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PAX6 Gene Associated with High Myopia: A Meta-analysis

Tang, Shu Min*; Rong, Shi Song; Young, Alvin L.; Tam, Pancy O. S.§; Pang, Chi Pui; Chen, Li Jia**

doi: 10.1097/OPX.0000000000000224
Original Articles

Purpose The PAX6 gene is among the most studied genes in high myopia, but reported findings of association studies on PAX6 and high myopia are inconsistent. We conducted a systematic review and meta-analysis to evaluate the association of PAX6 polymorphisms and high myopia.

Methods All case-control association studies on PAX6 and high myopia reported in EMBASE and MEDLINE were retrieved. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for single-nucleotide polymorphisms (SNPs) that have been involved in at least two studies. Heterogeneity and publication bias analyses were also conducted.

Results There were totally 63 publications on PAX6 and myopia. Among them, six articles met all the inclusion criteria, involving 3626 patients and 3262 controls of Asian ancestry. Five PAX6 SNPs, rs3026354, rs667773, rs2071754, rs644242, and rs3026393, were meta-analyzed in high myopia and two, rs667773 and rs644242, in extreme myopia. Single-nucleotide polymorphism rs644242 was associated with high myopia in the dominant model (OR = 0.87; 95% CI, 0.76 to 0.99; p = 0.035) and heterozygous model (OR = 0.85; 95% CI, 0.74 to 0.97; p = 0.019) and with extreme myopia in the dominant model (OR = 0.79; 95% CI, 0.65 to 0.95; p = 0.015), allelic model (OR = 0.81; 95% CI, 0.68 to 0.96; p = 0.014), and heterozygous model (OR = 0.80; 95% CI, 0.65 to 0.97; p = 0.024). However, the associations cannot withstand Bonferroni correction (p > 0.005). The other four SNPs did not show significant association with high myopia.

Conclusions Meta-analysis of existing data revealed a suggestive association of PAX6 rs644242 with extreme and high myopia, which awaits validation in further studies. Nevertheless, PAX6 may only confer a small effect to myopia development.







Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China (SMT, SSR, ALY, POST, CPP, LJC); and Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China (ALY, CPP, LJC).

Li Jia Chen Department of Ophthalmology and Visual Sciences The Chinese University of Hong Kong Prince of Wales Hospital Shatin, N.T., Hong Kong China e-mail:

The myopic eye focuses images in front of the retina and results in blurred distant vision. It is a major cause of visual impairment globally. In white and black populations, about 28.1 and 19.4% people have myopia1,2; whereas in Asia, 40 to 80% of the population is myopic.3–5 Although a large proportion of myopic eyes can be corrected with lens and refractive surgery, the advanced form of myopia, or high myopia, can greatly affect life quality. More importantly, individuals with high myopia are predisposed to vision-threatening complications, including glaucoma, macular choroidal degeneration, retinal detachment, myopic foveoschisis, and choroidal neovascularization.6–9

The pathogenesis of high myopia is not completely clear. It is a multifactorial disease resulting from the interaction between environmental and genetic factors. Less outdoor activities and inner-city urban areas are known risk factors for myopia.10–12 High heritability of high myopia has also been shown in twins and family-based studies,13,14 suggesting genetics as an evident risk factor for high myopia. In fact, high myopia can be sporadic or inherited in Mendelian patterns including autosomal dominant, autosomal recessive, and X-linked, with more than 20 known chromosomal loci and 25 candidate genes.7,15–22

The advent of genome-wide association studies (GWAS)23–30 and next-generation sequencing platform31 has led to recent identification of many susceptibility and causative genes for high myopia. Genome-wide association studies on refractive errors with larger sample sizes are more powerful in detecting subtle variants in myopia patients, and some of these variants seem to confer a risk for high myopia.17 Because both the GWAS and next-generation sequencing platforms are hypothesis-free, most of these newly identified genes have no known functional implications. They are thus new targets for further study of new disease pathways and for establishing the functional links between genes and myopia.

