Open Access
Glaucoma  |   March 2019
Association of Gene Polymorphisms With Primary Open Angle Glaucoma: A Systematic Review and Meta-Analysis
Author Affiliations & Notes
  • Min Chen
    Eye Center, the 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China
    Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China
  • Xiaoning Yu
    Eye Center, the 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China
    Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China
  • Jia Xu
    Eye Center, the 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China
    Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China
  • Jian Ma
    Eye Center, the 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China
    Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China
  • Xinyi Chen
    Eye Center, the 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China
    Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China
  • Binbin Chen
    Eye Center, the 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China
    Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China
  • Yuxiang Gu
    Eye Center, the 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China
    Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China
  • Kaijun Wang
    Eye Center, the 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China
    Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China
  • Correspondence: Kaijun Wang, The 2nd Affiliated Hospital, Medical College of Zhejiang University, No. 88 Jiefang Road, Hangzhou 310009, China; ze_wkj@zju.edu.cn
  • Footnotes
     MC and XY contributed equally to the work presented here and should therefore be regarded as equivalent authors.
Investigative Ophthalmology & Visual Science March 2019, Vol.60, 1105-1121. doi:10.1167/iovs.18-25922
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      Min Chen, Xiaoning Yu, Jia Xu, Jian Ma, Xinyi Chen, Binbin Chen, Yuxiang Gu, Kaijun Wang; Association of Gene Polymorphisms With Primary Open Angle Glaucoma: A Systematic Review and Meta-Analysis. Invest. Ophthalmol. Vis. Sci. 2019;60(4):1105-1121. doi: 10.1167/iovs.18-25922.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To confirm the association of all reported common polymorphisms with POAG.

Methods: We searched in PubMed and Web of Science (up to January 10, 2018) for genetic studies of POAG. All case control studies investigating the association between single-nucleotide polymorphisms (SNPs) and POAG risk were included. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by fixed- or random-effect model.

Results: This meta-analysis included 108 case control studies involving 35,389 POAG patients and 51,742 controls. The pooled results showed a significant association between 20 SNPs in 12 genes (148Asp/Glu in APE1 gene; rs449647 in APOE gene; rs1052990 and rs4236601 in CAV1/CAV2 gene; rs1799750 in MMP gene; c.603T3A (Met98Lys) in OPTN gene; rs7081455 in PLXDC2 gene; rs1279683 in SLC23A2 gene; 372 T/C in TIMP1 gene; rs1927911, rs2149356, rs4986791, rs7037117, and rs10759930 in TLR4 gene; rs4656461 in TMCO1 gene; 399Arg/Gln in XRCC1 gene; and rs540782, rs547984, and rs693421 in ZP4 gene) with POAG.

Conclusions: Based on the current meta-analysis, we indicate 20 SNPs in 12 genes (APE1, APOE, CAV1/CAV2, MMP, OPTN, PLXDC2, SLC23A2, TIMP1, TLR4, TMCO1, XRCC1, ZP4) as predictive risk factors for POAG. More studies with large sample sizes and various ethnicities are warranted in the future to provide more powerful evidence.

