Genetic Analysis of the Relationship between Bone Mineral Density and Low-Density Lipoprotein Receptor-Related Protein 5 Gene Polymorphisms

<div><p>Background</p><p>A number of studies have examined the association between the polymorphisms of the low-density lipoprotein receptor-related protein 5 gene (LRP5), but previous results have been inconclusive. Thus we performed a meta-analysis of studies on the association between the LRP5 polymorphisms and bone mineral density (BMD) to assess their pooled effects.</p> <p>Methods</p><p>Published literature from PubMed, EMBASE and ISI web of science were searched for eligible publications. Weighted mean difference (WMD) and 95% confidence interval (CI) was calculated using fixed- or random-effects model.</p> <p>Results</p><p>A total of 19 studies with 25773 subjects were considered in this meta-analysis. Of them, 17 examined the association between the A1330V polymorphism and BMD, 8 were focused on the V667M polymorphism, and 2 analyzed the Q89R polymorphism. Individuals with the A1330V AA genotype showed significantly higher BMD than those with the AV/VV genotypes [at lumbar spine (LS): WMD = 0.02g/cm², 95% CI = 0.01-0.03, <i>P</i> < 10^-4; at femur neck (FN): WMD = 0.01g/cm², 95% CI = 0.00-0.02, <i>P</i> = 0.01] or VV genotype (at LS: WMD = 0.02g/cm², 95% CI = 0.01-0.04, <i>P</i> = 0.01). Significant associations were also detected in the analysis for V667M (VV vs. VM/MM: WMD at LS = 0.02g/cm², 95% CI = 0.02-0.03, <i>P</i> < 10^-5; WMD at FN = 0.01g/cm², 95% CI = 0.01-0.02, <i>P</i> = 0.0002). As for Q89R, subjects with the QQ genotype tended to have higher BMD than those with the QR/RR genotypes at FN (WMD = 0.03g/cm², 95% CI = 0.01-0.05, <i>P</i> = 0.005).</p> <p>Conclusion</p><p>This meta-analysis demonstrated that the <i>LRP5</i> polymorphisms may be modestly associated with BMD of LS and FN.</p> </div

Summary of search strategy and result.

<p>Summary of search strategy and result.</p

WMD and 95% CI in LS BMD between A1330V AA and AV/VV genotypes.

<p>WMD and 95% CI in LS BMD between A1330V AA and AV/VV genotypes.</p

WMD and 95% CI in LS BMD between V667M VV and VM/MM genotypes.

<p>WMD and 95% CI in LS BMD between V667M VV and VM/MM genotypes.</p

MOESM6 of Improving chemical similarity ensemble approach in target prediction

Additional file 6.  Kinase test data set

WMD and 95% CI in FN BMD between V667M VV and VM/MM genotypes.

<p>WMD and 95% CI in FN BMD between V667M VV and VM/MM genotypes.</p

WMD and 95% CI in FN BMD between Q89R QQ and QR/RR genotypes.

<p>WMD and 95% CI in FN BMD between Q89R QQ and QR/RR genotypes.</p

WMD and 95% CI in FN BMD between A1330V AA and AV/VV genotypes.

<p>WMD and 95% CI in FN BMD between A1330V AA and AV/VV genotypes.</p

Block and open conformations of 146-N-glycan and the hydrophobic zone of 150-cavity.

<p>(A) 150-cavity volume of 2HTY chain A in 100 ns MD simulation. (B) The pie chart of three 146-N-glycan conformations clusters. (C) The blocking and opening 150-cavity conformations of 146-N-glycan. The 146-N-glycan was colored in orange. (D) The conformation of 146-N-glycan that covers NA substitute binding cavity. Residues V116, I117, Q136, A138 and V149 construct a hydrophobic zone of 150-cavity. The substitute binding cavity was colored in green and 146-N-glycan was colored in orange.</p

The Mechanism by which 146-N-Glycan Affects the Active Site of Neuraminidase

<div><p>One of the most conserved glycosylation sites of neuraminidase (NA) is 146-N-glycan. This site is adjacent to the 150-cavity of NA, which is found within the active site and thought to be a target for rational drug development against the antiviral resistance of influenza. Here, through a total of 2.4 μs molecular dynamics (MD) simulations, we demonstrated that 146-N-glycan can stabilize the conformation of the 150-loop that controls the volume of the 150-cavity. Moreover, with 146-N-glycan, our simulation result was more consistent with crystal structures of NAs than simulations conducted without glycans. Cluster analysis of the MD trajectories showed that 146-N-glycan adopted three distinct conformations: monomer-bridged, dimer-bridged and standing. Of these conformations, the dimer-bridged 146-N-glycan was the most stable one and contributed to stabilization of the 150-loop conformation. Furthermore, our simulation revealed that various standing conformations of 146-N-glycan could block the entrance of the binding pocket. This result was consistent with experimental data and explained the relatively low activity of inhibitors with flexible substituents toward the 150-cavity. Together, our results lead us to hypothesize that rigid and hydrophobic substituents could serve as better inhibitors targeting the 150-cavity.</p></div