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. 2022 Jul 21;17(7):e0271809. doi: 10.1371/journal.pone.0271809

The G allele of the IGF1 rs2162679 SNP is a potential protective factor for any myopia: Updated systematic review and meta-analysis

Bo Meng 1,*, Kang Wang 1, Yingxiang Huang 1, Yanling Wang 1
Editor: James Fielding Hejtmancik2
PMCID: PMC9302841  PMID: 35862416

Abstract

Background

The insulin-like growth factor 1 (IGF1) gene is located within the myopia-associated MYP3 interval, which suggests it may play an important role in the progression of myopia. However, the association between IGF1 SNPs and any myopia is rarely reported.

Methods

A comprehensive literature search was conducted on studies published up to July 22, 2021 in PubMed, EMBASE, CBM, COCHRANE, CNKI, WANFANG and VIP databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for single-nucleotide polymorphisms (SNPs) that have been evaluated in at least three studies.

Results

Nine studies involving 4596 subjects with any myopia and 4950 controls examined 25 SNPs in IGF1 gene, among which seven SNPs were included in this meta-analysis. Significant associations were not found in any genetic models between rs6214, rs12423791, rs5742632, rs10860862, rs5742629 and any myopia. Rs2162679 was suggestively associated with any myopia in the codominant model (GA vs. AA: OR = 0.87, 95% CI: 0.76–1.00) and the dominant model (GG+GA vs. AA: OR = 0.88, 95% CI = 0.78–1.00).

Conclusion

Meta-analysis of updated data reveals that the G allele of the IGF1 rs2162679 SNP is a potential protective factor for any myopia, which is worth further researches.

Introduction

Recently, myopia has emerged as a major public health concern worldwide. In the last several decades, the prevalence of myopia in the United States and Europe has increased [1, 2]. Asian countries have the highest rates of myopia, especially in east and Southeast Asia [3]. In China, Singapore and Taiwan, the prevalence of myopic subjects aged 12–39 years has rapidly increased to 67–96% [4–6]. Because of its higher prevalence, myopia imposes enormous economic and social burdens worldwide [7].

Although myopia is classified as a benign disorder that can be corrected with optical modalities, myopic eyes with a long axial lengths (≥26 mm) or a high degree of myopic refractive error (≤−6D), can cause blindness with complications such as glaucoma, macular degeneration, retinal detachment, myopic foveoschisis, and choroidal neovascularization [8, 9]. Myopia has already become the second most common cause of legal blindness [10, 11]. Therefore, it is very important to identify the potential risk factors to establish preventive strategies for myopia.

The pathogenesis of myopia remains unclear. Research has shown that myopia is a multi-factorial disease that results from an interaction between environmental and genetic factors [12–14]. Environmental factors include near work, outdoor activities, level of education, light exposure, diet and urbanization [15, 16]. For example, in two independent population-based cohorts of individuals from European descent, Verhoeven et al. [17] found that the genetic risk of an individual for myopia is significantly affected by his or her educational level. Higher education affects myopia by increasing the amount of time spent doing near work activities [18]. By contrast, children who spend more time engaged in outdoor activities have shown a reduced prevalence and a slower progression of myopia. Although the environment plays a role in the progression of myopia, results of twins and family-based studies have shown that the genetic component is significant [19, 20]. Association studies have led to the identification of many susceptibility and causative genes for myopia. These genes are enriched for certain functional annotations, such as neurotransmitter functions (GRIA4), ion channel activity (KCNQ5, CD55 and CACNA1D), retinoic acid metabolism (RDH5, CYP26A1 and RORB), extracellular matrix remodeling (LAMA2 and BMP2) and ocular development (SIX4, CHD7 and PRSS56) [21].

The IGF1 gene is located in 12q23.2 of the human genome and contains six exons [22]. One of the proteins encoded by this gene is similar to insulin in its structure and function. Previous animal studies showed that the IGF1 gene contributed to eye development and disease. For example, IGF1/FGF2-treated eyes in animal studies could have an increased vitreous chamber depth, decreased anterior chamber depth, and changes in the sclera [23]. Hellstrom et al. showed that lack of IGF1 in knockout mice prevented normal retinal vascular growth by preventing VEGF-induced activation of protein kinase B, a kinase that is critical for endothelial cell survival [24]. Additionally, Ruberte et al. [25] suggested that IGF1 played a role in the development of ocular complications in patients with diabetes for a long period of time. The IGF1 gene also is located within the myopia-associated MYP3 interval, which has been mapped using the linkage disequilibrium method. This suggests that IGF1 may play an important role in the progression of myopia. However, the association between IGF1 SNPs and any myopia is rarely reported. Therefore, we present herein an updated systematic review and meta-analysis to evaluate the potential association between IGF1 SNPs and any myopia.

Methods

Search strategy

The review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO, CRD42021274322) and performed according to the Preferred Reporting Items for Systematic review and Meta-Analyse Statement (PRISMA) guidelines. We searched the following databases: PubMed, EMBASE, Cochrane Library and several Chinese databases, such as the Chinese biomedical literature database (CBM), China National Knowledge Infrastructure (CNKI), WANFANG DATA and VIP database from their inception to July 22, 2021. The selected key words were used as free words, truncations and MeSH terms. Reference lists from the retrieved articles were manually screened for potential articles, if any, that had not been captured by the electronic search. No language restrictions were applied throughout the search process.

Inclusion and exclusion criteria

Inclusion criteria were as follows: 1) original case-control or family-based studies that evaluated the association between polymorphisms of IGF1 and any myopia; 2) numbers or frequencies in case and control groups reported for each genotype or allele; 3) if the study was reported in duplicate, the version with the most comprehensive content was included; and 4) studies including normal individuals with spherical equivalent refraction that ranged from -1.5 to 1.5 diopters and were free from any complications.

