Genetic associations with coronary heart disease: Meta-analyses of 12 candidate genetic variants

Aims

The aim of this study was to evaluate the combined contribution of 12 genetic variants to the risk of coronary heart disease (CHD).

Methods

Through a comprehensive literature search for genetic variants involved in the CHD association study, we harvested a total of 10 genes (12 variants) for the current meta-analyses. These genes consisted of GPX1 (rs1050450), PPARD (rs2016520), ALOX15 (rs34210653), SELPLG (rs2228315), FCGR2A (rs1801274), CCL5 (rs2107538), CYP1A1 (rs4646903), TP53 (rs1042522), CX37 (rs1764391), and PECAM1 (rs668, rs12953, and rs1131012).

Results

A total of 45 studies among 23,314 cases and 28,430 controls were retrieved for the meta-analyses of 12 genetic variants. The results showed a significant association between the GPX1 rs1050450 polymorphism and CHD (odd ratio (OR) = 1.61, 95% confidence interval (CI) = 1.25–2.07, P = 0.0002). Other meta-analyses of the rest 11 variants suggested a lack of association with the risk of CHD.

Conclusion

Our results confirmed that GPX1 rs1050450 was associated with susceptibility to CHD in Chinese and Indian populations.     

Relationship between chemokine (C–X–C motif) ligand 12 gene variant (rs1746048) and coronary heart disease: Case–control study and meta-analysis

The goal of our study is to evaluate the contribution of CXCL12 rs1746048 (hg19, chr10:44775574) to the risk of CHD in Han Chinese, and to summarize its role in CHD through meta-analysis of existing studies among various ethnic groups. Significant association is observed between rs1746048-C and an increased risk of CHD in Han Chinese (χ² = 5.41, df = 1, P = 0.02). Post hoc analysis reveals an even stronger association of rs1746048 with the risk of CHD for subjects aged 65 years or older (genotype: χ² = 8.39, df = 2, P = 0.015; allele: χ2 = 9.13, df = 1, P = 0.003, odd ratio (OR) = 1.91, 95% confidential interval (CI) = 1.25–2.91). A break down analysis by gender shows that rs1746048 is likely a CHD risk factor under the recessive model in males (CC + CT versus TT: P = 0.05, χ² = 3.59, df = 1, OR = 1.72, 95% CI = 1.00–3.04). In addition, a meta-analysis of ten studies among over 107,000 individuals confirms that rs1746048 is a risk factor of CHD (P < 0.0001, OR = 1.12, 95% CI = 1.09–1.15) and this agrees with the findings of our case–control study in Han Chinese.     

适当浓度的过氧化氢诱导人支气管上皮细胞发生钙振荡

包括过氧化氢（Hzoz）在内的活性氧通过引起细胞内钙的变化而造成细胞损伤。然而,不同浓度的H202可以导致细胞内不同的钙变化,并激活不同的信号通路。细胞内钙振荡是其中的一种钙信号变化形式,钙振荡可以调控转录因子NF—KB的活性。该研究探讨可以诱导支气管上皮细胞内钙振苏发生的H2o2浓度。体外培养人支气管上皮细胞,采取钙离子荧光探针Fura_2标记细胞。并使用离子成像系统,观测不同浓度的H：0：（0～1000μmol／L）作用下细胞内钙浓度的变化。结果发现,低于50μmol／L的H202仅仅引起“钙火花”;50～500μmol／L的H202导致细胞内钙振荡的发生;而1000μmol／L的H202引起细胞内持续的高钙;同时也证实150μmol／L的H202诱发明显的钙振荡,而钙振荡随后引起了NF—KB活性的升高。该研究提示,适当浓度的H：0：可以诱发支气管上皮细胞内钙振荡的发生,推测可能是活性氧导致慢性气道炎症损伤的一个机制。     

The Potential Neuroprotection Mechanism of GDNF in the 6-OHDA-Induced Cellular Models of Parkinson’s Disease

