Polymorphisms of extrinsic death receptor apoptotic genes (FAS −670 G>A,FASL −844 T>C) in coronary artery disease

Apoptosis plays an important role in atherogenesis and rupture of vulnerable plaques in coronary artery disease. FAS and FAS ligand (FASL) induce apoptosis when FAS binds to FAS-L. However sFas blocks apoptosis by binding to FAS and FASL or sFasL. The present study is sought to examine the role of extrinsic apoptotic genes (FAS, FASL) polymorphism and serum levels of FAS, FASL in the pathogenesis and susceptibility to CAD in south Indian population. The study included 300 CAD patients and 300 healthy controls. Lipid profiles, sFas, sFasL were estimated by commercially available kits. FAS ?670 G>A, FASL ?844 T>C genotypes were analyzed by PCR–RFLP. Secondary structures of pre mRNA were analyzed by the Vienna RNA webserver and gene–gene and gene–environment interactions were determined by MDR analysis. Total cholesterol, triglyceride and LDL levels were significantly high in CAD patients compared to the controls. Molecular analysis revealed that the frequency of the AA genotype of FAS (54 % vs 27 %) and CC genotypes of FASL (10.3 % vs 1.3 %) were high in CAD patients compared to controls. Secondary structure analysis of FAS and FASL confirmed our molecular analysis. sFas levels were low while serum sFasL were high in CAD patients. MDR analysis revealed synergistic effects of gene polymorphisms and additive effects of epidemiological factors on risk of CAD. Polymorphisms of FAS (?670 G/A), FASL (?844 T/C) and their circulating levels play an important role in the pathology of CAD.     

Association of β-fibrinogen gene −148C/T and −455G/A polymorphisms and coronary artery disease in Chinese population: A Meta analysis

The purpose of our study was to evaluate the correlation between the β-fibrinogen gene −148C/T and −455G/A polymorphisms and susceptibility to coronary artery disease in the Chinese population using a meta-analytic approach. Eligible studies about this correlation were identified by searching the PubMed, EMBASE, and CNKI databases. Of the 13 identified, 7 (with 1488 cases and 1234 controls) involved the −148C/T polymorphism and 9 (with 1023 cases and 1081 controls) involved the −455G/A polymorphism. No publication bias was detectable and heterogeneity testing found significant differences between the ORs for both groups of studies. The combined OR for the 7 studies on susceptibility to coronary artery disease in −148T allele carriers compared to the −148C/C wild-type homozygotes was 1.31 (95%CI: 0.94–1.84, P=0.11). The combined OR for the 9 studies on susceptibility to coronary artery disease in −455A allele carriers compared to the −455G/G wild-type homozygotes was 1.75 (95%CI: 1.24–2.46, P=0.001). Our results suggest the absence of an association between the β-fibrinogen gene −148C/T polymorphism and susceptibility to coronary artery disease and the possibility that −455G/A polymorphism (in particular, allele A) increases susceptibility to this disease in the Chinese population.     

Apo A5 −1131T/C, FgB −455G/A, −148C/T, and CETP TaqIB gene polymorphisms and coronary artery disease in the Chinese population: a meta-analysis of 15,055 subjects