Exclusion criteria were as follows: 1) animal studies, reviews, conference proceedings, case reports, editorials; and 2) articles providing incomplete data or that could not be acquired through various means.

Data extraction

Two independent authors screened all retrieved records and made decisions on which studies to include. Any disagreements were resolved by discussion. Further, any uncertainties were resolved by consultation with a third author. The information of first author, year of publication, ethnicity, genotyping type, sample size, polymorphisms studied, genotype distribution, minor allele, Hardy–Weinberg equilibrium (HWE) and conclusions on any myopia association were collected. If allele data were not available in original reports, they were calculated based on genotypic data.

Assessment of study quality

Study quality was assessed using revised criteria according to Little’s recommendations [26] for gene-disease associations, with an aim to investigate potential bias in summary results. These criteria included: 1) the genotyping method used; 2) definition of cases and methods of ascertainment; 3) socio-demographic characteristics of subjects; 4) confounding factors mentioned in articles; and 5) confidence intervals of genotype frequency. An overall quality score was generated, and studies with a score ≥3 were considered to have high quality.

Statistical analysis

All statistical analyses were performed using RevMan 5.3. Association of each SNP with myopia in pooled samples, along with pooled odds ratios (ORs) and 95% confidence intervals (95% CIs), were evaluated. The I2 statistic was used to quantify heterogeneity. In addition, funnel plot was used to evaluate the publication bias.

Results

Eligible studies and study characteristics

A total of 145 potentially relevant articles were retrieved. Ultimately, nine studies that met all criteria were included for this meta-analysis (Fig 1) [27–35].

Fig 1. Flowchart of study inclusion.

Fig 1

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Overall, 25 SNPs associated with the IGF1 gene were investigated at least once in nine studies. Among these SNPs, seven were tested in at least three studies and then were included in the meta-analysis. The study subjects were Chinese [29, 31, 32, 34, 35], Japanese [27, 28], Egyptian [33] and Polish [30] with sample sizes that ranged from 127 to 1339. The total sample size was 9546 (4596 individuals with any myopia and 4950 controls).

The methods of gene analysis included restriction fragment length polymorphism (RFLP), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF), RT-PCR, SnaPshot and polymerase chain reactionand ligase detection reaction (PCR-LDR). The quality scores of the included studies were greater than four, which indicated a favorable methodological quality. Table 1 summarizes the characteristics of the included studies.

Table 1. Characteristics of all studies included in the meta-analysis.

First author Year Ethnicity Genotying type Quality score SNP ID Sample Mean age(y) Mean refractive errors (D) Genotype distribution Minor allele HWE
Case Control
Case Control Case Control Case Control 1/1 1/2 2/2 1/1 1/2 2/2
Cheng 2020 Chinese PCR-LDR 5 rs6214 281 373 9.84±1.55 8.06±1.43 -2.55±1.64▲ 0.84±0.81▲ 59 140 82 89 186 98 A yes
rs5742653 -2.55±1.84△ 0.88±0.83△ 62 140 79 83 186 104 G yes
rs4764697 9 83 189 10 102 261 T yes
rs12423791 16 103 162 27 146 200 C yes
rs2162679 29 122 130 52 175 146 G yes
rs5742612 21 112 148 34 157 182 C yes
Zidan 2016 Egyptian RFLP 4 rs5742632 136 272 41.2±9.0 42.23±8.0 -4.41±1.42▲★;-9.34±3.1▲☆ 0.57±0.32▲ 27 97 148 11 45 80 C N/A
rs6214 40.7±8.7 -4.39±1.4△★;-9.28±2.9△☆ 0.59±0.31△ 44 123 105 12 46 78 A N/A
Wang 2016 Chinese SNaPshot 5 rs10860860 1244 1380 41.26±13.51 58.39±12.77 -10.12±3.45▲ N/A 31 331 882 36 373 971 T no
rs10860862 -10.03±3.16△ 38 357 849 41 393 946 T no
rs2946834 221 606 417 252 675 453 T yes
rs6214 280 620 344 321 689 370 A yes
rs12821878 3 121 1120 5 163 1212 A yes
rs35766 130 525 586 186 596 598 G yes
Zhao 2013 Chinese TOFMS 5 rs10860861 302 401 1.24±16.34 43.32±22.15 -16.54±5.26▲ 0.39±0.82▲ 44 148 110 66 197 138 C yes
rs10860862 -16.39±5.47△ 0.42±0.80△ 8 84 210 12 117 272 T yes
rs6214 89 145 68 101 200 100 G yes
rs5742629 48 167 87 58 186 157 G no
rs12423791 26 127 149 24 136 241 C yes
rs35766 134 131 37 207 157 37 G yes
rs1457601 18 130 154 21 140 240 A yes
Miyake 2013 Japanese TaqMan 4 rs6214 1339 1194 57.2±14.9 50.3±15.9 -12.69±4.54▲ N/A 277 641 373 268 585 341 C yes
rs978458 256 661 361 264 596 334 T yes
rs5742632 209 657 410 229 586 379 G yes
rs12423791 97 452 672 85 468 641 C yes
rs2162679 178 540 569 149 541 504 C yes
Yoshida 2013 Japanese TaqMan 5 rs6214 446 481 37.9±11.9 39.3±11.0 -11.7±2.24▲ -1.5~+1.5 58 205 183 55 215 211 G yes
rs11111262 -11.7±2.27△ 17 138 291 18 150 313 A yes
rs972936 93 221 132 118 240 123 G yes
rs5742629 70 214 162 94 237 150 G yes
rs12423791 32 174 240 45 204 232 C yes
rs2162679 44 193 209 55 215 211 G yes
rs5742612 41 188 217 50 211 220 C yes
Zhuang 2012 Chinese MALDI-TOF 5 rs10860861 421 401 38.29±16.57 68.77±10.65 -14.57±5.6▲ 0.39±0.82▲ 153 202 66 138 197 66 C yes
rs10860862 -14.51±5.64△ 0.42±0.8△ 294 117 10 272 117 12 T yes
rs6214 99 205 117 100 200 101 G yes
rs5742629 128 222 71 157 186 58 G yes
rs12423791 219 170 32 241 136 24 C yes
rs35766 44 187 190 37 157 207 G yes
rs1457601 217 180 24 240 140 21 A yes
Mak 2012 Chinese RFLP 5 rs12579077 300 300 18–45 18–45 ≤-8.0 -1.0~+1.0 38 109 153 36 128 136 C yes
rs35767 46 126 128 47 134 119 T yes
rs4764698 30 115 155 28 128 144 C yes
rs12423791 29 132 139 30 135 135 G yes
rs7956547 5 83 212 5 74 221 G yes
rs5742632 62 150 88 58 153 89 C yes
rs2373721 6 80 203 7 80 213 G yes
rs6539035 5 78 217 6 71 223 G yes
rs6214 74 146 80 85 137 78 A yes
rs5742723 30 118 152 31 127 142 A yes
Rydzanicz 2011 Polish RFLP 4 rs6214 127 148 27.1±22.63 38.6±18.54 -2.75±2.00▲ -0.03±1.26 22 72 64 16 78 54 A yes
rs10860860 40.2±20.43 -9.32±3.89△ 18 68 72 13 75 60 T yes
rs2946834 19 62 75 14 61 72 T yes
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HWE: Hardy-Weinberg Equilibrium; N/A: Not available; ▲Right eye

