Advertisement
Research Article

Myocilin Polymorphisms and Primary Open-Angle Glaucoma: A Systematic Review and Meta-Analysis

  • Jin-Wei Cheng equal contributor,

    equal contributor Contributed equally to this work with: Jin-Wei Cheng, Shi-Wei Cheng

    Affiliation: Department of Ophthalmology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China

    X
  • Shi-Wei Cheng equal contributor,

    equal contributor Contributed equally to this work with: Jin-Wei Cheng, Shi-Wei Cheng

    Affiliation: School of Life Sciences, Ludong University, Yantai, China

    X
  • Xiao-Ye Ma,

    Affiliation: Department of Ophthalmology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China

    X
  • Ji-Ping Cai,

    Affiliation: Department of Ophthalmology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China

    X
  • You Li,

    Affiliation: Department of Ophthalmology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China

    X
  • Guo-Cai Lu mail,

    newdrug@smmu.edu.cn (G-CL); ruiliwei@126.com (R-LW)

    Affiliation: Center for New Drug Evaluation, Institute of Basic Medical Science, Second Military Medical University, Shanghai, China

    X
  • Rui-Li Wei mail

    newdrug@smmu.edu.cn (G-CL); ruiliwei@126.com (R-LW)

    Affiliation: Department of Ophthalmology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China

    X
  • Published: September 28, 2012
  • DOI: 10.1371/journal.pone.0046632

Abstract

Background

Glaucoma is the leading cause of irreversible blindness in the world. Recent evidence indicates a role for genetic susceptibility to primary open-angle glaucoma (POAG). The relation between myocilin polymorphisms and POAG susceptibility has been studied in different populations.

Methods

A meta-analysis of 32 published genetic association case-control studies, which examined the relation between POAG and the R46X, R76K, Y347Y, T353I, and Q368X polymorphisms of the myocilin gene, was carried out.

Results

In meta-analysis, significant associations were observed between POAG risk and two myocilin polymorphisms with summarized odds ratio of 4.68 (95%CI, 2.02–10.85) for Q368X and 2.17 (95% CI, 1.32–3.57) for T353I. Both Q368X and T353I were significantly associated with high-tension glaucoma, with summarized odds ratio of 4.26 (1.69, 10.73) and 2.26 (1.37–3.72). In Westerners, significant association was observed for Q368X mutation (odds ratio, 5.17; 95% CI, 2.16–12.40). However, in Asians it was for T353I (odds ratio, 2.17; 95% CI, 1.32–3.57).

Conclusions

There is strong evidence that myocilin polymorphisms are associated with POAG susceptibility, and the prevalence of myocilin mutations might be ethnicity-dependent in Caucasians for Q368X and in Asians for T353I.

Introduction

Glaucoma, which causes optic nerve damage and visual field loss, is the leading causes of irreversible blindness worldwide [1]. A family history of the disease has long been recognized as a major risk factor for glaucoma, suggesting that specific gene defects contribute to the pathogenesis of the disorder [2]. The most common form of glaucoma is primary open-angle glaucoma (POAG), which is characterized with typical optic disc damage and visual field defects, in an eye which does not have evidence of angle closure on gonioscopy, accompanied with elevated or normal intraocular pressure (IOP). Several chromosomal loci have now been reported as linked to POAG, such as myocilin (MYOC; GLC1A, MIM 601652), optineurin (OPTN; GLC1E, MIM 602432), and WD repeat domain 36 (WDR36; GLC1G, MIM 609669) [3].

The MYOC gene, also known as trabecular meshwork-inducible glucocorticoid response (TIGR) gene, was the first discovered to be linked to POAG in 1997 [4]. Several large studies have suggested that MYOC mutations are associated with 2% to 4% of POAG in patient populations worldwide, with more than 30 disease-associated mutations identified [5], [6]. The overall frequency of disease-causing mutations at MYOC is similar among African (4.44%), Caucasian (3.86%) and Asian (3.30%) probands with POAG [7]. Most disease-associated mutations at MYOC exist only in a specific racial group. The most frequent mutation Gln368Stop was present only in Caucasian descendants, and the second most frequent mutation Arg46Stop was shared only by Asian populations. However, the association of MYOC with POAG has been a source of controversy. After the initial discovery of POAG-causing mutations, the mutations were subsequently observed in controls, which were considered as non-disease-causing polymorphisms [8], [9]. Otherwise, reports published previously showed apparent non-consistent results. In familial studies, over four fifths Gln368Stop-carriers did not have POAG [10]. Also, the most frequent mutation Arg46Stop in Asians was even more often found in normal controls than in POAG probands [11]. Because the currently published studies only refer to a modest sample size, each one might not achieve a reliable conclusion. Hence, to investigate the association of the MYOC genetic variation with POAG susceptibility, a newly meta-analysis of all of the available case-control studies was carried out.