The Apolipoprotein A5 (APO A5) ?1131T/C, fibrinogen β (FgB) ?455G/A, ?148C/T, and cholesteryl ester transfer protein (CETP) TaqIB gene polymorphisms have been indicated to be associated with the coronary artery disease (CAD) risk, but the individual study results are still inconsistent. To explore the relationship between APO A5 ?1131T/C, FgB ?455G/A, ?148C/T, and CETP TaqIB gene polymorphisms and CAD in the Chinese population, the current meta-analysis involving 15,055 subjects from 40 individual studies was conducted. The pooled odds ratio (OR) for the association between APO A5 ?1131T/C, FgB ?455G/A, ?148C/T, and CETP TaqIB gene polymorphisms and CAD and its corresponding 95 % confidence interval (95 % CI) were evaluated by random or fixed effect model. A significant association between APO A5 ?1131T/C gene polymorphism and CAD in the Chinese population was found under an allelic (OR: 1.33, 95 % CI: 1.22–1.44, P < 0.00001), recessive (OR: 1.67, 95 % CI: 1.25–2.25, P = 0.0006), dominant (OR: 0.820, 95 % CI: 0.767–0.876, P = 1.0 × 10^?10), homozygous (OR: 2.36, 95 % CI: 1.55–3.58, P < 0.0001) and heterozygous genetic models (OR: 1.136, 95 % CI:1.075–1.200, P = 1.0 × 10^?10). A significant association between FgB ?455G/A gene polymorphism and CAD was also detected in the Chinese population under an allelic (OR: 1.50, 95 % CI: 1.25–1.81, P < 0.0001), dominant (OR: 0.864, 95 % CI: 0.819–0.912, P = 1.0 × 10^?10), homozygous (OR: 1.616, 95 % CI: 1.213–2.152, P = 0.001) and heterozygous genetic models (OR: 1.245, 95 % CI:1.138–1.361, P = 1.0 × 10^?10). No significant association was found between them under a recessive genetic model (OR: 1.124, 95 % CI: 0.844–1.497, P = 0.424). A significant association was also found between FgB ?148C/T gene polymorphism and CAD in the Chinese population under an allelic (OR: 1.34, 95 % CI: 1.06–1.71, P = 0.02), recessive (OR: 1. 65, 95 % CI: 1.02–2.69, P = 0.04), dominant (OR: 0.924, 95 % CI: 0.872–0.978, P = 0.007) and homozygous genetic models (OR: 0.968, 95 % CI: 0.942–0.995, P = 0.018). No significant association was found between them under a heterozygous genetic model (OR: 0.979, 95 % CI: 0.937–1.023, P = 0.342). In the whole Chinese population, no significant association between the CETP TaqIB gene polymorphism and CAD was found under an allelic (OR: 1.17, 95 % CI: 0.94–1.45, P = 0.15), dominant (OR: 1.46, 95 % CI: 0.80–2.67, P = 0.22) or recessive genetic models (OR: 0.68, 95 % CI: 0.32–1.44, P = 0.31). However, in the subgroup analysis stratified by ethnicity, there was a significant association between them under an allelic (OR: 1.27, 95 % CI: 1.07–1.52, P = 0.007) and dominant genetic model (OR: 2.04, 95 % CI: 1.49–2.79, P < 0.00001) in the Han subgroup. In the Chinese population, the APO A5 ?1131T/C and FgB ?455G/A, ?148C/T gene polymorphisms were implied to be associated with CAD susceptibility. The APO A5 ?1131C, FgB ?455A, and ?148T alleles might confer susceptibility to CAD. CETP TaqIB gene polymorphism was suggested to be associated with CAD susceptibility in the Chinese Han population. Carriers with B1 allele of CETP TaqIB gene might be predisposed to CAD in the Chinese Han population.     

The C161T polymorphism in the peroxisome proliferator-activated receptor gamma gene (PPARγ) is associated with risk of coronary artery disease: a meta-analysis

The researches attempting to associate the PPARγ C161T polymorphism with coronary artery disease (CAD) yielded complicated and contradictory results. We aimed for more precise estimate of the relationship and conducted a comprehensive meta-analysis. Publications written in English or Chinese were screened in MEDLINE, Embase, CNKI, Wanfang and CBM. Data on 11 studies including 3,020 cases and 2,853 controls were extracted. A random-effects model was available to synthesize the inconsistent outcomes of the individual studies, while addressing between-study heterogeneity and publication bias. The PPARγ C161T polymorphism followed Hard-Weinberg Equilibrium for all studies (P > 0.05).Overall, there was no evidence for a significant association under all genetic models but with distinct heterogeneity (T vs. C: P = 0.29, OR = 0.91, 95 %CI 0.77–1.08, P _{heterogeneity} = 0.004, I ² = 61.2 %). However, in the subgroup analysis by ethnicity, the T allele carriers showed a prominent 26 % risk reduction of CAD among Chinese (dominant genetic model: P = 0.03, 95 %CI 0.57–0.97, P _{heterogeneity} = 0.03, I ² = 56.1 %). After dividing into population source, the significance of CAD risk reduction was strengthened in hospital-based studies (allele comparison: P = 0.04, OR = 0.82, 95 %CI 0.67–1.00, P _{heterogeneity} = 0.04, I ² = 52.5 %; dominant model: P = 0.01, OR = 0.73, 95 %CI 0.57–0.92, P _{heterogeneity} = 0.05, I ² = 50.8 %). There was no obvious publication bias verified in the method of funnel plot and Egger’s linear regression test (t = ?0.11, P = 0.913). Taken together, our results revealed the PPARγ C161T polymorphism might play a moderate protective effect on developing CAD among Chinese, but not among Caucasians.     

Four Common Vascular Endothelial Growth Factor Polymorphisms (?2578C>A, ?460C>T, +936C>T,and +405G>C) in Susceptibility to Lung Cancer: A Meta-Analysis

Background and Objective

Vascular endothelial growth factor (VEGF) is one of the key initiators and regulators of angiogenesis and it plays a vital role in the onset and development of malignancy. The association between VEGF gene polymorphisms and lung cancer risk has been extensively studied in recent years, but currently available results remain controversial or ambiguous. The aim of this meta-analysis is to investigate the associations between four common VEGF polymorphisms (i.e., −2578C>A, −460C>T, +936C>T and +405C>G) and lung cancer risk.