△Left eye

★Simple myopia

☆High-grade myopia; 1/1: genotype with homozygous allele 1; 1/2: genotype with heterozygous alleles; 2/2: genotype with homozygous allele 2.

Association of IGF1 SNPs with any myopia

Rs2162679 was tested in three studies [27, 28, 32] with 2014 cases and 2048 controls. Fixed -effects models were used to calculate the pooled ORs. Our findings suggested that there were no significant associations for the allelic model (G vs. A: OR = 0.93, 95% CI: 0.85–1.02, P = 0.14), dominant model (GG+GA vs. AA: OR = 0.88, 95% CI = 0.78–1.00, P = 0.05), recessive model (GG vs. GA+AA: OR = 0.99, 95% CI = 0.82–1.19, P = 0.92 and codominant model (GG vs. AA: OR = 0.92, 95% CI = 0.76–1.13, P = 0.43). There were suggestive associations for the codominant model (GA vs. AA: OR = 0.87, 95% CI = 0.76–1.00, P = 0.04) (Fig 2, Table 2).

Fig 2. Meta-analysis of the association of IGF1 rs2162679 with any myopia.

Fig 2

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Bars with squares in the middle represent 95% confidence intervals (95% CIs) and odds ratios (ORs). The central vertical solid line indicates ORs for the null hypothesis.

Table 2. Main results of the pooled ORs between IGF1 SNPs and any myopia.

SNPs Models Tested NO. study Pooled OR 95% CI P P Q I2
rs2162679 Allelic model G vs. A 3 0.93 0.85–1.02 0.14 0.22 33%
Dominant model GG+GA vs. AA 3 0.88 0.78–1.00 0.05 0.5 0%
Recessive model GG vs. GA+AA 3 0.99 0.82–1.19 0.92 0.17 43%
Codominant model GG vs. AA 3 0.92 0.76–1.13 0.43 0.16 46%
GA vs. AA 3 0.87 0.76–1.00 0.04 0.77 0%
rs6214 Allelic model A vs. G 9 0.98 0.91–1.06 0.64 0.02 58%
Dominant model AA+AG vs. GG 9 1.03 0.90–1.18 0.65 0.04 50%
Recessive model AA vs. AG+GG 9 1 0.89–1.11 0.94 0.31 14%
Codominant model AA vs. GG 9 1.02 0.87–1.20 0.82 0.11 39%
AG vs. GG 9 1.02 0.90–1.15 0.73 0.17 31%
rs12423791 Allelic model C vs. G 6 0.95 0.81–1.11 0.51 0.005 70%
Dominant model CC+CG vs. GG 6 0.96 0.80–1.16 0.68 0.03 61%
Recessive model CC vs. CG+GG 6 0.92 0.73–1.15 0.45 0.14 40%
Codominant model CC vs. GG 6 0.93 0.71–1.22 0.61 0.13 41%
CG vs. GG 6 0.97 0.82–1.16 0.76 0.09 48%
rs5742632 Allelic model C vs. G 3 0.97 0.88–1.07 0.57 0.38 0%
Dominant model CC+CG vs. GG 3 1.01 0.88–1.17 0.88 0.69 0%
Recessive model CC vs. CG+GG 3 0.89 0.75–1.07 0.22 0.32 13%
Codominant model CC vs. GG 3 0.91 0.75–1.12 0.38 0.39 0%
CG vs. GG 3 1.04 0.90–1.21 0.59 0.86 0%
rs10860862 Allelic model T vs. G 3 1.02 0.91–1.14 0.8 0.7 0%
Dominant model TT+TG vs. GG 3 1 0.87–1.16 0.98 0.76 0%
Recessive model TT vs. TG+GG 3 1.06 0.84–1.35 0.62 0.89 0%
Codominant model TT vs. GG 3 1.05 0.73–1.51 0.81 0.81 0%
TG vs. GG 3 1 0.86–1.16 1 0.83 0%
rs35766 Allelic model G vs. A 3 0.93 0.74–1.16 0.51 0.01 78%
Dominant model GG+GA vs. AA 3 0.95 0.69–1.31 0.77 0.02 74%
Recessive model GG vs. GA+AA 3 0.81 0.65–1.00 0.05 0.24 29%
Codominant model GG vs. AA 3 0.83 0.56–1.21 0.32 0.07 62%
GA vs. AA 3 1.01 0.77–1.32 0.97 0.08 60%
rs5742629 Allelic model G vs. A 3 0.94 0.71–1.25 0.67 0.002 84%
Dominant model GG+GA vs. AA 3 1.02 0.65–1.59 0.94 0.003 83%
Recessive model GG vs. GA+AA 3 0.81 0.62–1.06 0.13 0.15 47%
Codominant model GG vs. AA 3 0.87 0.53–1.42 0.58 0.02 75%
GA vs. AA 3 1.09 0.73–1.65 0.67 0.01 78%
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Rs6214 was tested in nine studies [27–29, 31–36] with 4715 cases and 4814 controls. Random -effects models were used to calculate the pooled ORs. Our findings suggested that there were no significant associations for the allelic model (A vs. G: OR = 0.98, 95% CI: 0.91–1.06, P = 0.64), dominant model (AA+AG vs. GG: OR = 1.03, 95% CI = 0.90–1.18, P = 0.65), recessive model (AA vs. AG+GG: OR = 1.00, 95% CI = 0.89–1.11, P = 0.94 and codominant model (AA vs. GG: OR = 1.02, 95% CI = 0.87–1.20, P = 0.82 and AG vs. GG: OR = 1.02, 95% CI = 0.90–1.15, P = 0.73) (Fig a in S1 File, Table 2).

