The Role of TLR4 896 A>G and 1196 C>T in Susceptibility to Infections: A Review and Meta-Analysis of Genetic Association Studies

Background

Toll-like receptor 4 plays a role in pathogen recognition, and common polymorphisms may alter host susceptibility to infectious diseases.

Purpose

To review the association of two common polymorphisms (TLR4 896A>G and TLR4 1196C>T) with infectious diseases.

Data Sources

We searched PubMed and EMBASE up to March 2013 for pertinent literature in English, and complemented search with references lists of eligible studies.

Study Selection

We included all studies that: reported an infectious outcome; had a case-control design and reported the TLR4 896A>G and/or TLR4 1196C>T genotype frequencies; 59 studies fulfilled these criteria and were analyzed.

Data Extraction

Two authors independently extracted study data.

Data Synthesis

The generalized odds ratio metric (OR_G) was used to quantify the impact of TLR4 variants on disease susceptibility. A meta-analysis was undertaken for outcomes reported in >1 study. Eleven of 37 distinct outcomes were significant. TLR4 896 A>G increased risk for all parasitic infections (OR_G 1.59; 95%CI 1.05-2.42), malaria (1.31; 95%CI 1.04-1.66), brucellosis (2.66; 95%CI 1.66-4.27), cutaneous leishmaniasis (7.22; 95%CI 1.91-27.29), neurocysticercosis (4.39; 95%CI 2.53-7.61), Streptococcus pyogenes tonsillar disease (2.93; 95%CI 1.24-6.93) , typhoid fever (2.51; 95%CI 1.18-5.34) and adult urinary tract infections (1.98; 95%CI 1.04-3.98), but was protective for leprosy (0.36; 95%CI 0.22-0.60). TLR4 1196 C>T effects were similar to TLR4 896 A>G for brucellosis, cutaneous leishmaniasis, leprosy, typhoid fever and S. pyogenes tonsillar disease, and was protective for bacterial vaginosis in pregnancy (0.55; 95%CI 0.31-0.98) and Haemophilus influenzae tonsillar disease (0.42; 95%CI 0.17-1.00). The majority of significant associations were among predominantly Asian populations and significant associations were rare among European populations.

Conclusions

Depending on the type of infection and population, TLR4 polymorphisms are associated with increased, decreased or no difference in infectious disease. This may be due to differential functional expression of TLR4, the co-segregation of TLR4 variants or a favorable inflammatory response.     

Distribution Patterns and Conservation Perspectives of the Endemic Flora of Peloponnese (Greece)

An inventory of the endemic vascular plants of the Peloponnese (395 species and subspecies) has been created based on literature, herbarium and field data. Endemics?? distribution patterns, altitudinal distribution and habitat specificity were investigated. A rarity score for each endemic has been calculated based on its population size, geographic range and habitat specificity. The main mountainous areas of the Peloponnese are largely congruent to the hotspots of endemism. Altitudinal range and niche breadth of the endemics were positively correlated to their range size. The elevational gradient of the endemic species richness showed a hump-shaped pattern, in contrast to the monotonically decreasing pattern of total species richness. Endemic species were found to support boundary theory, while total species richness distribution followed the Rapoport??s elevational rule. The elevational distribution of the average rarity score and the average weighted threat of the endemics resulted in low values for mid-elevation intervals and increased values for low and high altitude areas, indicating that conservation efforts should focus on the two extremes of the elevational gradient. Area prioritization methods were applied using a rarity/complementarity based algorithm with two species weighting schemes. Their results were largely congruent confirming the significance of the main mountainous areas for the conservation of the endemics. Spatial overlap among selected grid cells using the rarity/complementarity analysis and Natura 2000 network was found to be low. Our results revealed the conservation importance of at least one new area located on Kythera Island.     

Preparation of DL-2,3,4-trihydroxybutylarsonic acid and dl-2,3-dihydroxybutane-1,4-bis(arsonic acid): starting compounds for novel arsonolipids

The reaction of DL-1,3-butadiene diepoxide and of DL-1,4-dibromo-2,3-butanediol with aqueous alkaline sodium arsenite, "Na(3)AsO(3)", gave mixtures of the title arsonic acids which can be separated by anion exchange resin. Characterization of by-products leads to a better understanding of these reactions. These compounds are valuable intermediates for the preparation of novel arsonic acids and bis(arsonic acids).     

