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

Abstract

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.

Figure 1. Flow chart of literature search and study selection.

Figure 2. Forest plots describing overall meta-analysis (left) and cumulative meta-analysis (right) of the associations between IVS+4 T>C polymorphism and POAG risk.

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.

Figure 3. Forest plots describing overall meta-analysis (left) and cumulative meta-analysis (right) of the associations between IVS+32 C>T polymorphism and POAG risk.

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.

Figure 4. Forest plots describing subgroup analyses of the association between OPA1 polymorphisms and risk for NTG.

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.

Figure 5. Forest plots describing subgroup analyses of the association between OPA1 polymorphisms and risk for HTG.

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.

Figure 6. Begg’s funnel plot of OPA1 polymorphisms and NTG for allelic model.

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.