Rs12423791 was tested in six studies [27–29, 31, 32, 35] with 2971 cases and 3150 controls. Random-effects models were used to calculate the pooled ORs. Our findings demonstrated that there were no significant associations between rs12423791 and any myopia in the allelic model (C vs. G: OR = 0.95, 95% CI: 0.81–1.11, P = 0.51), dominant model (CC+CG vs. GG: OR = 0.96, 95% CI = 0.80–1.16, P = 0.68), recessive model (CC vs. CG+GG: OR = 0.92, 95% CI = 0.73–1.15, P = 0.45 and codominant model (CC vs. GG: OR = 0.93, 95% CI = 0.71–1.22, P = 0.61 and CG vs. GG: OR = 0.97, 95% CI = 0.82–1.16, P = 0.76) (Fig b in S1 File, Table 2).

Rs5742632 was tested in three studies [28, 29, 33] with 1848 cases and 1630 controls. Fixed -effects models were used to calculate the pooled ORs. Our findings suggested that there were no significant associations for the allelic model (C vs. G: OR = 0.97, 95% CI: 0.88–1.07, P = 0.57), dominant model (CC+CG vs. GG: OR = 1.01, 95% CI = 0.88–1.17, P = 0.88), recessive model (CC vs. CG+GG: OR = 0.89, 95% CI = 0.75–1.07, P = 0.22 and codominant model (CC vs. GG: OR = 0.91, 95% CI = 0.75–1.12, P = 0.38 and CG vs. GG: OR = 1.04, 95% CI = 0.90–1.21, P = 0.59) (Fig c in S1 File, Table 2).

Rs10860862 was tested in three studies [31, 34, 35] with 1967 cases and 2182 controls. Fixed-effects models were used to calculate the pooled ORs. Our findings demonstrated that there were no significant associations between rs10860862 and any myopia in the allelic model (T vs. G: OR = 1.02, 95% CI: 0.91–1.14, P = 0.80), dominant model (TT+TG vs. GG: OR = 1.00, 95% CI = 0.87–1.16, P = 0.98), recessivemodel (TT vs. TG+GG: OR = 1.06, 95% CI = 0.84–1.35, P = 0.62 and codominant model (TT vs. GG: OR = 1.05, 95% CI = 0.73–1.51, P = 0.81 and TG vs. GG: OR = 1.00, 95% CI = 0.86–1.16, P = 1.00) (Fig d in S1 File, Table 2).

Rs35766 was tested in three studies [31, 34, 35] with 1964 cases and 2182 controls. Random-effects models were used to calculate the pooled ORs. Our findings suggested that there were no significant associations for the allelic model (G vs. A: OR = 0.93, 95% CI: 0.74–1.16, P = 0.51), dominant model (GG+GA vs. AA: OR = 0.95, 95% CI = 0.69–1.31, P = 0.77), recessive model (GG vs. GA+AA: OR = 0.81, 95% CI = 0.65–1.00, P = 0.05 and codominant model (GG vs. AA: OR = 0.83, 95% CI = 0.56–1.21, P = 0.32 and GA vs. AA: OR = 1.01, 95% CI = 0.77–1.32, P = 0.97) (Fig e in S1 File, Table 2).

SNP rs5742629 was investigated in three studies [27, 31, 35] with 1169 cases and 1283 controls. Our findings indicated that no significant associations were present between this SNP and any myopia using the allelic model (G vs. A: OR = 0.94, 95% CI: 0.71–1.25, P = 0.67), dominant model (GG+GA vs. AA: OR = 1.02, 95% CI = 0.65–1.59, P = 0.94), recessive model (GG vs. GA+AA: OR = 0.81, 95% CI = 0.62–1.06, P = 0.13 and codominant model (GG vs. AA: OR = 0.87, 95% CI = 0.53–1.42, P = 0.58 and GA vs. AA: OR = 1.09, 95% CI = 0.73–1.65, P = 0.67) (Fig f in S1 File, Table 2).

Publication bias

The shape of the funnel plot did not suggest any obvious asymmetry between the seven SNPs and any myopia (see S2 File).