Glaucoma is the leading cause of irreversible blindness and affects more than 70 million people in the world.13 It has been estimated that over 11.1 million people will be bilaterally blind from primary glaucoma by 2020.4 POAG is the most common type of glaucoma, accounting for 74% of all glaucoma cases.4 
POAG is characterized by progressive loss of retinal ganglion cells (RGCs), damage of the optic nerve, and subsequent irreversible visual field loss.5 So far, the pathogenesis of POAG is not entirely clear. Epidemiologic studies suggest various risk factors, including age, elevated IOP, vascular factors, systemic disease, diabetes, myopia, family history, and cigarette smoking.6 Genetic factors are also thought to be a potential risk to POAG patients.7 So far, more than 20 candidate chromosomal loci have been linked to POAG.8 Among them, genes causing monogenic forms of POAG include myocilin (MYOC), optineurin (OPTN), and WD repeat-domain 36 (WDR36).7 Besides, genome-wide association studies (GWASs) have identified several susceptibility loci, such as CAV1/CAV2,9 CDKN2B-AS1 gene,10,11 SIX6 gene,12 NTM and CNTNAP4 genes,13 and so on. 
In recent years, the relationship between genetic polymorphisms and glaucoma has attracted much concern. Several studies have identified many genetic variants that might contribute to POAG.14,15 However, the association of individual genes, including allele frequency, odds ratio (OR), and statistical significance, vary across different study cohorts, due to clinical heterogeneity, different ethnic populations, and sample sizes. Therefore, we conducted a systematic review and meta-analysis to summarize the effects of all reported gene polymorphisms and clarify their possible association with POAG. 
Materials and Methods
This meta-analysis complies with the Preferred Reporting Items for Systematic Review and Meta-Analysis statement16 (Supplementary Files S1). 
Literature Search
A systematic literature search in PubMed and Web of Science was conducted to identify all published genetic studies on the association of polymorphisms with POAG, covering publications up to January 10, 2018. The key words used for the literature search were as follows: (“single nucleotide polymorphisms” OR “gene” OR “SNPs”) AND (“open angle” OR “open-angle”). Titles and abstracts were screened to identify potentially relevant studies by two investigators (CM and YXN) independently. Hand searching of reviews was performed to obtain additional studies. All related articles published in English-language journals were retrieved for analysis (Supplementary Files S2). 
Inclusion and Exclusion Criteria
Literature selection had to meet the following criteria: (1) unrelated case control of cohort studies investigating the relationship between a certain single-nucleotide polymorphisms (SNP) and POAG; (2) allele or genotype counts or frequency of common SNPs in both the case and control groups available from the articles; and (3) sufficient information for estimating OR or relevant risk (RR) with corresponding 95% confidence interval (CI). The exclusion criteria were as follows: (1) case report or case series; (2) meeting abstract, editorial comment, letters, or review papers; (3) animal studies; and (4) family or pedigree studies. For studies that were published by the same group on the same gene and makers, only the most recent or complete study was used in this meta-analysis. 
Literature Review and Data Extraction