Methods

A comprehensive search was conducted to identify all eligible studies to estimate the association between VEGF polymorphisms and lung cancer risk. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of this association.

Results

A total of 14 published case-control studies with 4,664 cases and 4,571 control subjects were identified. Our meta-analysis provides strong evidence that VEGF −2578C>A polymorphism is capable of increasing lung cancer susceptibility, especially among smokers and lung squamous cell carcinoma (SCC) patients. Additionally, for +936C>T polymorphism, increased lung cancer susceptibility was only observed among lung adenocarcinoma patients. In contrast, VEGF −460C>T polymorphism may be a protective factor among nonsmokers and SCC patients. Nevertheless, we did not find any association between +405C>G polymorphism and lung cancer risk, even when the groups were stratified by ethnicity, smoking status or histological type.

Conclusion

This meta-analysis recommends more investigations into the relationship between −2578C>A and −460C>T lung cancer risks. More detailed and well-designed studies should be conducted to identify the causal variants and the underlying mechanisms of the possible associations.     

Association of T3111C polymorphism in 3′-untranslated region of the <Emphasis Type="Italic">Clock</Emphasis> gene with the risk of essential arterial hypertension and coronary artery disease in the Russian population (Residents of Karelia)

Allele and genotype distributions of the T3111C polymorphism in 3′-untranslated region of the Clock gene were examined in the groups of Russian patients with essential arterial hypertension (EAH) and coronary artery disease (CAD), and in control group of Russia residents of the Republic of Karelia. The genotype frequency distributions of the polymorphism examined in the EAH and CAD patients were statistically significantly different from that in the individuals without clinical signs of these diseases. The CC genotype frequency in EAH and CAD males was higher, and in the corresponding females it was lower than in males and females from the control group. Male CC carriers were characterized by a possible increased risk of EAH: OR (95% CI) = 1.42 (0.56; 3.58). Moreover, the presence of the CC genotype in males could increase the risk of CAD: OR (95% CI) = 1.58 (0.63; 3.93).     

Association of C47T polymorphism in <Emphasis Type="Italic">SOD2</Emphasis> gene with coronary artery disease: a case–control study and a meta-analysis

Oxidative damage promotes atherosclerosis. SOD2 is an important antioxidant enzyme. A case–control study and a meta-analysis were performed to assess the association of C47T polymorphism in SOD2 gene with premature, late-onset and overall coronary artery disease (CAD) risk. A hospital-based case–control study was conducted with 269 premature CAD cases, 278 late-onset CAD cases and 299 healthy controls. Polymerase chain reaction (PCR) and Pyrosequencing were used to detect the polymorphism. Multinomial logistic regression model was performed to estimate odds ratio (OR) with 95% confidence intervals (CIs) and adjust potential confounders. A meta-analysis was performed using eight outcomes including our result. Fixed or random effect pooled measure was selected on the basis of homogeneity test among studies. Heterogeneity among studies was evaluated using I ². Meta-regression was used to explore potential sources of between-study heterogeneity. Publication bias was estimated using Peters’s linear regression test. In our case–control study, compared with the TT as the reference, the mutant genotype of CC + TC was significantly associated with a reduced premature CAD risk both in univariate (OR = 0.60, 95% CI = 0.41–0.87) and multivariate (OR = 0.59, 95% CI = 0.40–0.87) logistic regressions, but not with late-onset CAD risk. After excluding one article that deviated from Hardy–Weinberg equilibrium in controls, this meta-analysis showed a significant association of the C allele with reduced risk of CAD in dominant (FEM: OR = 0.69, 95% CI = 0.61–0.78), recessive (OR = 0.64, 95% CI = 0.50–0.82), and codominant (FEM: OR = 0.73, 95% CI = 0.65–0.80) models. Our study suggested that the mutant genotype of CC + TC was significantly associated with a reduced CAD risk.     

A shift to 50°C provokes death in distinct ways for glucose- and oleate-grown cells of <Emphasis Type="Italic">Yarrowia lipolytica</Emphasis>

Based on the observation that shocks provoked by heat or amphiphilic compounds present some similarities, this work aims at studying whether cells grown on oleate (amphiphilic pre-stress) acquire a tolerance to heat shock. In rich media, changing glucose for oleate significantly enhanced the cell resistance to the shock, however, cells grown on a minimal oleate medium lost their ability to grow on agar with the same kinetic than glucose-grown cells (more than 7-log decrease in 18 min compared with 3-log for oleate-grown cells). Despite this difference in kinetics, the sequence of events was similar for oleate-grown cells maintained at 50°C with a (1) loss of ability to form colonies at 27°C, (2) loss of membrane integrity and (3) lysis (observed only for some minimal-oleate-grown cells). Glucose-grown cells underwent different changes. Their membranes, which were less fluid, lost their integrity as well and cells were rapidly inactivated. But, surprisingly, their nuclear DNA was not stained by propidium iodide and other cationic fluorescent DNA-specific probes but became stainable by hydrophobic ones. Moreover, they underwent a dramatic increase in membrane viscosity. The evolution of lipid bodies during the heat shock depended also on the growth medium. In glucose-grown cells, they seemed to coalesce with the nuclear membrane whereas for oleate-grown cells, they coalesced together forming big droplets which could be released in the medium. In some rare cases of oleate-grown cells, lipid bodies were fragmented and occupied all the cell volume. These results show that heat triggers programmed cell death with uncommon hallmarks for glucose-grown cells and necrosis for methyl-oleate-grown cells.     