Discussion

As of August 4, 2021, the Online Mendelian Inheritance in Man (OMIM) database has listed 483 genetic factors associated with myopia. Additionally, two independent genome-wide association studies that involved large cohorts of refractive error patients identified loci at chromosome 15q14 and 15q25 [37, 38]. However, investigating the genetics of complex disorders such as any myopia remains a great challenge. Furthermore, the CREAM consortium conducted multi-center GWAS meta-analyses and identified susceptibility genes that affected diverse biological pathways [39], although they found no evidence of associations between IGF1 SNPs and myopia. Extended axial length is known to be an important characteristic of the progress of myopia, which is associated with scleral remodeling. It is important to carefully analyze genes in the scleral remodeling pathway. As mentioned above, IGF1 could contribute to ocular enlargement by changing the structure of the sclera [23].

SNP rs2162679 of IGF1 has been reported to be associated with several kinds of cancer [40–42], which reminds us that IGF1 SNPs might play similar role in the onset or progesssion of myopia and cancer. In this study, our meta-analysis shows there is association between IGF1 rs2162679 and any myopia in codominant model (GA vs. AA) and dominant model (GG+GA vs. AA). The genotype GA and GG+GA in rs2162679 have a lower risk of any myopia than those with the genotype AA. The G allele in this position may protect against the onset or progesssion of myopia.

Rs6214 is located within the intron of IGF1. In 2010, Metlapally et al. [43] and Zidan et al. [33] found that rs6214 was positively associated with any myopia/high-grade myopia after correcting for multiple testing. However, in other studies, no significant association for rs6214 was found using single marker analysis [27–32, 34, 35]. Zhuang et al. [31] and Zhao et al. [35] reported that rs12423791 was significantly associated with high myopia in a Chinese population. Although Mak et al. [29] found no association in a Chinese population, they identified a three-SNP haplotype consisting of rs12423791 with a significant association between high myopia and control participants using a variable-sized sliding-window strategy. The final results of this meta-analysis indicated that rs6214 and rs12423791 were not associated with any myopia. In this present study, we included three studies for meta-analysis of rs5742632, rs5742632, rs35766 and rs5742629 respectively. However, our analysis revealed no association between these SNPs and any myopia in genetic models.

Additionally, some other SNPs are notable, although we could not carry out meta-analysis. For example, rs12579077 and rs35767 were reported in the study of Mak et al. [29] in 2012, which are both located in the promoter region. Additionally, we have conducted SNP function prediction using the “SNPinfo Web Server”, which suggests that the two SNPs may play important roles in susceptibility to high myopia. Additionally, rs12423791, rs7956547 and rs5742632 comprise a unit that may be associated with genetic susceptibility to high myopia in Chinese adults. Rs5742714 is located in the 3ʹ-UTR of the IGF1 gene. Variants in the 3ʹ-UTR affect the binding region of microRNA, which plays an important role in disease by regulating translation of mRNA. Rs35766 is located in the 5ʹ-near region. The 5ʹ-near region may have a role in regulating the transcription of mRNA. In our present study, we found that rs35766 and rs1457601 were detected by one study [31] that suggested associations with high myopia. Although these two SNPs are located in the 5ʹ-near region of the IGF1 gene, which may play important roles in the process of transcriptional regulation, these associations need to be validated in further studies. Additionally, rs1457601 also is located in the 5ʹ-near region. ALD map based on 1000 genome data provides potential evidence of a haplotypic effect between SNP rs1457601 and other SNPs, such as rs74633605, rs79196465 and rs79218426. Accordingly, the rs1457601 haplotypes also warrant future study.

There are several limitations to this present study. Firstly, the SNPs that we studied were all located in one chromosome according to existing data and haplotype analysis was not performed, which may have affected our results to some extent. It is necessary to pay more attention to haplotype analysis and SNPs on other chromosomes, especially those located in functional regions. Secondly, the major ethnic subjects was Asian, such as Japanese and Chinese. Besides, there are few studies on the polymorphism of any myopia, especially mild and moderate myopia. This two may affect the extrapolation of the conclusions. It is necessary to conduct further studies in other ethnic populations and subjects with different degrees of myopia. Thirdly, myopia is a complex disease affected by hereditary and environmental factors. Environmental factors may cause genetic changes. Gene-environment interactions should also be taken into consideration.

Conclusion

In conclusion, this meta-analysis suggests that the G allele of the IGF1 rs2162679 SNP is a potential protective factor for any myopia, which is worth further researches. Haplotype analysis and gene-environment interactions should also be taken into consideration.

Supporting information

S1 File. Meta-analysis of the association of other IGF1 SNPs with any myopia.

(DOCX)

Click here for additional data file. (202.2KB, docx)
S2 File. Funnel plot analysis for publication bias.

(DOCX)

Click here for additional data file. (63.1KB, docx)
S3 File. Search strategy.

(DOCX)

Click here for additional data file. (12.8KB, docx)
S4 File. Prisma 2009 checklist.

(DOCX)

Click here for additional data file. (26.3KB, docx)

Acknowledgments

Our research team completed this meta-analysis independently and there are no people or groups to acknowledge to.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