Most reported candidate genes for high myopia are heterogeneous in their associations with myopia across different study populations. Such heterogeneity could be caused by small sample sizes in individual studies rendering insufficient statistical power, variations in study design, differential selection of genetic markers of inconsistent predictive values, and the diversities in the ethnic backgrounds of the study cohorts.

The paired box gene 6 (PAX6, OMIM 607108) gene has been vigorously studied in high myopia. PAX6 is located on chromosome 11p13, with 14 exons encoding a 436–amino acid full-length protein. The PAX6 protein contains a conserved paired box domain and a homeobox domain that binds DNA, regulates gene expression, and is closely involved in oculogenesis.32 Animal studies showed that PAX6 was crucial for lens development,33 and its mutations have been directly linked to aniridia, presenile cataract, aniridia-related keratopathy, and foveal hypoplasia.34

In 2004, Hammond et al.35 first suggested that genetic variations in the promoter might play a role in myopia development. Later, two family-based studies showed the presence of PAX6 variants in family members of extreme refractive error, especially in Asian populations.36,37 Moreover, Ng et al.38 reported that the AC and AG dinucleotide repeats in the PAX6 P1 promoter affected its transcription activities and was associated with high myopia. In 2011, Liang et al.39 reported a single-nucleotide polymorphism (SNP) rs662702 at the 3′UTR of PAX6 as a risk marker for extreme myopia; and Jiang et al.40 reported that PAX6 haplotypes were associated with high myopia. In 2012, Miyake et al.41 reported that the A allele of rs644242 in PAX6 was significantly protective for both high and extreme myopias.

However, other reported studies did not show an association of PAX6 with high myopia. Mutti et al.42 detected no association between PAX6 and myopia in a family-based study. Genotypic results of 596 persons of the 1958 British Birth Cohort excluded the direct link between tag-SNPs spreading PAX6 and SOX2 and refractive errors.43 Tsai et al.44 had shown an association of rs667773 with extreme myopia, but not high myopia. Dai et al.45 had also found a lack of association between PAX6 and high myopia in Chinese. The association of the PAX6 gene and its individual variants with high myopia therefore remains inconsistent and inconclusive. Here we present a systematic review and meta-analysis of all association studies on PAX6 and myopia to summarize and evaluate the effects of PAX6 polymorphisms on high myopia.

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Searching Strategy and Inclusion Criteria

Online databases, EMBASE and MEDLINE (Medical Literature Analysis and Retrieval System Online, via Ovid platform), were used for electronic search from their starting date to October 15, 2013. The following keywords were used as free words and also as MeSH terms: “myopia,” “myopic,” “nearsighted,” “near sight,” “refractive error,” “paired box 6,” “PAX6,” “MGDA,” “polymorphism(s),” “variant(s),” and “mutation(s).” Detailed search strategies were given in Table 1. Reference lists of the retrieved articles and reviews were manually screened for additional articles, if any, that had not been captured by the electronic search.



The inclusion criteria were defined as (1) original case-control and/or family-based studies evaluating the association between PAX6 polymorphisms and myopia; (2) numbers or frequencies in case and control groups reported for each genotype and/or allele; (3) study samples being unrelated individuals drawn from clearly defined populations; and (4) studies including normal individuals with spherical refraction ranged from -1.5 to 1.5 diopters (D) and free from any complications as control subjects. High myopia was defined as the axial length of 26 mm or higher and/or a refractive error of -6 D or less, and extreme myopia was defined as axial length of 28 mm or higher and/or a refractive error of -10 D or less.

Animal studies, case reports, reviews, abstracts, conference proceedings, editorials, and reports with incomplete data were excluded.