Results

A total of 665 articles were identified across PubMed and Embase, and 57 full-text articles were retrieved. Finally, 32 studies met criteria and were included in the present meta-analysis [8], [9], [11][40]. The flow of study selection is shown in Figure 1, and the detailed characteristics of the studies were shown in Table 1. 6,729 patients and 4,871 controls were included in this study. Among those 32 included studies, 18 were conducted in Asians, 12 in Caucasians, and 1 in mixed. There were 19 studies for high-tension glaucoma (HTG), 1 study for normal-tension glaucoma (NTG), and 11 studies for both HTG and NTG. For R46X, R76K, Y347Y, T353I, and Q368X, meta-analyses were conducted within 11, 26, 11, 12, and 9 studies, respectively.

thumbnail

Figure 1. Flow diagram of study selection.

doi:10.1371/journal.pone.0046632.g001
thumbnail

Table 1. Characteristics of publications included in meta-analysis of myocilin polymorphism and POAG.

doi:10.1371/journal.pone.0046632.t001

The association between the MYOC Q368X mutation and POAG was investigated with a total of 3,820 cases and 2,144 controls. Meta-analysis suggested that Q368X mutation carriage might be a risk factor for POAG with a summarized OR of 4.68 (95%CI, 2.02–10.85) (Figure 2), and no heterogeneity between studies (P = 0.76; I2 = 0.00%) was observed. There was no publication bias (P = 0.40 for Begg rank correlation analysis; P = 0.30 for Egger weighted regression analysis). In subgroup analysis by ethnicity, the association was significant in Caucasians, but not in Asians and Africans (Table 2). The association was also significant for HTG.

thumbnail

Figure 2. Meta-analysis of the association between primary open-angle glaucoma and myocilin Q368X mutation.

doi:10.1371/journal.pone.0046632.g002
thumbnail

Table 2. Summary odds ratios from the meta-analysis of the association between primary open-angle glaucoma and myocilin polymorphisms.

doi:10.1371/journal.pone.0046632.t002

It has been shown in Figure 3 that the T353I mutation was significantly associated with POAG (OR, 2.17; 95% CI, 1.32–3.57), with no evidence of heterogeneity among the overall 12 studies (P = 0.85; I2 = 0.00%). No publication bias was observed (P = 0.58 for Begg rank correlation analysis; P = 0.97 for Egger weighted regression analysis). Significant relation was also observed in Asians (Table 2). The ORs of T353I mutation were 2.26 (1.37–3.72) for HTG and 1.58 (0.40–6.22) for NTG.

thumbnail

Figure 3. Meta-analysis of the association between primary open-angle glaucoma and myocilin T353I mutation.

doi:10.1371/journal.pone.0046632.g003

Meta-analyses suggested that the other three MYOC polymorphisms Y347Y, R76K, and R46X were not associated with increased risk of POAG, with summarized ORs of 1.20 (0.91–1.57), 0.86 (0.69–1.08), and 1.02 (0.61–1.70) (Table 2). There was also no significant relation in the subgroup analyses by ethnicity or diagnosis criteria.

Discussion

Myocilin is an eye protein found in the trabecular extracellular matrix, within the anatomic region that controls fluid flow, therefore, it might be the source of the resistance to aqueous humor outflow that causes the elevation of IOP in POAG [6]. Previous genome-wide analysis in a Drosophila ocular hypertension model identified transcripts with altered regulation and showed induction of the unfolded protein response upon overexpression of transgenic human glaucoma-associated myocilin [41]. This meta-analysis examined the MYOC Q368X, T353I, Y347Y, R76K, and R46X polymorphisms and their relationship to susceptibility to POAG. Thirty two articles addressing the most widely studied MYOC polymorphisms were identified, and their effects were summarized by means of meta-analysis. Significant associations with POAG susceptibility were observed for two loci mutations Q368X and T353I. Q368X variant carried near a 4.7-fold increased risk of POAG, and T353I variant carried near a 2.2-fold increase in POAG risk.