Two reviewers (CM and YXN) independently reviewed and extracted data from the eligible studies. Disagreements were resolved by discussion between all authors until consensus was reached. The following information was extracted from each article: first author, year of publication, region, ethnicity of study subjects, sex composition, mean age, sample size, subtypes of POAG, genotyping method and genotype frequency, and Hardy-Weinberg equilibrium result in controls, and so on. When the allelic counts were not reported in some articles, they were calculated from the genotype data or estimated by using the allelic frequencies and sample sizes if genotype counts were not given. If the allele and/or genotype data in high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) were reported separately, the data were combined into one group as POAG. 
Quality Assessment
The methodologic quality of eligible studies was evaluated independently by two authors (CM and YXN), according to the Newcastle-Ottawa scale (NOS) for genetic association studies.17 NOS quality scores ranged between 0 and 9 stars. Studies with a score of 5 stars or greater were considered high quality (Supplementary Files S3). 
Statistical Analysis
Meta-analysis for each polymorphism was performed if it was reported in two or more studies. The strength of association between SNPs and POAG was estimated by OR/RR values with corresponding 95% CI. The pooled OR/RRs were analyzed for the allele model (T versus C), homozygote model (CC versus TT), heterozygote model (TC versus CC), dominant model (TT + TC versus CC), and recessive model (TT versus CT + CC), respectively. Statistical analyses were performed by using the Stata version 12.0 software (Stata Corporation, College Station, TX, USA). A pooled P value of less than 0.05 was considered to have significant genetic association. 
The I2 index score was applied to evaluate the potential heterogeneity among the individual studies, with I2 score greater than 50% regarded as having a high degree of heterogeneity.18 In addition, a Q-statistic test was performed, and P less than 0.01 was considered to have significant heterogeneity. The summary OR and 95% CI for each polymorphism were pooled by using the fixed-effects model (Mantel-Haenszel) when no significant heterogeneity was observed among studies. Otherwise, the random-effects model (DerSimonian and Laird) was applied.19 Sensitivity analysis was performed to evaluate the stability of individual studies. Potential publication bias was evaluated by Begg's funnel plot test.20 
Results
Literature Search
The process of literature selection is presented in Figure 1. Initially, we identified a total of 3805 articles; 3642 were identified from electronic databases by using the search strategy, and hand searching identified 163 additional records from reference lists of included studies. Three thousand four hundred seventy-eight studies remained after removal of 327 duplicates, which underwent a careful screening of title and abstract. Among them, 3329 articles were excluded because 1687 were about irrelevant topics, 155 were not original studies, 363 were reviews and meta-analyses, 394 were functional studies, 62 were family or pedigree studies, and 668 were animal studies. We retrieved the full text of the remaining 149 studies for review. Forty-one articles were further excluded for the following reasons: seven were not case control studies2127; 27 articles did not provide genotype or allele data2854; and seven articles did not provide proper OR/RR values.13,5560 Thus, 108 studies were finally included in this meta-analysis.10,12,61167 
Figure 1
 
