postheparin plasma LPL/HL ratio is a determinant of low HDL2 cholesterol in insulin resistance. The esterification of free cholesterol by LCAT increases HDL particle size. Plasma cholesterol esterification is unaltered or increased in type 2 diabetes mellitus, probably depending on the extent of triglyceride elevation. Subsequent CETP action results in transfer of cholesteryl esters from HDL towards triglyceride-rich lipoproteins, and is involved in decreasing HDL size. An increased plasma cholesteryl ester transfer is frequently observed in insulin-resistant conditions, and is considered to be a determinant of low HDL cholesterol. Phospholipid transfer protein generates small pre beta-HDL particles that are initial acceptors of cell-derived cholesterol. Its activity in plasma is elevated in insulin resistance and type 2 diabetes mellitus in association with high plasma triglycerides and obesity. In insulin resistance, the ability of plasma to promote cellular cholesterol efflux may be maintained consequent to increases in PLTP activity and pre beta-HDL. However, cellular cholesterol efflux to diabetic plasma is probably impaired. Besides, cellular abnormalities that are in part related to impaired actions of ATP binding cassette transporter 1 and scavenger receptor class B type I are likely to result in diminished cellular cholesterol efflux in the diabetic state. Whether hepatic metabolism of HDL-derived cholesterol and subsequent hepatobiliary transport is altered in insulin resistance and type 2 diabetes mellitus is unknown. Specific CETP inhibitors have been developed that exert major HDL cholesterol-raising effects in humans and retard atherosclerosis in animals. As an increased CETP-mediated cholesteryl ester transfer represents a plausible metabolic intermediate between high triglycerides and low HDL cholesterol, studies are warranted to evaluate the effects of these agents in insulin resistance- and diabetes-associated dyslipidaemia

Type 2 diabetes mellitus is associated with differential effects on plasma cholesteryl ester transfer protein and phospholipid transfer protein activities and concentrations

Human plasma contains two lipid transfer proteins, cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), which are crucial in reverse cholesterol transport. Plasma CETP and PLTP activity levels and concentrations in 16 type 2 diabetic patients and 16 matched healthy subjects were determined, and these data were correlated to clinical variables, including insulin sensitivity and lipid levels. Plasma triglycerides were higher (p <0.02) and high-density lipoprotein (HDL) cholesterol (p <0.02) was lower in diabetic patients. Plasma CETP activity and concentrations were not significantly different between diabetic and healthy subjects, but CETP specific activity was lower in diabetic patients (p <0.001). Multiple regression analysis showed that plasma CETP activity was positively related to CETP concentration (p=0.0001) and negatively to the diabetic state (p <0.002) or to HbA1c (p <0.02). PLTP activity (p <0.05) and specific activity were higher (p <0.05), whereas there was no difference in PLTP concentration between the two groups. There was no significant bivariate correlation between PLTP concentration and activity, in either healthy or diabetic subjects. Multiple regression analysis did disclose positive relationships of PLTP activity with PLTP concentration (p=0.0001), plasma triglycerides (p=0.0001) and waist/hip ratio (p=0.0001), but not with the diabetic state or HbA1c. Neither CETP nor PLTP activity was independently associated with insulin sensitivity. Specific CETP activity is decreased in type 2 diabetes mellitus. In contrast, specific PLTP activity is higher in diabetes, as a result of the association of plasma PLTP activity with plasma triglycerides and obesity. Measurement of both plasma lipid transfer protein activity and mass levels may thus provide extra information in diabetes mellitu