Strength of the associations in the subgroup analyses with respect to study population was not consistent. In Caucasians, significant association was observed for Q368X mutation, and, in Asians, it was for T353I. Because the rate of Q368X mutation was rare, of being 0.6% in Asians and 0.3% in Africans respectively [13], [33], the single study with small sample size might lead to the “negative” result in two populations. However, the absence of Q368X mutation was observed in other African [25], [40], [41] and Asian [13], [16], [18], [32] populations. Also, the T353I mutation was absent in Caucasian and African populations. Therefore, a different pattern of MYOC sequence variants might exist among different ethnic populations.

Normal tension glaucoma is a common form of open-angle glaucoma throughout the world, and yet there are many unanswered questions regarding both the mechanisms of the optic neuropathy. A certain level of IOP is the predominant causative risk factor in POAG, while additional IOP-independent factors take increasing importance in NTG [42]. It was proved that NTG was associated with mutations in OPTN [43]. However, a previous meta-analysis demonstrated no evidence of strong association between OPTN polymorphisms and susceptibility to HTG [44]. Therefore, both types of POAG might implicate different genetic susceptibility. In the present meta-analysis, both Q368X and T353I mutation of MYOC were generally shown to confer an increased risk of POAG with elevated IOP, but not for NTG. Although limited number of studies in the stratified analysis might explain, at least in part, the existing inconsistency. The disease-specific observation might suggest that there was different genetic susceptibility between HTG and NTG. Further studies addressing the association of MYOC on HTG and NTG, respectively, are warranted to verify the current findings.

Two previous meta-analyses have assessed the association between MYOC polymorphisms and POAG susceptibility [45], [46]. A previous meta-analysis, which based on 11 case-control studies, suggested an association of MYOC Q368X mutation and POAG [45]. Another meta-analysis of 4 case-control studies suggested that MYOC.mt1 polymorphism does not have significant influence on the risk of POAG development [46]. However, the previously published meta-analyses on the association of MOYC and POAG included the relatively less information and failed to confirm a strong and consistent association. The strength of present meta-analysis investigating the relationship between the MOYC polymorphic variant and susceptibility to POAG is based on the large amount of published data giving greater information.

Although we tried to conduct a thorough review of the existing literature, this study has several potential limitations. First, the possibility of selection biases cannot be completely excluded because all of the included studies were observational, and the potential confounding effect of age and sex might make the interpretation of the results and stratified analyses difficult. Second, only five POAG mutations were included in this analysis. Other potential polymorphisms, such as those at G12R, T123T, D208E, T285T, I288I, T325T, K398R, and A488A, were not included. Third, only published studies were included. Although multiple databases and websites were searched, unfortunately, it is possible that we may have failed to include some papers, especially those published in other languages. We can't find any evidence of publication bias by funnel plots, however, considerable between-study heterogeneity was found for R76K.

In conclusion, this systematic review summarized the strong evidence for an association between myocilin polymorphisms and POAG. Our results suggested Q368X and T353I variants of myocilin gene can be taken as reference loci for exploring POAG susceptibility, both in high-tension glaucoma. Furthermore, the prevalence of the two mutations of myocilin gene might be ethnicity-dependent, namely, in Caucasians for Q368X and in Asians for T353I.

Methods

Search Strategy

Studies addressing the association between MYOC mutations and polymorphisms and POAG were identified by searching for articles in the PubMed, and EMBASE until 31 December 2011. A broad search strategy combined terms related to gene (including keyword search using myocilin, MYOC, trabecular meshwork-induced glucocorticoid response protein, TIGR, GLC1A) and terms related to disease (including MeSH search using exp “glaucoma, open angle”, and keyword search using “open angle glaucoma” and its abbreviation). Additional studies were also identified by a hand search of all the references of retrieved articles.

We included only published manuscripts, without any language restriction. All the studies must meet the following inclusion criteria: (1) case-control study; (2) patients had to be POAG; and (3) Only the most widely mutations and polymorphisms were considered: R46X, R76K, Y347Y, T353I, Q368X. Exclusion criteria were: 1) studies with family-based designs; 2) studies on other polymorphisms other than the target polymorphisms.

Data extraction

Data extraction was performed by two reviewers independently and in duplicate. For each study, the following data were extracted: first authors and publication year, country of origin, study base, study participant ethnicity, numbers of cases and controls, diagnosis criteria, demographic data, and genotype distributions for each polymorphism among cases and controls.