Flow chart of the study selection procedure.
Figure 1
 
Flow chart of the study selection procedure.
Characteristics of Included Studies
The main characteristics of the included studies are summarized in Table 1. This meta-analysis involved 108 case control studies, with a total of 35,398 POAG cases and 51,742 controls. The publication years of the included studies ranged from 2002 to 2018. The distributions of genotypes of all SNPs in the control groups were consistent with the Hardy-Weinberg equilibrium in all studies. All studies had adequate quality because the NOS scores in each study were above 5 stars and the mean score was 7.3. The quality of these studies is summarized in Supplementary Files S3
Table 1
 
Characteristics of the Studies Included in the Meta-Analysis
Table 1
 
Characteristics of the Studies Included in the Meta-Analysis
Meta-Analysis of the Genetic Association With POAG
Significant Association Between SNPs and POAG
Twenty SNPs in 12 genes reported in candidate studies showed significant association with POAG in this meta-analysis (Table 2). 
Table 2
 
Significant Association of Gene Polymorphisms With POAG
Table 2
 
Significant Association of Gene Polymorphisms With POAG
For SNP 148Asp/Glu in the APE1 gene, two studies (562 POAG cases and 644 controls) were involved.74,90 Significant association was found between this SNP and POAG risk in homozygote (OR 5.91, 95% CI: 1.24–28.17; P = 0.85, I2 = 0.00) and recessive models (OR 5.26, 95% CI: 1.12–24.82; P = 0.85, I2 = 0.00), but not in allelic, heterozygote, or dominant models (Table 2, Supplementary Files S4). 
For SNP rs449647 in the APOE gene, five studies (1937 cases and 1958 controls) were included for calculation.78,79,138,144,148 Significant association was found in the overall populations in allelic (OR 1.33, 95% CI: 1.13–1.57; P = 0.54, I2 = 0.00), homozygote (OR 1.61, 95% CI: 1.05–2.45; P = 0.53, I2 = 0.00), heterozygote (OR 1.32, 95% CI: 1.08–1.62; P = 0.95, I2 = 0.00), and dominant comparisons (OR 1.37, 95% CI: 1.12–1.66; P = 0.80, I2 = 0.00), but not in the recessive model (Table 2, Supplementary Files S5). 
Two SNPs in the CAV1/CAV2 gene showed significant association with POAG in allelic models (rs1052990, OR 1.17, 95% CI: 1.04–1.31; P = 0.00, I2 = 87.30; rs4236601, OR 1.24, 95% CI: 1.16–1.32; P = 0.06, I2 = 51.10). No significant association was found in SNP rs4236601 in homozygote, heterozygote, dominant, or recessive models (Table 2, Supplementary Files S6).65,72,77,82,84,85,115 
For SNP rs1799750 in the MMP gene, four studies (885 POAG cases and 875 controls) were involved.94,95,104,121 The pooled results showed that rs1799750 was significantly correlated with POAG in recessive model (OR 1.64, 95% CI: 1.05–2.56; P = 0.01, I2 = 73.90). No evidence of association was observed in rs3918242 in the MMP gene94,95 (Table 2, Supplementary Files S7). 
For SNP c.603T3A (Met98Lys) in the OPTN gene, five studies (1339 POAG cases and 939 controls) were included for calculation.123,137,144,145,152 Significant association was found in the overall populations in homozygote (OR 52.58, 95% CI: 1.12–5.97; P = 0.41, I2 = 0.00) and recessive models (OR 2.50, 95% CI: 1.09–5.77; P = 0.55, I2 = 0.00). No evidence of association was found in c.412G3A (Thr34Thr) in the OPTN gene in all genetic models (Table 2, Supplementary Files S8). 
SNP rs7081455 in the PLXDC2 gene was reported in three studies, involving a total of 1428 POAG cases and 1222 controls.64,101,128 Significant association was found in the overall populations in the allelic model (OR 1.46, 95% CI: 1.28–1.68; P = 0.697, I2 = 0.00, Table 2, Supplementary Files S9). 
SNP rs1279683 in the SLC23A2 gene was reported in two studies, involving a total of 400 POAG cases and 400 controls.97,117 Significant association was found in the overall populations in the allelic model (OR 1.43, 95% CI: 1.10–1.87; P = 0.04, I2 = 76.20, Table 2, Supplementary Files S10). 