References

  • 1.Vitale S, Sperduto RD, Ferris FL, 3rd. Increased prevalence of myopia in the United States between 1971–1972 and 1999–2004. Arch Ophthalmol. 2009; 127(12):1632–9. 10.1001/archophthalmol.2009.303 [DOI] [PubMed] [Google Scholar]
  • 2.Williams KM, Bertelsen G, Cumberland P, Wolfram C, Verhoeven VJ, Anastasopoulos E, et al. Increasing Prevalence of Myopia in Europe and the Impact of Education. Ophthalmology. 2015; 122(7):1489–97. 10.1016/j.ophtha.2015.03.018 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Morgan IG, French AN, Ashby RS, Guo X, Ding X, He M, et al. The epidemics of myopia: Aetiology and prevention. Progress in retinal and eye research. 2018; 62134–49. doi: 10.1016/j.preteyeres.2017.09.004 [DOI] [PubMed] [Google Scholar]
  • 4.Morgan IG, Ohno-Matsui K, Saw SM. Myopia. Lancet. 2012; 379(9827):1739–48. doi: 10.1016/S0140-6736(12)60272-4 [DOI] [PubMed] [Google Scholar]
  • 5.Wang J, Ying GS, Fu X, Zhang R, Meng J, Gu F, et al. Prevalence of myopia and vision impairment in school students in Eastern China. BMC ophthalmology. 2020; 20(1):2. doi: 10.1186/s12886-019-1281-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Mak CY, Yam JC, Chen LJ, Lee SM, Young AL. Epidemiology of myopia and prevention of myopia progression in children in East Asia: a review. Hong Kong medical journal = Xianggang yi xue za zhi. 2018; 24(6):602–09. doi: 10.12809/hkmj187513 [DOI] [PubMed] [Google Scholar]
  • 7.Shapira Y, Mimouni M, Machluf Y, Chaiter Y, Saab H, Mezer E. The Increasing Burden of Myopia in Israel among Young Adults over a Generation: Analysis of Predisposing Factors. Ophthalmology. 2019; 126(12):1617–26. doi: 10.1016/j.ophtha.2019.06.025 [DOI] [PubMed] [Google Scholar]
  • 8.Ikuno Y. Overview Of the Complications Of High Myopia. Retina. 2017; 37(12):2347–51. doi: 10.1097/IAE.0000000000001489 [DOI] [PubMed] [Google Scholar]
  • 9.Ueta T, Makino S, Yamamoto Y, Fukushima H, Yashiro S, Nagahara M. Pathologic myopia: an overview of the current understanding and interventions. Global health & medicine. 2020; 2(3):151–55. doi: 10.35772/ghm.2020.01007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Paylakhi S, Labelle-Dumais C, Tolman NG, Sellarole MA, Seymens Y, Saunders J, et al. Muller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error. PLoS genetics. 2018; 14(3):e1007244. doi: 10.1371/journal.pgen.1007244 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Harb EN, Wildsoet CF. Origins of Refractive Errors: Environmental and Genetic Factors. Annual review of vision science. 2019; 547–72. doi: 10.1146/annurev-vision-091718-015027 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Pozarickij A, Williams C, Hysi PG, Guggenheim JA, Eye UKB, Vision C. Quantile regression analysis reveals widespread evidence for gene-environment or gene-gene interactions in myopia development. Communications biology. 2019; 2167. doi: 10.1038/s42003-019-0387-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Wenbo L, Congxia B, Hui L. Genetic and environmental-genetic interaction rules for the myopia based on a family exposed to risk from a myopic environment. Gene. 2017; 626305–08. doi: 10.1016/j.gene.2017.05.051 [DOI] [PubMed] [Google Scholar]
  • 14.Enthoven CA, Tideman JWL, Polling JR, Tedja MS, Raat H, Iglesias AI, et al. Interaction between lifestyle and genetic susceptibility in myopia: the Generation R study. European journal of epidemiology. 2019; 34(8):777–84. doi: 10.1007/s10654-019-00512-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Rose KA, French AN, Morgan IG. Environmental Factors and Myopia: Paradoxes and Prospects for Prevention. Asia-Pacific journal of ophthalmology. 2016; 5(6):403–10. doi: 10.1097/APO.0000000000000233 [DOI] [PubMed] [Google Scholar]
  • 16.Ramamurthy D, Lin Chua SY, Saw SM. A review of environmental risk factors for myopia during early life, childhood and adolescence. Clinical & experimental optometry. 2015; 98(6):497–506. doi: 10.1111/cxo.12346 [DOI] [PubMed] [Google Scholar]
  • 17.Verhoeven VJ, Buitendijk GH, Consortium for Refractive E, Myopia, Rivadeneira F, Uitterlinden AG, et al. Education influences the role of genetics in myopia. European journal of epidemiology. 2013; 28(12):973–80. doi: 10.1007/s10654-013-9856-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Muhamedagic L, Muhamedagic B, Halilovic EA, Halimic JA, Stankovic A, Muracevic B. Relation between near work and myopia progression in student population. Mater Sociomed. 2014; 26(2):100–3. doi: 10.5455/msm.2014.26.100-103 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Lopes MC, Andrew T, Carbonaro F, Spector TD, Hammond CJ. Estimating heritability and shared environmental effects for refractive error in twin and family studies. Invest Ophthalmol Vis Sci. 2009; 50(1):126–31. doi: 10.1167/iovs.08-2385 [DOI] [PubMed] [Google Scholar]
  • 20.Tsai MY, Lin LL, Lee V, Chen CJ, Shih YF. Estimation of heritability in myopic twin studies. Jpn J Ophthalmol. 2009; 53(6):615–22. doi: 10.1007/s10384-009-0724-1 [DOI] [PubMed] [Google Scholar]
  • 21.Hysi PG, Wojciechowski R, Rahi JS, Hammond CJ. Genome-wide association studies of refractive error and myopia, lessons learned, and implications for the future. Invest Ophthalmol Vis Sci. 2014; 55(5):3344–51. doi: 10.1167/iovs.14-14149 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Smith PJ, Spurrell EL, Coakley J, Hinds CJ, Ross RJ, Krainer AR, et al. An exonic splicing enhancer in human IGF-I pre-mRNA mediates recognition of alternative exon 5 by the serine-arginine protein splicing factor-2/alternative splicing factor. Endocrinology. 2002; 143(1):146–54. doi: 10.1210/endo.143.1.8598 [DOI] [PubMed] [Google Scholar]