The glial cell line-derived neurotrophic factor (GDNF) potential as a therapeutic agent for the treatment of Parkinson’s Disease (PD) has been extensively explored. However, the mechanism of the GDNF neuroprotective effects is still unclear. In this study, the neuroprotective mechanism of the GDNF in the PD cellular models, which was obtained by the 6-hydroxydopamine (6-OHDA)-induced dopaminergic (DA) cell line MN9D damage was investigated by microarray. Interestingly, 54 constitutively increased or decreased genes were detected, 17 of which have not been reported previously. The expression of 5 up-regulated and 5 down-regulated genes which displayed the most obvious changes compared to the no GDNF treatment cells and was previously proven to be related to cell survival was validated by real-time PCR and western blot. Moreover, the up-regulated gene Ager and down-regulated gene Ccnl2 which were related to the PI-3K/Akt signaling pathway, but not researched in the neuron-cells, were investigated by overexpression and RNA interference. Overexpression of Ager or knockdown the expression of Ccnl2 decreased the damage to MN9D cells caused by 6-OHDA and reduced their apoptosis. All these results suggested that the protective effects of the GDNF on the 6-OHDA damaged MN9D cells could be understood by enhancing the expression of the apoptosis inhibiting genes and decreasing the expression of the apoptosis promoting genes. Thus, this study might provide a number of specific candidates and potential targets to investigate the protective mechanism of GDNF in DA neurons.     

The relationship between the presence of ADHD and certain candidate gene polymorphisms in a Turkish sample

Due to the high heritability of attention-deficit hyperactivity disorder (ADHD), parents of children with ADHD appear to represent a good sample group for investigating the genetics of the disorder. The aim of this study was to investigate the association between ADHD and six polymorphisms in five candidate genes [5-HT2A (rs6311), NET1 (rs2242447), COMT (rs4818), NTF3 (rs6332), SNAP-25 (rs3746544) and (rs1051312)]. We included 228 parents of children diagnosed with ADHD and 109 healthy parents as the control group. The polymorphisms were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) assays and analyzed using the chi-square test and the multinomial logit model. SNAP-25 (rs3746544) polymorphism was associated with loading for ADHD, while 5-HT2A (rs6311) and NET1 (rs2242447) polymorphisms were associated with ADHD. On the other hand, there was no significant association between the SNAP-25 (rs1051312), NTF3 (rs6332), or COMT (rs4818) gene polymorphisms and ADHD.     

Cranial morphology of an Early Cretaceous Monjurosuchid (Reptilia: Diapsida) from Liaoning Province of China and evolution of the choristoderan palate

A new specimen of Philydrosaurus proseilus from the Early Cretaceous Chiufotang (Jiufotang) Formation preserves the first complete palate of a monjurosuchid choristodere. As in other choristoderes, the palate of Philydrosaurus is akinetic, extended by a broad contact between the vomer and maxilla, and equipped with multiple batteries of palatal teeth. This specimen provides phylogenetically significant information and clarifies the distribution of many apomorphies within Choristodera. Philydrosaurus is primitive relative to the Neochoristodera in that it exhibits only a moderate degree of posterior displacement of the choanae and retains a relatively large interpterygoid vacuity. However, Philydrosaurus also exhibits several derived features previously considered diagnostic of the Neochoristodera, including establishment of a long midline contact of the pterygoids and development of a distinct nasopalatal trough extending from the choana. The choristodere palate exhibits significant modification of the primitive diapsid condition, including elongation of the vomers, establishment of a vomer–maxilla contact, posterior displacement of the choanae, development of the nasopalatal trough, and reduction of the interpterygoid vacuity.     