SNP 372 T/C in the TIMP1 gene was reported in two studies, involving a total of 451 POAG cases and 509 controls.94,104 Significant association was found in the overall populations in the recessive model (OR 1.50, 95% CI: 1.12–2.01; P = 0.69, I2 = 0.00, Table 2, Supplementary Files S11). 
Nine SNPs in the TLR4 gene were included in this meta-analysis and five of them conferred significant risk of POAG.66,70,101,107,114,134,153 Rs1927911 (4 studies, 669 POAG patients and 830 controls) was found to have significant association with POAG in allelic (OR 1.28, 95% CI: 1.03–1.57; P = 0.07, I2 = 57.20), homozygote (OR 1.43, 95% CI: 1.00–2.05; P = 0.20, I2 = 34.70), heterozygote (OR 1.46, 95% CI: 1.06–1.99; P = 0.06, I2 = 58.90), and dominant models (OR 1.45, 95% CI: 1.07–1.97; P = 0.05, I2 = 62.00), but not in the recessive model.66,70,114,134 Rs2149356 (4 studies, 669 POAG patients and 830 controls) was found to have significant association with POAG in allelic (OR 1.35, 95% CI: 1.04–1.76; P = 0.01, I2 = 73.00), homozygote (OR 1.61, 95% CI: 1.07–2.43; P = 0.11, I2 = 50.70), heterozygote (OR 1.53, 95% CI: 1.01–2.32; P = 0.01, I2 = 76.10), dominant (OR 1.56, 95% CI: 1.04–2.33; P = 0.00, I2 = 77.90), and recessive comparisons (OR 1.33, 95% CI: 1.03–1.73; P = 0.51, I2 = 0.00).66,70,114,134 For rs4986791 (2 studies, 272 POAG patients and 204 controls), significant association was found in the overall population in allelic (OR 2.54, 95% CI: 1.21–5.32; P = 0.42, I2 = 0.00) and heterozygote models (OR 2.31, 95% CI: 1.06–5.00; P = 0.35, I2 = 0.00).66,70 For rs7037117 (4 studies, 769 POAG patients and 961 controls), significant association was found only in homozygote comparison (OR 1.50, 95% CI: 1.01–2.24; P = 0.62, I2 = 0.00), but not in allelic, heterozygote, dominant, and recessive models.70,101,114,134 For rs10759930 (4 studies, 666 POAG patients and 937 controls), significant association was found in allelic (OR 1.34, 95% CI: 1.06–1.70; P = 0.02, I2 = 69.90), homozygote (OR 1.64, 95% CI: 1.10–2.43; P = 0.10, I2 = 52.40), heterozygote (OR 1.55, 95% CI: 1.28–1.88; P = 0.01, I2 = 72.80), dominant (OR 1.58, 95% CI: 1.08–2.29; P = 0.01, I2 = 75.70), and recessive comparisons (OR 1.29, 95% CI: 1.01–1.65; P = 0.58, I2 = 0.00).70,107,114,134 However, poor association was found in rs1927914, rs7045953, rs11536889, and rs12377632 in the TLR4 gene66,70,114,134 (Table 2, Supplementary Files S12). 
SNP rs4656461 in the TMCO1 gene has been reported in four studies; involving a total of 2384 POAG cases and 7668 controls.10,75,82,85 Significant association was found in the overall populations in the allelic comparison (OR 1.46, 95% CI: 1.32–1.62; P = 0.00, I2 = 87.50, Table 2, Supplementary Files S13). 
SNP 399Arg/Gln in the XRCC1 gene was reported in three studies involving a total of 742 POAG cases and 840 controls. Significant association was found in the overall populations in allelic (OR 1.23, 95% CI: 1.07–1.43; P = 0.39, I2 = 0.00), heterozygote (OR 1.70, 95% CI: 1.21–2.38; P = 0.13, I2 = 50.70), and dominant models (OR 1.58, 95% CI: 1.08–2.29; P = 0.19, I2 = 39.30), although no significant association was found in 194Arg/Trp in the XRCC1 gene under allelic, heterozygote, and dominant models (Table 2, Supplementary Files S14). 
Three SNPs in the ZP4 gene showed significant association with POAG. For rs540782 (2 studies, 919 POAG cases and 843 controls), significant association was found in the allelic model (OR 1.31, 95% CI: 1.15–1.50; P = 0.39, I2 = 0.00).128,154 For rs547984 (3 studies, 1334 POAG cases and 1087 controls), significant association was found in the overall populations in the allelic model (OR 1.25, 95% CI: 1.10–1.42; P = 0.32, I2 = 11.40).64,128,155 For rs693421 (2 studies, 1011 POAG cases and 978 controls), significant association was found in the overall populations in the allelic model (OR 1.26, 95% CI: 1.11–1.43; P = 0.05, I2 = 75.20)101,128 (Table 2, Supplementary Files S15). 