Statistical Analysis

The association between MYOC polymorphism and POAG was calculated using co-dominant model. We used the odds ratio (OR) and corresponding 95% confidence intervals (CI) as the metric of choice. The statistical analysis was performed by Comprehensive Meta-Analysis (V2.0; Biostat, Englewood Cliffs, New Jersey, USA). The between-study heterogeneity was tested by the Q test and I2 test. If no heterogeneity detected (P>0.1), a fixed effects model was selected to pool the data. A random-effect model, otherwise, was employed after exploring the causes of heterogeneity. Stratified analyses were conducted with respect to ethnicity (Africans, Asians and Caucasians) and diagnosis criteria (NTG, HTG). Begg's rank correlation method and Egger's weighted regression method were used to statistically assess publication bias.

Author Contributions

Conceived and designed the experiments: JWC SWC GCL RLW. Performed the experiments: JWC SWC XYM JPC YL GCL RLW. Analyzed the data: JWC SWC. Contributed reagents/materials/analysis tools: GCL. Wrote the paper: JWC SWC XYM JPC YL GCL RLW.

References

  1. 1. Quigley HA (1996) Number of people with glaucoma worldwide. Br J Ophthalmol 80: 389–393. doi: 10.1136/bjo.80.5.389
  2. 2. Weih LM, Nanjan M, McCarty CA, Taylor HR (2001) Prevalence and predictors of open-angle glaucoma: results from the visual impairment project. Ophthalmology 108: 1966–1972. doi: 10.1016/s0161-6420(01)00799-0
  3. 3. Wiggs JL (2007) Genetic etiologies of glaucoma. Arch Ophthalmol 125: 30–37. doi: 10.1001/archopht.125.1.30
  4. 4. Stone EM, Fingert JH, Alward WL, Nguyen TD, Polansky JR, et al. (1997) Identification of a gene that causes primary open angle glaucoma. Science 275: 668–670. doi: 10.1126/science.275.5300.668
  5. 5. Fingert JH, Stone EM, Sheffield VC, Alward WL (2002) Myocilin glaucoma. Surv Ophthalmol 47: 547–561. doi: 10.1016/s0039-6257(02)00353-3
  6. 6. Orwig SD, Lieberman RL (2011) Biophysical characterization of the olfactomedin domain of myocilin, an extracellular matrix protein implicated in inherited forms of glaucoma. PLoS One 6: e16347. doi: 10.1371/journal.pone.0016347
  7. 7. Gong G, Kosoko-Lasaki O, Haynatzki GR, Wilson MR (2004) Genetic dissection of myocilin glaucoma. Hum Mol Genet 13: R91–102.
  8. 8. Faucher M, Anctil JL, Rodrigue MA, Duchesne A, Bergeron D, et al. (2002) Founder TIGR/myocilin mutations for glaucoma in the Québec population. Hum Mol Genet 11: 2077–2090. doi: 10.1093/hmg/11.18.2077
  9. 9. Jansson M, Marknell T, Tomic L, Larsson LI, Wadelius C (2003) Allelic variants in the MYOC/TIGR gene in patients with primary open-angle, exfoliative glaucoma and unaffected controls. Ophthalmic Genet 24: 103–110. doi: 10.1076/opge.24.2.103.13997
  10. 10. Allingham RR, Wiggs JL, De La Paz MA, Vollrath D, Tallett DA, et al. (1998) Gln368STOP myocilin mutation in families with late-onset primary open-angle glaucoma. Invest Ophthalmol Vis Sci 39: 2288–95.
  11. 11. Pang CP, Leung YF, Fan B, Baum L, Tong WC, et al. (2002) TIGR/MYOC gene sequence alterations in individuals with and without primary open-angle glaucoma. Invest Ophthalmol Vis Sci 43: 3231–3235.
  12. 12. Alward WL, Fingert JH, Coote MA, Johnson AT, Lerner SF, et al. (1998) Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A). N Engl J Med 338: 1022–1027. doi: 10.1056/nejm199804093381503
  13. 13. Fingert JH, Héon E, Liebmann JM, Yamamoto T, Craig JE, et al. (1999) Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet 8: 899–905. doi: 10.1093/hmg/8.5.899