Arsonoliposomes: Effect of Lipid Composition on Their Stability and Morphology

The influence of the lipid composition of arsonoliposomes on their membrane integrity was investigated to evaluate whether it is possible to combine their action with drugs that can be encapsulated in their aqueous interior. This was investigated by measuring the retention of vesicle-encapsulated calcein (100 mM) during incubation, in the absence and presence of serum proteins. Liposomes containing various concentrations of arsonolipid (with the palmitoyl side chain) as well as egg-lecithin (phosphatidylcholine, PC) and cholesterol (lipid/chol 2:1 mol:mol) were prepared. In some experiments, PC was replaced by the synthetic phospholipid DSPC. All PC/arsonoliposomes tested are stable after 24 h of incubation in buffer at 37°C. After incubation in the presence of serum proteins, arsonoliposomes that contain low amounts of arsonolipid (up to 5 mol% of the lipid content without cholesterol) are stable, whereas increased release of calcein is observed when vesicle arsonolipid concentration is raised (from 5 to 15 mol%). Further increase of arsonolipid content results in immediate decrease of calcein latency while the remaining calcein is rapidly released during incubation. DSPC/arsonoliposomes are comparably more stable, and membrane integrity is independent of the vesicle arsonolipid content, in the range investigated (15–40 mol% of the lipid content without cholesterol). Thereby, we conclude that more stable arsonoliposomes that incorporate high arsonolipid concentrations may be produced when PC is replaced by DSPC. The latter arsonoliposomes provide a system that may be used for combining arsonolipid activity with the activity of other drugs.     

Validation of rat reference genes for improved quantitative gene expression analysis using low density arrays

Real-time PCR has become increasingly important in gene expression profiling research, and it is widely agreed that normalized data are required for accurate estimates of messenger RNA (mRNA) expression. With increased gene expression profiling in preclinical research and toxicogenomics, a need for reference genes in the rat has emerged, and the studies in this area have not yet been thoroughly evaluated. The purpose of our study was to evaluate a panel of rat reference genes for variation of gene expression in different tissue types. We selected 48 known target genes based on their putative invariability. The gene expression of all targets was examined in 11 types of rat tissues using TaqMan low density array (LDA) technology. The variability of each gene was assessed using a two-step statistical model. The analysis of mean expression using multiple reference genes was shown to provide accurate and reliable normalized expression data. The least five variable genes from each specific tissue were recommended for future tissue-specific studies. Finally, a subset of investigated rat reference genes showing the least variation is recommended for further evaluation using the LDA platform. Our work should considerably enhance a researcher's ability to simply and efficiently identify appropriate reference genes for given experiments.     

Insularity affects head morphology,bite force and diet in a Mediterranean lizard

Island environments differ with regard to numerous features from the mainland and may induce large‐scale changes in most aspects of the biology of an organism. In this study, we explore the effect of insularity on the morphology and performance of the feeding apparatus, a system crucial for the survival of organisms. To this end, we examined the head morphology and feeding ecology of island and mainland populations of the Balkan green lizard, Lacerta trilineata. We predicted that head morphology, performance and diet composition would differ between sexes and habitats as a result of varying sexual and natural selection pressures. We employed geometric morphometrics to test for differences in head morphology, measured bite forces and analysed the diet of 154 adult lizards. Morphological analyses revealed significant differences between sexes and also between mainland and island populations. Relative to females, males had larger heads, a stronger bite and consumed harder prey than females. Moreover, island lizards differed in head shape, but not in head size, and, in the case of males, demonstrated a higher bite force. Islanders had a wider food niche breadth and included more plant material in their diet. Our findings suggest that insularity influences feeding ecology and, through selection on bite force, head morphology. © 2014 The Linnean Society of London, Biological Journal of the Linnean Society, 2014, 112 , 469–484.     

Lipid peroxidation in chronic gastritis; any influence of Helicobacter pylori?

In an attempt to investigate the significance of lipid peroxidation in the pathogenesis of gastritis associated with or without Helicobacter pylori infection, malonodialdehyde (MDA) levels were measured by the thiobarbiturate assay in the gastric juice of 101 patients undergoing upper GI endoscopy and correlated with histopathological findings. Elevated MDA levels were found in all patients with gastritis compared with controls. MDA levels were significantly correlated with the extent of the mucosal inflammation and with disease activity in patients with reactive gastritis. In patients with H. pylori associated gastritis MDA levels were not correlated with disease activity but rather with the degree of atrophy. In this case, MDA levels were equal or even less than in patients with reactive gastritis. MDA levels were not affected by the history of consumption of PPIs, of H(2)-blockers or of NSAIDs over the last month before the endoscopy. It is concluded that lipid peroxidation is a mechanism involved in the pathogenesis of gastritis associated or not to H. pylori infection.