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Literature Review and Data Extraction

All retrieved records were screened and reviewed by two independent investigators (S.M.T. and S.S.R.). Data were extracted with standardized data sheets. Uncertainties were resolved by consensus with a third investigator (L.J.C.). Data collected from each study included first author, year of publication, country of study, ethnicity, definition of myopia, sample size in individual group, polymorphisms studied, and allelic and genotypic counts. If allele data were not available in the original report, we calculated the corresponding allelic counts and frequencies based on the genotype data. If the test for Hardy-Weinberg equilibrium was not reported, we tested it in the control group.

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Statistical Analysis

Hardy-Weinberg equilibrium was evaluated with χ 2 test. Both allelic and genotypic associations were meta-analyzed. For genotypic comparison, to dissect the association patterns, dominant, recessive, homozygous, and heterozygous were applied in the investigation of the disease association. Association of each SNP with myopia in the pooled samples, along with the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs), were evaluated using a Mantel-Haenszel method in both fixed- and random-effects models.46 The Cochran Q statistic testing for heterogeneity across studies and the I2 statistic quantifying the proportion of total variation attributable to between-study heterogeneity were calculated. The Q statistic was considered significant if p < 0.1, and I2 above 50% indicated large heterogeneity. If significant heterogeneity was detected, results from the random-effects model should be adopted, otherwise, the fixed-effects model. Modified Egger regression test was used to assess the potential publication bias,47 where a value of p < 0.1 was considered statistically significant. The Review Manager software (RevMan, version 5.2; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen; 2012) and the HardyWeinberg package (version 1.3) in R language (version 2.15.0, were used for data analysis. In association analyses, the Bonferroni correction was used to account for multiple testing.48 Because five genetic models (allelic, dominant, recessive, heterozygous, and homozygous) were tested in two subgroups of myopia (high and extreme myopia) for each SNP, a value of p < 0.005 was considered statistically significant.

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Up to October 15, a total of 63 publications in EMBASE and MEDLINE describing PAX6 and myopia were identified using our searching strategy. Thorough evaluation of the details revealed 29 of them were duplicates and 13 had irrelevant emphasis. They were excluded from the meta-analysis. Also excluded were nine reports that were animal studies, case reports, or letter. In total, 12 studies were eligible for further assessment.30,35–45 Among them, four were pedigree-based studies. Two were family-based association analyses,37,42 one was a twin study,35 and the other involved four pedigrees.36 However, in the two studies using family-based association test or transmission disequilibrium test, the numbers of the transmitted alleles were not reported, whereas the studies in twins and the four pedigrees did not provide includable data; therefore, these four studies were not included in our meta-analysis. One GWAS study mentioned PAX6, but the data were not reported.30 Another study of the association of PAX6 with refractive errors did not provide genotype data or OR,43 thus, it was not included for meta-analysis. Eventually, six studies that met all the inclusion criteria were included for meta-analysis.38–41,44,45 Figure 1 denotes the workflow of study inclusion, and Table 2 summarizes the characteristics of included studies. In all these studies, high myopia was defined as an axial length of 26 mm or higher and a refractive error of -6 D or less, whereas extreme myopia was defined as an axial length of 28 mm or higher or a refractive error of -10 D or less.38–41,44,45





In total, 18 SNPs have been investigated at least once in these six studies, among which five SNPs were tested in at least two studies: rs667773, rs3026354, rs2071754, rs3026393, and rs644242 (Table 2). Five studies gave particular interest to extreme myopia, and two SNPs (rs644242 and rs667773) were analyzed.38,39,41,44,45 A total of 3626 cases with high myopia and 3262 controls in the six studies were examined in the current meta-analysis. All the study subjects were Asians (Chinese and Japanese); thus, we did not conduct subgroup analysis by ethnicity.

