Association of OPA1 polymorphisms with NTG and HTG: a meta-analysis.

BACKGROUND: Genetic polymorphisms of the Optic atrophy 1 gene have been implicated in altering the risk of primary open angle glaucoma (POAG), especially the susceptibility to normal tension glaucoma (NTG), but the results remain controversial. METHODS: Multiple electronic databases (up to January 20, 2012) were searched independently by two investigators. A meta-analysis was performed on the association between Optic atrophy 1 polymorphisms (rs 166850 and rs 10451941) and normal tension glaucoma (NTG)/high tension glaucoma (HTG). Summary odds ratios (ORs) and 95% confidence intervals (CI) were estimated. RESULTS: Seven studies of 713 cases and 964 controls for NTG and five studies of 1200 cases and 971 controls for HTG on IVS8+4C>T (rs 166850) and IVS8+32T>C (rs10451941) were identified. There were significant associations between the OPA1 rs10451941polymorphism and NTG susceptibility for all genetic models(C vs. T OR = 1.26, 95% CI 1.09-1.47, p = 0.002; CC vs. TT: OR = 1.52, 95% CI 1.04-2.20, p = 0.029; CC vs. CT+TT: OR = 1.64, 95% CI 1.16-2.33, p = 0.005; CC+CT vs. TT: OR = 1.21, 95% CI 1.02-1.44, p = 0.032). However, no evidence of associations was detected between the OPA1 IVS8+32C>T polymorphism and POAG susceptibility to HTG. Similarly, clear associations between the rs 166850 variant and NTG were observed in allelic and dominant models (T vs. C OR = 1.52, 95% CI 1.16-1.99, p = 0.002; TT+TC vs. CC OR = 1.50, 95% CI 1.13-2.01, p = 0.006) but not to HTG. In subgroup analyses by ethnicity, we detected an association between both OPA1 polymorphisms and risk for NTG in Caucasians but not in Asians. By contrast, no significant findings were noted between OPA1 variants for HTG, either in Caucasians or in Asians. CONCLUSIONS: Both the IVS8+4C>T and IVS8+32T>C variants may affect individual susceptibility to NTG. Moreover, stratified analyses for NTG detecting the effects of both OPA1 polymorphisms seemed to vary with ethnicity. Further investigations are needed to validate the association

Results of meta-analysis for OPA1 polymorphisms and risk of primary open angle glaucoma.

<p>Results of meta-analysis for OPA1 polymorphisms and risk of primary open angle glaucoma.</p

Flow chart of literature search and study selection.

<p>Flow chart of literature search and study selection.</p

Begg’s funnel plot of OPA1 polymorphisms and NTG for allelic model.

<p>A: IVS8+4 T vs C; B:IVS8+32 C vs T. Each circle represents a separate study for the indicated association, and its size is proportional to the sample size of each study.</p

Forest plots describing subgroup analyses of the association between OPA1 polymorphisms and risk for HTG.

<p>The size of the square indicate the relative weight of each study.Bars,95% confidence interval(95% CI) A. subgroup analysis of IVS8+4 C>T stratified by ethnicity in order of publication year;B subgroup analysis of IVS8+32 T>C stratified by ethnicity in order of publication year.</p

Forest plots describing overall meta-analysis (left) and cumulative meta-analysis (right) of the associations between IVS+32 C>T polymorphism and POAG risk.

<p>Odds ratios shown for individual studies for allelic model genotype contrasts (T vs. C). Cumulative odds ratios shown for each additional information step obtained by stepwise inclusion of every new study into pooled estimate. A. meta-analysis of association between IVS+32 C>T variant and NTG in order of sample size. B. meta-analysis of association between IVS+32 C>T variant and HTG in order of sample size.</p

Forest plots describing overall meta-analysis (left) and cumulative meta-analysis (right) of the associations between IVS+4 T>C polymorphism and POAG risk.

<p>Odds ratios shown for individual studies for allelic model genotype contrasts (C vs. T). Cumulative odds ratios shown for each additional information step obtained by stepwise inclusion of every new study into pooled estimate. A. meta-analysis of association between IVS+4 T>C variant and NTG in order of sample size; B. meta-analysis of association between IVS+4 T>C variant and HTG in order of sample size.</p

Timing-dependent LTP and LTD in mouse primary visual cortex following different visual deprivation models

<div><p>Visual deprivation during the critical period induces long-lasting changes in cortical circuitry by adaptively modifying neuro-transmission and synaptic connectivity at synapses. Spike timing-dependent plasticity (STDP) is considered a strong candidate for experience-dependent changes. However, the visual deprivation forms that affect timing-dependent long-term potentiation(LTP) and long-term depression(LTD) remain unclear. Here, we demonstrated the temporal window changes of tLTP and tLTD, elicited by coincidental pre- and post-synaptic firing, following different modes of 6-day visual deprivation. Markedly broader temporal windows were found in robust tLTP and tLTD in the V1M of the deprived visual cortex in mice after 6-day MD and DE. The underlying mechanism for the changes seen with visual deprivation in juvenile mice using 6 days of dark exposure or monocular lid suture involves an increased fraction of NR2b-containing NMDAR and the consequent prolongation of NMDAR-mediated response duration. Moreover, a decrease in NR2A protein expression at the synapse is attributable to the reduction of the NR2A/2B ratio in the deprived cortex.</p></div

Both monocular deprivation and dark exposure expand the temporal windows for tLTP and tLTD.

<p>(A) Conditioning paradigms for tLTP; (E) Conditioning paradigms for tLTD; (B) Bath application of the β-adrenergic agonist isoproterenol (Iso:10 μM, gray bar) increases EPSP slope (open circles) and allows induction of LTP with pairing at +10 ms (filled circles) and +100ms(open circles) in cells from monocular deprived mice. (C)Pairing at +10 ms (open circles) and +100ms (filled circles) in the cells from dark-reared mice result in the induction of LTP. (D) In cells from normal reared mice, isoproterenol promotes the induction of tLTP when pre-then-post delay is 10 ms, but not when it is 100ms. (F) In the presence of the α1 adrenergic agonist methoxamine (Metox: 5 μM for 10 min, grid bar) pairing with -10 ms (filled circles) and -100ms (open circles) induces LTD in cells from monocular-deprived mice. (G)Bath application of the α1 adrenergic agonist methoxamine allows induction of LTD with -10ms (solid circles) or −100 ms (open circles) pairing in cells from dark-reared mice. (H)In cells from normal reared mice,tLTD can be induced with methoxamine when post-then-pre delay is -10ms,but no tlTD is observed when the delay is -100ms. Traces (top) are average of ten consecutive responses recorded before (thin) and after pairing (thick). Note no Changes in pair pulse ratio (PP Ratio) (Bottom graph) for pairing. Plotted data is average ± SEM; Calibration:6 mV, 10 ms.</p