Stratified Analysis of Candidate SNPs Associated With POAG
Stratified analysis for candidate SNPs associated with POAG was further performed if it was reported in two or more studies. Subgroup analysis stratified by HTG and NTG showed that APOE rs449647 had significant association with HTG in allele (OR 1.89, 95% CI: 1.20–2.96, P = 0.006), heterozygote (OR 1.74, 95% CI: 1.06–2.86, P = 0.030), and dominant models (OR 1.83, 95% CI: 1.14–2.96, P = 0.013), but not with NTG in any of the genetic models. PLXDC2 rs7081455 also indicated significant association with HTG in allele model (OR 1.41, 95% CI: 1.09–1.81, P = 0.008). OPTN c.603T>A (Met98Lys) showed significant association with NTG in allele (OR 1.53, 95% CI: 1.21–1.94, P = 0.000), homozygote (OR 2.82, 95% CI: 1.14–6.93, P = 0.024), heterozygote (OR 1.48, 95% CI: 1.13–1.93, P = 0.004), dominant (OR 1.55, 95% CI: 1.19–2.01, P = 0.001), and recessive models (OR 2.55, 95% CI: 1.05–6.22, P = 0.039). For the TLR4 gene, only rs10759930 indicated significant association with NTG in homozygote (OR 1.43, 95% CI: 1.06–1.94, P = 0.020) and heterozygote models (OR 1.27, 95% CI: 1.02–1.59, P = 0.031, Supplementary Files S16). 
In the stratification analyses by ethnicity, four SNPs in three genes indicated significant association with POAG in Asians, including rs449647 in the APOE gene, c.603T>A (Met98Lys) in the OPTN gene, rs1927911 and rs2149356 in the TLR4 gene, and rs547984 in the ZP4 gene. Besides, APOE rs449647, CAV1/CAV2 rs4236601, and MMP rs1799750 showed significant association with POAG in Caucasians. Only rs4656461 in the TMCO1 gene showed significant association with POAG in Australian (Supplementary Files S16). 
Lack of Association Between SNPs and POAG
Twenty-seven SNPs in 19 genes showed no significant association with POAG in this meta-analysis, including rs1900004 and rs7916697 in the ATOH7 gene,75,85,102,109,110 rs1001179 in the CAT gene,61,15 rs1063192, and rs4977756 in the CDKN2B gene,10,12,67,69,71,75,82,85,102,103,110,157 rs12994401 in the chromosome2p gene,88,99,101,119,120,125,151 rs1800440 in the CYP1B1 gene,89,118,158 rs754203 in the CYP46A1 gene,101,113,124 rs3764028 in the GRIN2B gene,78,86 -511C/T in the IL-1b gene,94,135,136 rs3825942, rs1048661, and rs2165241 in the LOXL1 gene,27,76,80,81,91,93,98,126,130132 rs1801133 in the MTHFR gene,89,105,118,127,129,133,141,149,150 324Gln/His in the MUTYH gene,74,96 rs2070744 in the NOS3 gene,83,106,111,112,118 326Ser/Cys in the OGG1 gene,74,96 rs166850 and rs10451941 in the OPA1 gene,89,118,122,142144,146,147,159 rs1042522 in the p53 gene,86,118,160163 rs10483727 and rs33912345 in the SIX1/SIX6 gene,12,62,67,75,82,85,103,110 rs7961953 in the TMTC2 gene,64,105 -863C/A, -238G/A, and rs1800629 in the TNF-a gene,89,100,118,140,164167 and rs1042522 in the TP53 gene86,118 (Supplementary Files S17). 
Sensitivity Analysis
To examine the stability of pooled results, sensitivity analysis was conducted by sequentially excluding individual studies and calculating the pooled ORs for the remaining studies. The outcomes did not alter the significance of pooled OR estimates, which indicated that our results were stable and reliable (data not shown). 
Publication Bias
Begg's test did not detect evidence of publication bias in the overall analyses for 20 SNPs in 12 genes, which show significant association with POAG in candidate studies (Begg's test, Z < 1.96, P > 0.05, Table 2, Supplementary File S16). 
Discussion
This is the first meta-analysis that summarized all reported gene SNPs and relevant phenotypes associated with POAG. We confirmed significant associations of 20 SNPs in 12 genes with POAG risk. Meanwhile, 27 SNPs in 19 genes were revealed to have no significant association with POAG. Possible functions and hypothetical involvement in POAG of candidate gene SNPs were summarized in Figure 2 and Table 3
Figure 2
 