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Publication Bias

No significant publication bias or other potential biases were detected by Egger test (p ≥ 0.17) for those SNPs reported by more than two studies. However, our meta-analysis provided a low power to detect bias because of the small number of studies included (<10).39,44

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Association of PAX6 Polymorphisms with High Myopia

A total of 4576 subjects (2304 high myopia patients vs. 2272 controls) from two studies were tested for rs644242.39,41 The dominant model (AA + AC vs. CC; OR = 0.87; 95% CI, 0.76 to 0.99; p = 0.035; P Q = 0.23; I 2 = 31%; Fig. 2A) and heterozygous model (AC vs. CC; OR = 0.85; 95% CI, 0.74 to 0.97; p = 0.019; P Q = 0.68; I 2 = 0; Fig. 2B) best explained its effects and indicated a nominally significant association with high myopia risk. The allelic model did not show a significant association, although the OR for the minor allele A was toward the same trend to that of the dominant model (OR = 0.90; 95% CI, 0.71 to 1.15; p = 0.39; P Q = 0.034; I 2 = 78%; Fig. 2C). Of note, these associations could not withstand Bonferroni correction (p > 0.005).



Single-nucleotide polymorphism rs2071754 had been investigated in 2948 high myopia patients and 2913 controls.39–41 The recessive model (AA vs. AG + GG) showed a significant association with high myopia (OR = 0.86; 95% CI, 0.77 to 0.98; p = 0.019; P Q < 0.001; I 2 = 97%; Table 3) in a fixed-effects model. However, as it met the criteria for significant heterogeneity, the random-effects model was adopted (OR = 0.68; 95% CI, 0.33 to 1.41; p = 0.30; Table 3). The pooled ORs in other genetic models from both fixed- and random-effects analyses were not significant (p > 0.20; P Q > 0.30; I 2 = 0; Table 3). Figure 3A shows the forest plot of the allelic association, which lacks any significance (OR = 1.0).





Four studies tested the association of rs667773 with high myopia in a total of 971 cases and 649 controls.38,40,44,45 No associations existed between high myopia and rs667773 in all five genetic models (p > 0.05; Table 3, Fig. 3B). No significant heterogeneity was detected (Table 3).

Single-nucleotide polymorphism rs3026393 was investigated by three studies with a total of 3522 subjects.39,40,45 Pooled estimates showed that rs3026393 was not associated with high myopia risk in any genetic model (p > 0.05; Table 3, Fig. 3C). Significant heterogeneity was detected in the dominant model (P Q = 0.028; Table 3).

No association was detected between rs3026354 and high myopia (n = 3159; p > 0.5) with low heterogeneity (P Q > 0.23; Table 3, Fig. 3D).

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Association of PAX6 Polymorphisms with Extreme Myopia

Five studies had conducted subgroup analysis for extreme myopia38,39,41,44,45; whereas in the study of Dai et al.,45 only patients with extreme myopia were included as cases. The A allele of rs644242 showed a significantly protective effect for extreme myopia in the dominant model (OR = 0.79; 95% CI, 0.65 to 0.95; p = 0.015; P Q = 0.59; I 2 = 0; Fig. 4A1), whereas the pooled OR was also significant in the allelic model (OR = 0.81; 95% CI, 0.68 to 0.96; p = 0.014; P Q = 0.86; I 2 = 0; Fig. 4A2) and heterozygous model (AC vs. CC; OR = 0.80; 95% CI, 0.65 to 0.97; p = 0.024; P Q = 0.294; I 2 = 9.14%; Fig. 4A3) with low heterogeneities (Table 4). However, the associations could not withstand Bonferroni correction (p < 0.005). Meta-analysis for rs667773 did not show a significant association with extreme myopia, and there was evident heterogeneity for the dominant and allelic models (Table 4; Fig. 4B).