A combined steepest descent and genetic algorithm (SD/GA) approach for the optimization of solvation parameters

An accurate solvation model is essential for computer modeling of protein folding and other biomolecular self-assembly processes. Compared to explicit solvent models, implicit solvent models, such as the Poisson-Boltzmann (PB) with solvent accessible surface area model (PB/SA), offer a much faster speed—the most compelling reason for the popularity of these implicit solvent models. Since these implicit solvent models typically use empirical parameters, such as atomic radii and the surface tensions, an optimal fit of these parameters is crucial for the final accuracy of properties such as solvation free energy and folding free energy. In this paper, we proposed a combined approach, namely SD/GA, which takes the advantage of both local optimization with the steepest descent (SD), and global optimization with the genetic algorithm (GA), for parameters optimization in multi-dimensional space. The SD/GA method is then applied to the optimization of solvation parameters in the non-polar cavity term of the PB/SA model. The results show that the newly optimized parameters from SD/GA not only increase the accuracy in the solvation free energies for ～200 organic molecules, but also significantly improve the free energy landscape of a β-hairpin folding. The current SD/GA method can be readily applied to other multi-dimensional parameter space optimization as well.     

Involvement of Volume-Activated Chloride Channels in H2O2 Preconditioning Against Oxidant-Induced Injury Through Modulating Cell Volume Regulation Mechanisms and Membrane Permeability in PC12 Cells

The functions of chloride channels in preconditioning-induced cell protection remain unclear. In this report, we show that the volume-activated chloride channels play a key role in hydrogen peroxide (H₂O₂) preconditioning-induced cell protection in pheochromocytoma PC12 cells. The preconditioning with 100 μM H₂O₂ for 90 min protected the cells from injury induced by long period exposure to 300 μM H₂O₂. The protective effect was attenuated by pretreatment with the chloride channel blockers, 5-nitro-2-3-phenylpropylamino benzoic acid (NPPB) and tamoxifen. H₂O₂ preconditioning directly activated a chloride current, which was moderately outward-rectified and sensitive to the chloride channel blockers and hypertonicity-induced cell shrinkage. H₂O₂ preconditioning functionally up-regulated the activities of volume-activated chloride channels and enhanced the regulatory volume decrease when exposure to extracellular hypotonic challenges. In addition, acute application of H₂O₂ showed distinctive actions on cell volume and membrane permeability in H₂O₂ preconditioned cells. In H₂O₂ preconditioned cells, acute application of 300 μM H₂O₂ first promptly induced a decrease of cell volume and enhancement of cell membrane permeability, and then, cell volume was maintained at a relatively stable level and the facilitation of membrane permeability was reduced. Conversely, in control cells, 300 μM H₂O₂ induced a slow but persistent apoptotic volume decrease (AVD) and facilitation of membrane permeability. H₂O₂ preconditioning also significantly up-regulated the expression of ClC-3 protein, the molecular candidate of the volume-activated chloride channel. These results suggest that H₂O₂ preconditioning can enhance the expression and functional activities of volume-activated chloride channels, thereby modulate cell volume and cell membrane permeability, which may contribute to neuroprotection against oxidant-induced injury.     

Structural basis of calcineurin activation by calmodulin

Calcineurin is the only known calmodulin (CaM) activated protein phosphatase, which is involved in the regulation of numerous cellular and developmental processes and in calcium-dependent signal transduction. Although commonly assumed that CaM displaces the autoinhibitory domain (AID) blocking substrate access to its active site, the structural basis underlying activation remains elusive. We have created a fused ternary complex (CBA) by covalently linking three polypeptides: CaM, calcineurin regulatory B subunit (CnB) and calcineurin catalytic A subunit (CnA). CBA catalytic activity is comparable to that of fully activated native calcineurin in the presence of CaM. The crystal structure showed virtually no structural change in the active site and no evidence of CaM despite being covalently linked. The asymmetric unit contains four molecules; two parallel CBA pairs are packed in an antiparallel mode and the large cavities in crystal packing near the calcineurin active site would easily accommodate multiple positions of AID-bound CaM. Intriguingly, the conformation of the ordered segment of AID is not altered by CaM; thus, it is the disordered part of AID, which resumes a regular α-helical conformation upon binding to CaM, which is displaced by CaM for activation. We propose that the structural basis of calcineurin activation by CaM is through displacement of the disordered fragment of AID which otherwise impedes active site access.