  • 23.Ritchey ER, Zelinka CP, Tang J, Liu J, Fischer AJ. The combination of IGF1 and FGF2 and the induction of excessive ocular growth and extreme myopia. Exp Eye Res. 2012; 991–16. doi: 10.1016/j.exer.2012.03.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Lee JE. Low IGF-1 suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity, by Hellstrom A., Perruzzi C.Ju M, Engstrom E., Hard A, Liu J., Albertson-Wikland K., Carlsson B., Niklasson A., Sjodell L., LeRoith D., Senger D., and Smith L. PNAS 98:5804–8, 2001. Surv Ophthalmol. 2003; 48(2):234–5. 10.1016/s0039-6257(02)00455-1 [DOI] [PubMed] [Google Scholar]
  • 25.Ruberte J, Ayuso E, Navarro M, Carretero A, Nacher V, Haurigot V, et al. Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease. J Clin Invest. 2004; 113(8):1149–57. doi: 10.1172/JCI19478 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Little J, Bradley L, Bray MS, Clyne M, Dorman J, Ellsworth DL, et al. Reporting, appraising, and integrating data on genotype prevalence and gene-disease associations. Am J Epidemiol. 2002; 156(4):300–10. doi: 10.1093/oxfordjournals.aje.a000179 [DOI] [PubMed] [Google Scholar]
  • 27.Yoshida M, Meguro A, Yoshino A, Nomura N, Okada E, Mizuki N. Association study of IGF1 polymorphisms with susceptibility to high myopia in a Japanese population. Clin Ophthalmol. 2013; 72057–62. 10.2147/opth.s52726 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Miyake M, Yamashiro K, Nakanishi H, Nakata I, Akagi-Kurashige Y, Tsujikawa A, et al. Insulin-like growth factor 1 is not associated with high myopia in a large Japanese cohort. Mol Vis. 2013; 191074–81. [PMC free article] [PubMed] [Google Scholar]
  • 29.Mak JYY, Yap MKH, Fung WY, Ng PW, Yip SP. Association of IGF1 gene haplotypes with high myopia in Chinese adults. Archives of Ophthalmology. 2012; 130(2):209–16. doi: 10.1001/archophthalmol.2011.365 [DOI] [PubMed] [Google Scholar]
  • 30.Rydzanicz M, Nowak D, Karolak J, Frajdenberg A, Podfigurna-Musielak M, Mrugacz M, et al. IGF-1 gene polymorphisms in Polish families with high-grade myopia. Mol Vis. 2011; 17 Rydzanicz M.; Nowak D.; Karolak J.; Gajecka M., gamar@man.poznan.pl) Institute of Human Genetics, Polish Academy of Sciences, Poznan, 60–479, Poland):2428–39. [PMC free article] [PubMed] [Google Scholar]
  • 31.Zhuang W, Yang P, Li Z, Sheng X, Zhao J, Li S, et al. Association of insulin-like growth factor-1 polymorphisms with high myopia in the Chinese population. Mol Vis. 2012; 18634–44. [PMC free article] [PubMed] [Google Scholar]
  • 32.Cheng T, Wang J, Xiong S, Zhang B, Li Q, Xu X, et al. Association of IGF1 single-nucleotide polymorphisms with myopia in Chinese children. PeerJ. 2020; 8e8436. doi: 10.7717/peerj.8436 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Zidan HE, Rezk NA, Fouda SM, Mattout HK. Association of Insulin-Like Growth Factor-1 Gene Polymorphisms with Different Types of Myopia in Egyptian Patients. Genetic testing and molecular biomarkers. 2016; 20(6):291–6. doi: 10.1089/gtmb.2015.0280 [DOI] [PubMed] [Google Scholar]
  • 34.Wang P, Liu X, Ye Z, Gong B, Yang Y, Zhang D, et al. Association of IGF1 and IGF1R gene polymorphisms with high myopia in a Han Chinese population. Ophthalmic genetics. 2017; 38(2):122–26. doi: 10.3109/13816810.2016.1145699 [DOI] [PubMed] [Google Scholar]
  • 35.Zhao Jj ZW. Association of insulin-like growth factor-1 polymorphisms with extreme high myopia in Chinese population. Zhonghua Yan Ke Za Zhi. 2013; 49334–9. [PubMed] [Google Scholar]
  • 36.Rydzanicz M, Nowak DM, Karolak JA, Frajdenberg A, Podfigurna-Musielak M, Mrugacz M, et al. IGF-1 gene polymorphisms in Polish families with high-grade myopia. Mol Vis. 2011; 172428–39. [PMC free article] [PubMed] [Google Scholar]
  • 37.Solouki AM, Verhoeven VJ, Van Duijn CM, Verkerk AJ, Ikram MK, Hysi PG, et al. A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14. Nat Genet. 2010; 42(10):897–901. doi: 10.1038/ng.663 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Hysi PG, Young TL, Mackey DA, Andrew T, Fernandez-Medarde A, Solouki AM, et al. A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25. Nat Genet. 2010; 42(10):902–5. doi: 10.1038/ng.664 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Sun J, Zhou J, Zhao P, Lian J, Zhu H, Zhou Y, et al. High prevalence of myopia and high myopia in 5060 Chinese university students in Shanghai. Invest Ophthalmol Vis Sci. 2012; 53(12):7504–9. doi: 10.1167/iovs.11-8343 [DOI] [PubMed] [Google Scholar]
  • 40.Xu GP, Chen WX, Zhao Q, Zhou H, Chen SZ, Wu LF. Association between the insulin-like growth factor 1 gene rs2195239 and rs2162679 polymorphisms and cancer risk: a meta-analysis. BMC medical genetics. 2019; 20(1):17. doi: 10.1186/s12881-019-0749-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Oh SY, Shin A, Kim SG, Hwang JA, Hong SH, Lee YS, et al. Relationship between insulin-like growth factor axis gene polymorphisms and clinical outcome in advanced gastric cancer patients treated with FOLFOX. Oncotarget. 2016; 7(21):31204–14. doi: 10.18632/oncotarget.9100 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Henningson M, Hietala M, Torngren T, Olsson H, Jernstrom H. IGF1 htSNPs in relation to IGF-1 levels in young women from high-risk breast cancer families: implications for early-onset breast cancer. Familial cancer. 2011; 10(2):173–85. doi: 10.1007/s10689-010-9404-z [DOI] [PubMed] [Google Scholar]
  • 43.Metlapally R, Ki CS, Li YJ, Tran-Viet KN, Abbott D, Malecaze F, et al. Genetic association of insulin-like growth factor-1 polymorphisms with high-grade myopia in an international family cohort. Invest Ophthalmol Vis Sci. 2010; 51(9):4476–9. doi: 10.1167/iovs.09-4912 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