α7 mutants mimicking atypical motifs (YxxCC of loop-C, and E to H at −1′ in TM2) in the C. elegans LEV-8 subunit affect nicotinic acetylcholine receptor function

The ACR-8-like group of C. elegans nicotinic acetylcholine receptor (nAChR) subunits contain unusual motifs in the ACh binding site and in the −1′ position of transmembrane region two (TM2). Using site-directed mutagenesis (SDM) we have introduced these motifs into chicken α7 as it has not been possible to express C. elegans nAChR in vitro. Oocytes expressing α7 with the C. elegans binding motif show a reduced affinity and efficacy for both ACh and nicotine. The blocking action of the anthelmintic drug levamisole is reduced. The TM2 motif resulted in a non-functional receptor. We conclude that the TM2 motif profoundly restricts cation movement through the α7 channel but does not confer anion permeability. The altered form of the ACh binding motif is likely to result in a receptor with altered pharmacology, adding potential functional diversity at synapses in the nervous system and neuromuscular junctions of C. elegans.     

Association between the −11377 C/G and −11391 G/A polymorphisms of adiponectin gene and adiponectin levels with susceptibility to type 1 and type 2 diabetes mellitus in population from the west of Iran,correlation with lipid profile

Adipose tissue, an endocrine organ, secretes bioactive factors including adiponectin. Adiponectin is a protein hormone that enhances insulin sensitivity through increased fatty acid oxidation and inhibition of hepatic glucose production. We assessed the association of the adiponectin promoter region polymorphisms −11391 G/A and −11377 C/G with susceptibility to type 1 (T1DM) and type 2 (T2DM) diabetes mellitus in the population of west Iran. Also, we investigated the effect of adiponectin level and lipid profile on T1DM and T2DM development. In this case-control study, we recruited 189 patients with diabetes (100 T2DM and 89 T1DM) and 161 sex and age-matched unrelated healthy controls. Adiponectin mutations were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the protein level was measured by the enzyme-linked immunosorbent assay. Other biochemical parameters were determined by routine laboratory methods. The G allele of adiponectin gene at −11377 position (C/G) significantly increased the risk of T1DM. With respect to genotype models, codominant (2.97 times), dominant (3.6-fold), and over-codominant (2.9-fold) patients with T1DM who carried −11377 C > G single-nucleotide polymorphisms were significantly susceptible to the development of the disease. A significantly higher level of adiponectin in T1DM was oberved compared with the control group. In contrast, patients with T2DM had lower adiponectin levels compared with healthy controls. The genotype distributions of −11391 G/A polymorphisms were the same for patients with diabetes and control groups. The presence of G allele at −11377 C/G adiponectin gene significantly increased serum adiponectin level and may be a risk factor for T1DM susceptibility among the western Iranian population.     

Erratum to: Florez-McClure ML,Hohsfield LA,Fonte G,Bealor MT,Link CD. Decreased insulin-receptor signaling promotes the autophagic degradation of β-amyloid peptide in C. elegans. Autophagy 2007; 3:569-80

Autophagy is a cell-autonomous mechanism of innate immunity that protects the cytosol against bacterial infection. Invasive bacteria, including Listeria monocytogenes, have thus evolved strategies to counteract a process that limits their intracellular growth. ActA is a surface protein produced by L. monocytogenes to polymerize actin and mediate intra- and intercellular movements, which plays a critical role in autophagy escape. We have recently investigated the role of another L. monocytogenes surface protein, the internalin InlK, in the infection process. We showed that in the cytosol of infected cells, InlK interacts with the Major Vault Protein (MVP), the main component of cytoplasmic ribonucleoprotein particles named vaults. Although MVP has been implicated in a variety of key cellular process, its role remains elusive. We demonstrated that L. monocytogenes is able, via InlK, to decorate its surface with MVP in order to escape autophagic recognition. Strikingly, this new strategy used by L. monocytogenes to avoid autophagy is independent of ActA, suggesting that InlK-MVP interactions and actin polymerization are two processes that favor in the same manner the infection process. Understanding the role of MVP may provide new insights into bacterial infection and autophagy.