Possible functions and hypothetical involvement in POAG of candidate gene SNPs.
Figure 2
 
Possible functions and hypothetical involvement in POAG of candidate gene SNPs.
Table 3
 
Candidate POAG Associated Genes, Possible Functions, and Hypothetical Involvement in POAG
Table 3
 
Candidate POAG Associated Genes, Possible Functions, and Hypothetical Involvement in POAG
Outflow Pathway–Related Genes
Matrix metalloproteinases (MMPs) are endopeptidases involved in the proteolysis of extracellular matrix (ECM) proteins.168 Decreased activity of MMPs in the aqueous humor might result in abnormal accumulation of matrix in POAG patients.169 It was reported that the rs1799750 of the MMP1 gene may be a risk factor associated with POAG in a Polish94,104 and a Pakistani population.95 Three hundred seventy-two T/C polymorphisms in tissue inhibitors for metalloproteinases (TIMPs) encoding genes have also been identified in POAG patients.94 Plexin domain containing 2 (PLXDC2) is a cell-surface transmembrane protein, which was identified as a receptor for pigment epithelium–derived factor (PEDF).170 The PLXDC2 genetic variant may lead to a different responsiveness to PEDF and increased IOP. Mabuchi et al.64 found that there was a significant difference in the rs7081455 in PLXDC2 gene allele frequencies between POAG patients and control subjects in a Japanese population. 
The three genes may be associated with outflow pathway and increased IOP. Our meta-analysis found significant association with POAG in rs1799750 of the MMP1 gene (recessive model), 372 T/C of the TIMP1 gene (recessive model), and rs7081455 of the PLXDC2 gene (allelic model). 
Oxidative Stress–Related Genes
Oxidative stress is one of the risk factors for POAG.171 Cells developed special mechanisms to remove DNA damage and base exaction repair (BER) is the most important pathway.172 APE1 is a crucial enzyme that participates in the BER pathway. The 148 Asp/Glu polymorphism of APE1 gene may have a relationship with hypersensitivity to ionizing radiation and play a protective role in POAG progression.173 OPTN is the second gene identified by genetic linkage analysis, which may be responsible for approximately 1.5% of NTG cases.174 It was reported that OPTN protects cells from oxidative stress and inhibits cytochrome c release from mitochondria.175 Vitamin C is an important water-soluble antioxidant.176 The SLC23A2 gene encodes the vitamin C co-transporter gene, which plays an important role in vitamin C transmembrane transport. It was reported that rs1279683 polymorphism of the SLC23A2 gene was associated with lower plasma vitamin C concentrations and higher risk of POAG.97,117 XRCC1 protein was encoded by the x-ray repair cross-complementing group1 (XRCC1) gene, which can coordinate the various components of the BER mechanism. Genetic polymorphism of XRCC1 can change the structure of this protein and result in impaired DNA repair capacity.177 It has been reported that the 399Arg/Gln genotype of the XRCC1 gene was associated with an increased risk of POAG.74,96 
The overall results of our study showed significant association with POAG in 148Asp/Glu of the APE1 gene (homozygote and recessive models), c.412G3A (Thr34Thr) of the OPTN gene (homozygote model), rs1279683 of the SLC23A2 gene (allelic model), and 399Arg/Gln of the XRCC1 gene (allelic, heterozygote, and dominant model). 
Apoptosis and Neurodegeneration–Related Genes
Apolipoprotein E (APOE) belongs to the class of lipoproteins that regulate the metabolism of lipids in the body. Many studies have shown that apolipoprotein E is associated with the neurodegenerative diseases, such as Alzheimer disease and glaucoma.178 APOE (-219G) is associated with increased optic nerve damage, and APOE (-491T) interacts with an SNP in the MYOC promoter (-1000G), which is associated with the increased IOP in POAG.148 CAV1 and CAV2 code for caveolin protein family members caveolin 1 and caveolin 2.179 These proteins inhibit endothelial nitric oxide synthase activity within the caveolae. This interaction may alter nitric oxide generation and change trabecular meshwork function, both of which have been implicated in POAG pathogenesis.180 The TMCO1 gene encodes a transmembrane protein, which may localize to the Golgi apparatus and endoplasmic reticulum or mitochondria in different cell types, and with a proposed role in apoptosis.10 The toll-like receptor 4 (TLR4) gene encodes for a transmembrane pathogen recognition receptor involved in the detection of lipopolysaccharides of gram-negative bacteria and other exogenous or endogenous ligands.181 TLR4 signaling has been implicated in the pathogenesis of IOP-induced RGC death. Upregulation of the TLR4 gene may lead to enhanced neurodegeneration, which has been demonstrated in glaucomatous animals.182 Recently, multiple SNPs (rs10759930, rs1927914, and rs7037117, rs10759930, rs1927914, rs1927911, rs12377632, and rs2149356) in the TLR4 gene have been reported with POAG.134 