  14. 14. Yoon SJ, Kim HS, Moon JI, Lim JM, Joo CK (1999) Mutations of the TIGR/MYOC gene in primary open-angle glaucoma in Korea. Am J Hum Genet 64: 1775–1778. doi: 10.1086/302407
  15. 15. Kubota R, Mashima Y, Ohtake Y, Tanino T, Kimura T, et al. (2000) Novel mutations in the myocilin gene in Japanese glaucoma patients. Hum Mutat 16: 270. doi: 10.1002/1098-1004(200009)16:3<270::aid-humu13>3.0.co;2-m
  16. 16. Lam DS, Leung YF, Chua JK, Baum L, Fan DS, et al. (2000) Truncations in the TIGR gene in individuals with and without primary open-angle glaucoma. Invest Ophthalmol Vis Sci 41: 1386–1391.
  17. 17. Vázquez CM, Herrero OM, Bastús BM, Pérez VD (2000) Mutations in the third exon of the MYOC gene in spanish patients with primary open angle glaucoma. Ophthalmic Genet 21: 109–115. doi: 10.1076/1381-6810(200006)2121-8ft109
  18. 18. Mabuchi F, Yamagata Z, Kashiwagi K, Tang S, Iijima H, et al. (2001) Analysis of myocilin gene mutations in Japanese patients with normal tension glaucoma and primary open-angle glaucoma. Clin Genet 59: 263–268. doi: 10.1034/j.1399-0004.2001.590408.x
  19. 19. Mataftsi A, Achache F, Héon E, Mermoud A, Cousin P, et al. (2001) MYOC mutation frequency in primary open-angle glaucoma patients from Western Switzerland. Ophthalmic Genet 22: 225–231. doi: 10.1076/opge.22.4.225.2218
  20. 20. Fan B, Liang X, Peng Z, Dong X, Liu Y, et al. (2002) Study on single nucleotide polymorphism of TIGR gene in primary open-angle glaucoma patients. Zhonghua Yi Xue Za Zhi 82: 743–747.
  21. 21. Hulsman CA, De Jong PT, Lettink M, Van Duijn CM, Hofman A, et al. (2002) Myocilin mutations in a population-based sample of cases with open-angle glaucoma: the Rotterdam Study. Graefes Arch Clin Exp Ophthalmol 240: 468–474. doi: 10.1007/s00417-002-0455-1
  22. 22. Mukhopadhyay A, Acharya M, Mukherjee S, Ray J, Choudhury S, et al. (2002) Mutations in MYOC gene of Indian primary open angle glaucoma patients. Mol Vis 8: 442–448.
  23. 23. Izumi K, Mashima Y, Obazawa M, Ohtake Y, Tanino T, et al. (2003) Variants of the myocilin gene in Japanese patients with normal-tension glaucoma. Ophthalmic Res 35: 345–350. doi: 10.1159/000074075
  24. 24. Melki R, Belmouden A, Brézin A, Garchon HJ (2003) Myocilin analysis by DHPLC in French POAG patients: increased prevalence of Q368X mutation. Hum Mutat 22: 179. doi: 10.1002/humu.9165
  25. 25. Melki R, Idhajji A, Driouiche S, Hassani M, Boukabboucha A, et al. (2003) Mutational analysis of the Myocilin gene in patients with primary open-angle glaucoma in Morocco. Ophthalmic Genet 24: 153–160. doi: 10.1076/opge.24.3.153.15610
  26. 26. Fan BJ, Leung YF, Pang CP, Baum L, Tam OS, et al. (2004) Single nucleotide polymorphisms of the myocilin gene in primary open-angle glaucoma patients. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 21: 70–73.
  27. 27. Fan BJ, Leung YF, Wang N, Lam SC, Liu Y, et al. (2004) Genetic and environmental risk factors for primary open-angle glaucoma. Chin Med J (Engl) 117: 706–710.
  28. 28. Ishikawa K, Funayama T, Ohtake Y, Tanino T, Kurosaka D, et al. (2004) Novel MYOC gene mutation, Phe369Leu, in Japanese patients with primary open-angle glaucoma detected by denaturing high-performance liquid chromatography. J Glaucoma 13: 466–471. doi: 10.1097/0.ijg.0000138204.6d