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In the current systematic review and meta-analysis that covered six case-control association studies, we found rs644242 in the PAX6 gene to have a suggestive association with both high and extreme myopia, whereas there was no association between SNPs rs667773, rs3026354, rs2071754, or rs3026393 and myopia. Interestingly, the ORs of rs644242 for extreme myopia (OR = 0.79 and 0.80 in the dominant and heterozygous models, respectively) were lower than for high myopia (OR = 0.87 and 0.85, respectively), indicating that the protective effect might be stronger for extreme myopia. Moreover, the allelic association was significant in extreme myopia (OR = 0.81; p = 0.01) but not in high myopia (OR = 0.90; p = 0.39), and the pooled OR for extreme myopia as compared with high myopia only was 0.93, adding evidence that the A allele of rs644242 is a stronger protective allele for extreme myopia. Because such a difference in ORs is small, a study on a much larger sample size, with more than 10,000 patients and 10,000 controls (assuming α = 0.05, power = 80%, and OR = 0.93 between extreme and high myopia), is needed to confirm the heterogeneity in the ORs. Moreover, to account for multiple testing, we adopted Bonferroni correction, which helps eliminate false-positive findings. After correction, the association of rs644242 with both high and extreme myopia could not withstand (p > 0.005). Therefore, further studies are warranted to consolidate the association between rs644242 and myopia.

Of note, family-based studies, which were not included in the meta-analysis, also showed an evident link between PAX6 and high myopia. In 2004, Hammond et al.35 first reported a significant linkage (with a maximum LOD of 6.1) of the PAX6 locus to refractive errors in a twins-based study, thus, PAX6 was suggested to be a susceptibility gene for myopia. Later, Hewitt et al.36 recruited four pedigrees known to have different mutations in the PAX6 gene and found them to be significantly associated with high myopia. Single-nucleotide polymorphisms rs3026390 and rs3026393 of PAX6 were also found to be associated with high myopia in the family-based study of Han et al.37 These familial studies, together with our meta-analysis of association studies, indicate that PAX6 is a susceptibility gene for high myopia and/or extreme myopia.

The PAX6 protein is a transcriptional factor that regulates the development of the eyeball. It is closely associated with developmental ocular disorders such as aniridia and foveal hyperplasia.32 In a case series of patients with PAX6 mutations, the patient carriers were not only associated with aniridia but also had other manifestations like high myopia.49 PAX6 plays a key role in oculogenesis. The dosage of PAX6 could influence the oculogenesis in mice.50 Insufficiency and overexpression of PAX6 can both influence embryonic eyeball development. Therefore, in mice, the extremely abnormal dosage of PAX6 could induce multiple ocular defects, such as microphthalmia and anophthalmia.50 However, because of the variances among different species, a human in embryonic stage suffering from overexpression or insufficiency of PAX6 has a high rate of stillbirth or a low survival rate after birth, resulting from multiple-organ defects.51 In animal studies, myopic models were related to an abnormal expression of PAX6 in the postnatal stage. Researchers found that the expression of PAX6 in the retina was elevated in hyperopic defocused baby monkeys,52 and the expression of PAX6 was reduced in chicken with form-deprivation myopia.53 In addition, chronic hyperinsulinemia was one pathogenesis of juvenile-onset myopia, and insulin was known to act as a strong stimulus of axial length in myopia chicken,54 whereas PAX6 could transactivate the insulin promoters; therefore, elevated insulin levels by overexpressed PAX6 might stimulate elongation of the eyeball.55 Despite all these findings in animal models, it should be noted that myopia is a complex disease resulting from the interaction of multiple genetic and environmental risk factors and usually develops after birth. PAX6 is only one of the associated genes for myopia, and as indicated in our study, the effect size of the PAX6 SNP in myopia is small. Therefore, the PAX6 gene may, if any, contribute to a small proportion of myopia pathogenesis. However, how the SNP rs644242 works to alter the function of PAX6 still needs further investigations.

Recently, Liang et al.39 found another SNP rs662702 at the 3′UTR of PAX6 associated with extreme myopia. This SNP is in complete linkage disequilibrium with rs644242. It is located 5 kilobases upstream of rs644242 and is in the transcription factor binding site of PAX6. Moreover, rs662702 could interact with microRNA-328 and might be subsequently involved in the disrupted expressions of transforming growth factor-β3, matrix metalloproteinase 2, collagen I, and integrin-β1 in the retinal pigment epithelium and sclera mimicking myopia pathogenesis.56 This functional association indicates that the A allele of rs644242 may act on myopia pathogenesis through multiple protein interactions. Moreover, a recent genome-wide association study showed that polymorphisms around CTNND2 were associated with high myopia.9 The close interaction between Ctnnd2 and Pax6 57 suggested that the development of myopia involves gene-gene interaction.