In this meta-analysis, pooled results showed that rs449647 of the APOE gene showed significant association with POAG in allelic, homozygote, heterozygote, and dominant comparison; rs1052990 and rs4236601 of the CAV1/CAV2 gene showed significant association with POAG in the allelic model; SNP rs4656461 of the TMCO1 gene showed significant association with POAG in allelic model, and five SNPs (rs1927911, rs2149356, rs4986791, rs7037117, and rs10759930) of the TLR4 gene confer an increased risk of POAG. 
Other POAG-Associated Genes
The zona pellucida glycoprotein 4 (ZP4) gene is involved in functions related to fertilization and preimplantation development. SNPs and/or mutations in this gene were reported in association with ovarian diseases.183 Reported association of ZP4 SNPs with POAG was controversial. In 2009, Nakano et al.128 reported that three candidate SNPs (rs547984, rs540782, rs693421, and rs2499601) in the ZP4 gene were modestly associated with the pathogenesis of POAG. Subsequent studies have failed to replicate this association between rs540782 and POAG in Indian,184 Afro-Caribbean,102 Japanese,185 and Saudi154 populations. Rs547984 in the ZP4 gene also lacked association with POAG in a Saudi cohort.155 In our meta-analysis, three SNPs (rs540782, rs547984, and rs693421) in the ZP4 gene proved to have significant association with POAG in the allelic model. 
Strengths and Limitations
Our meta-analysis has several strengths. As far as we know, this is the first meta-analysis that summarized all reported gene SNPs and relevant phenotypes associated with POAG. The results were robust due to the large number of cases and controls. Quality assessment, sensitivity analysis, and Begg's test were used to assess the potential biases, and failed to detect a significant bias in any of the genetic models, which demonstrated the credibility of the present meta-analysis. 
However, some limitations should be mentioned in this meta-analysis. First, adjusted factors, such as age, sex, and genotyping procedure, did not apply in the pooled results assessment. Second, the possibility of publication bias may exist because studies without statistically significant results would not be published. Only articles published in English-language journals were included, which might lead to language bias and the omission of inconclusive or negative studies in non-English articles. Third, Begg's funnel plot test may not play a perfect role in the present meta-analysis owing to an insufficient number of studies. 
Conclusions
This systematic review and meta-analysis provided an overview of all reported gene SNPs in POAG. Our results highlighted 20 SNPs in 12 genes (APE1, APOE, CAV1/CAV2, MMP, OPTN, PLXDC2, SLC23A2, TIMP1, TLR4, TMCO1, XRCC1, ZP4) as predictive risk factors for POAG. Further efforts should be made to generate a better understanding of the potential pathways and mechanisms. Well-designed and large-scale studies in various populations should be carried out in the future to provide more powerful evidence. 
Acknowledgments
Supported by the National Natural Science Foundation of China (No. 81700829 and 81800869; Beijing, China) and the Zhejiang Provincial Natural Science Foundation of China (No. LY19H120006 and LY17H120002; Hangzhou, Zhejiang, China). 
Disclosure: M. Chen, None; X. Yu, None; J. Xu, None; J. Ma, None; X. Chen, None; B. Chen, None; Y. Gu, None; K. Wang, None 
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Figure 1
 
Flow chart of the study selection procedure.
Figure 1
 
Flow chart of the study selection procedure.
Figure 2
 
Possible functions and hypothetical involvement in POAG of candidate gene SNPs.
Figure 2
 
Possible functions and hypothetical involvement in POAG of candidate gene SNPs.
Table 1
 
Characteristics of the Studies Included in the Meta-Analysis
Table 1
 
Characteristics of the Studies Included in the Meta-Analysis
Table 2
 
Significant Association of Gene Polymorphisms With POAG
Table 2
 
Significant Association of Gene Polymorphisms With POAG
Table 3
 
Candidate POAG Associated Genes, Possible Functions, and Hypothetical Involvement in POAG
Table 3
 
Candidate POAG Associated Genes, Possible Functions, and Hypothetical Involvement in POAG
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