  29. 29. Fan BJ, Wang DY, Fan DS, Tam PO, Lam DS, et al. (2005) SNPs and interaction analyses of myocilin, optineurin, and apolipoprotein E in primary open angle glaucoma patients. Mol Vis 11: 625–631.
  30. 30. Rakhmanov VV, Nikitina NIa, Zakharova FM, Astakhov IuS, Kvasova MD, et al. (2005) Mutations and polymorphisms in the genes for myocilin and optineurin as the risk factors of primary open-angle glaucoma. Genetika 41: 1567–1574. doi: 10.1007/s11177-005-0232-4
  31. 31. Funayama T, Mashima Y, Ohtake Y, Ishikawa K, Fuse N, et al. (2006) SNPs and interaction analyses of noelin 2, myocilin, and optineurin genes in Japanese patients with open-angle glaucoma. Invest Ophthalmol Vis Sci 47: 5368–5375. doi: 10.1167/iovs.06-0196
  32. 32. Yao HY, Cheng CY, Fan BJ, Tam OS, Tham CY, et al. (2006) Polymorphisms of myocilin and optineurin in primary open angle glaucoma patients. Zhonghua Yi Xue Za Zhi 86: 554–559.
  33. 33. Bhattacharjee A, Acharya M, Mukhopadhyay A, Mookherjee S, Banerjee D, et al. (2007) Myocilin variants in Indian patients with open-angle glaucoma. Arch Ophthalmol 125: 823–829. doi: 10.1001/archopht.125.6.823
  34. 34. Kumar A, Basavaraj MG, Gupta SK, Qamar I, Ali AM, et al. (2007) Role of CYP1B1, MYOC, OPTN, and OPTC genes in adult-onset primary open-angle glaucoma: predominance of CYP1B1 mutations in Indian patients. Mol Vis 13: 667–676.
  35. 35. Lopez-Martinez F, Lopez-Garrido MP, Sanchez-Sanchez F, Campos-Mollo E, Coca-Prados M, et al. (2007) Role of MYOC and OPTN sequence variations in Spanish patients with primary open-angle glaucoma. Mol Vis 13: 862–872.
  36. 36. Yen YC, Yang JJ, Chou MC, Li SY (2007) Identification of mutations in the myocilin (MYOC) gene in Taiwanese patients with juvenile-onset open-angle glaucoma. Mol Vis 13: 1627–1634.
  37. 37. Bayat B, Yazdani S, Alavi A, Chiani M, Chitsazian F, et al. (2008) Contributions of MYOC and CYP1B1 mutations to JOAG. Mol Vis 14: 508–517.
  38. 38. Jia LY, Tam PO, Chiang SW, Ding N, Chen LJ, et al. (2009) Multiple gene polymorphisms analysis revealed a different profile of genetic polymorphisms of primary open-angle glaucoma in northern Chinese. Mol Vis 15: 89–98.
  39. 39. Chen JH, Xu L, Li Y, Dong B (2011) Study on MYOC/TIGR gene mutations in primary open-angle glaucoma. Zhonghua Yan Ke Za Zhi 47: 122–128.
  40. 40. Whigham BT, Williams SE, Liu Y, Rautenbach RM, Carmichael TR, et al. (2011) Myocilin mutations in black South Africans with POAG. Mol Vis 17: 1064–1069.
  41. 41. Challa P, Herndon LW, Hauser MA, Broomer BW, Pericak-Vance MA, et al. (2002) Prevalence of myocilin mutations in adults with primary open-angle glaucoma in Ghana, West Africa. J Glaucoma 11: 416–20. doi: 10.1097/00061198-200210000-00008
  42. 42. Shields MB (2008) Normal-tension glaucoma: is it different from primary open-angle glaucoma? Curr Opin Ophthalmol 19: 85–8. doi: 10.1097/icu.0b013e3282f3919b
  43. 43. Wiggs JL (2007) Genetic etiologies of glaucoma. Arch Ophthalmol 125: 30–7. doi: 10.1001/archopht.125.1.30
  44. 44. Cheng JW, Li P, Wei RL (2010) Meta-analysis of association between optineurin gene and primary open-angle glaucoma. Med Sci Monit 16: CR369–77.
  45. 45. Liu T, He XG (2007) Meta-analysis on the association of Myocilin Q368X mutation and primary open angle glaucoma. Zhonghua Yan Ke Za Zhi 43: 361–6.
  46. 46. Liu T, Zeng D, Zeng C, He X (2008) Association between MYOC.mt1 promoter polymorphism and risk of primary open-angle glaucoma: a systematic review and meta-analysis. Med Sci Monit 14: RA87–93.