Except for rs644242, other PAX6 SNPs were not associated with high myopia. PAX6 rs667773 was first associated with extreme myopia (OR = 5.27; 95% CI, 2.03 to 13.63; p < 0.001) in the study of Tsai et al.44 However, such association was not replicated in the study of Dai et al.,45 which involved a larger sample size. In addition, Zayats et al.58 suggested that the small sample size and wide variability in allele frequency in the study of Tsai et al. might lead to a false-positive association between rs667773 and extreme myopia. In our sensitivity analysis of rs667773 in extreme myopia, the heterogeneity was significantly diminished (OR = 0.92; 95%, 1.66 to 1.29; p = 0.63; P Q = 0.41; I 2 = 0%) after excluding the study of Tsai et al. Still, we found no evidence supporting the association of rs667773 with extreme myopia or high myopia. In fact, none of the five studies had provided significant evidence supporting a significant association between rs667773 and high myopia (Fig. 3B). We thus conclude that rs667773 is not a genetic marker for high myopia or extreme myopia.

For the other three SNPs in our meta-analysis, rs2071754, rs3026354, and rs3026393, none was associated with high myopia in respective original studies.39–41,44 Our analysis also confirmed a lack of significant association. In addition, there are a group of SNPs that have been studied and some of them showed a significant association with high myopia. For example, rs662702 was found to be associated with extreme myopia in the study of Liang et al.39 Also, Han et al.37 had detected associations between SNPs rs3026390 and rs3026393 and high myopia in a family-based study, with the haplotypes with the T allele of rs3026393 demonstrating an increased transmission. However, no replication data have been reported for these associations. Therefore, whether they are genuine myopia-associated SNPs have yet to be further investigated.

In the current meta-analysis, we adopted a standard and stringent strategy for study inclusion. The test for heterogeneity and potential biases should render our interpretation more solid. Moreover, our study revealed several limitations in the understanding of PAX6 in myopia genetics. First, the results were generated from a limited number of studies, resulting in borderline pooled p values. Therefore, the association of PAX6 with high and extreme myopia should be validated in more study cohorts. Nevertheless, although the family-based studies could not be included in the meta-analysis, their findings did provide supportive evidence for a link between PAX6 and myopia.35,37,42 Second, a high heterogeneity in some models was detected, which was likely caused by various definitions of the control group and from the innate differences in minor allele frequencies across study populations. In this situation, our interpretation of the findings has been strengthened by the use of the random-effects model, yielding more conservative ORs. Third, the existing studies were mainly based on cohorts of Asians. It may restrict our conclusions within the Asian population and indicates the need for studies in other ethnic populations.

In conclusion, this systematic review and meta-analysis suggested an association of the PAX6 SNP rs644242 with extreme and high myopia. However, the association could not withstand Bonferroni correction and the effect size of PAX6 is small. Therefore, in view of the fact that myopia is a polygenic disease, PAX6 may, if any, confer a small effect on myopia development.

Li Jia Chen

Department of Ophthalmology and Visual Sciences

The Chinese University of Hong Kong

Prince of Wales Hospital

Shatin, N.T., Hong Kong



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This work was supported in part by a direct grant for research of the Chinese University of Hong Kong (grant no. 4054065).

Shu Min Tang and Shi Song Rong contributed equally to this article and are considered first coauthors. There are no conflicts of interest for any author.

Received March 31, 2013; accepted January 13, 2014.

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myopia; PAX6; association study; meta-analysis; systematic review

© 2014 American Academy of Optometry