James Fielding Hejtmancik

9 Jun 2022

PONE-D-22-06967The G allele of the IGF1 rs2162679 SNP is a potential protective factor for any myopiaPLOS ONE

Dear Dr. Meng,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

While both reviewers appreciate the contributions of this meta-analysis, but both have a number of comments that need to be addressed.  Although some are fairly minor, there are some inconsistencies with regard to the description of the outcomes in the Results and Discussion section and the need to correct for multiple testing, or at least discuss this and why it is not necessary, as well as some problems with the figures and tables.  Each of these need to be addressed.

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James Fielding Hejtmancik, M.D., Ph.D.

Academic Editor

PLOS ONE

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Additional Editor Comments:

While both reviewers appreciate the contributions of this meta-analysis, but both have a number of comments that need to be addressed. Although some are fairly minor, there are some inconsistencies with regard to the description of the outcomes in the Results and Discussion section and the need to correct for multiple testing, or at least discuss this and why it is not necessary, as well as some problems with the figures and tables. Each of these need to be addressed.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this manuscript the authors reported The G allele of the IGF1 rs2162679 SNP is a potential protective factor for any myopia. the project is well conceived, the following comments for consideration:

1. in this study the comparisons were done between the different groups and SNPs using analysis of variance, the authors need to do multiple testing to reject false hypotheses.

2. In the Results rs2162679, "significant association" should be changed to "suggestive association."

3. In the Results , the paragraph descriptions of rs2162679 that supporting file should be (Table 1, Table 2) instead of (Fig 1, Table 2), this paragraph not related with Fig 1.

4. in Abstract and Discussion the author said rs2162679

was significantly associated with any myopia in the codominant model (GA vs. AA: OR

= 0.87, 95% CI: 0.76-1.00) and the dominant model (GG+GA vs. AA: OR = 0.88, 95%

CI = 0.78-1.00).

but in results the author said rs2162679 "there were no significant associations for the allelic model (G vs. A: OR = 0.93,

95% CI: 0.85-1.02, P=0.14), dominant model (GG+GA vs. AA: OR = 0.88, 95% CI =

0.78-1.00, P=0.05), recessive model (GG vs. GA+AA: OR = 0.99, 95% CI = 0.82-1.19,

P=0.92 and codominant model (GG vs. AA: OR = 0.92, 95% CI = 0.76-1.13, P=0.43).", this is inconsistency, authors need to correct that.

5. the authors need add in figure legend for Fig 1 and Fig 2 .

Reviewer #2: Meng B, et al., presented a manuscript performing a meta-analysis to investigate the association of IGF1 SNPs and myopia. Authors analyzed nine studies and included 7 SNPs in this meta-analysis. They found that Rs2162679 was significantly associated with myopia in both the codominant and the dominant model, and the G allele of the IGF1 rs2162679 SNP is a potential protective factor for any myopia. This manuscript is well written and minor revision is needed to address the following points:

1. Please include “meta-analysis” in the title

2. Add a reference to Page 7 Line 12-13 for the “Myopia has already become the second most common cause of legal blindness”

3. Page 8 Line 9: delete “[22]”

4. Table 1 is truncated on the right side and is not fully shown in the manuscript

5. Check the format of all references.

**********

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Reviewer #1: No

Reviewer #2: No

**********

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PLoS One. 2022 Jul 21;17(7):e0271809. doi: 10.1371/journal.pone.0271809.r002

Author response to Decision Letter 0

3 Jul 2022

The statement "The authors received no specific funding for this work." has been included in the cover letter.

The statement "The authors have declared that no competing interests exist." has been included in the cover letter.

Attachment

Submitted filename: Response to Reviewers.doc

Click here for additional data file. (36.5KB, doc)

Decision Letter 1

James Fielding Hejtmancik

8 Jul 2022

The G allele of the IGF1 rs2162679 SNP is a potential protective factor for any myopia: Updated systematic review and meta-analysis

PONE-D-22-06967R1

Dear Dr. Meng,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

James Fielding Hejtmancik, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have addressed each of the reviewers' comments.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: the authors have been addressed all my concerns in the revised manuscript. overall, the results are complete and advance the field.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

**********

Acceptance letter

James Fielding Hejtmancik

12 Jul 2022

PONE-D-22-06967R1

The G allele of the IGF1 rs2162679 SNP is a potential protective factor for any myopia: Updated systematic review and meta-analysis

Dear Dr. Meng:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. James Fielding Hejtmancik

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 File. Meta-analysis of the association of other IGF1 SNPs with any myopia.

    (DOCX)

    Click here for additional data file. (202.2KB, docx)
    S2 File. Funnel plot analysis for publication bias.

    (DOCX)

    Click here for additional data file. (63.1KB, docx)
    S3 File. Search strategy.

    (DOCX)

    Click here for additional data file. (12.8KB, docx)
    S4 File. Prisma 2009 checklist.

    (DOCX)

    Click here for additional data file. (26.3KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.doc

    Click here for additional data file. (36.5KB, doc)

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.

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