Molecular Vision 2025; 31:570-582
<http://www.molvis.org/molvis/v31/570>
Received 03 July 2025 | Accepted 28 December 2025 | Published 30 December 2025
Molecular Vision 2025; 31:570-582
<http://www.molvis.org/molvis/v31/570>
Received 03 July 2025 |
Accepted 28 December 2025 |
Published 30 December 2025
Jie Peng,1 Yina Wang,2 Jiaqing Lu,2 Ying Wang,3 Yongning Dong,3 Jie Fang,1 Xu Chen1
1Wuxi Huishan District People's Hospital, Wuxi, China; 2Affiliated Hospital of Jiangnan University, Wuxi, China; 3Wuxi School of Medicine, Jiangnan University, Wuxi, China
Correspondence to: Xu Chen, Wuxi Huishan District People's Hospital, Wuxi, China; email: cxhsry@outlook.com
Purpose: Genetic polymorphisms in syntrophin beta-1 (SNTB1) have been implicated in altering protein function or expression, potentially influencing ocular growth regulation. Genome-wide association studies (GWASs) suggest that specific SNTB1 variants may correlate with high myopia susceptibility across diverse populations. However, findings remain inconsistent, highlighting the need for further investigation into population-specific genetic effects and underlying mechanisms.
Methods: Accordingly, the PubMed and Wanfang databases were searched for articles published until June 1, 2025, using the keywords SNTB1 or syntrophin beta-1, polymorphism, and myopia or shortsightedness. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to examine the association. The SNTB1 rs6469937 polymorphism genotypes were identified with the TaqMan assay.
Results: Four related studies were conducted to better understand the association between SNTB1 gene polymorphisms and high myopia risk. The SNTB1 rs4455882 site was associated with a decreased overall high myopia risk (e.g., G vs. A; OR = 0.815; 95% CI, 0.688–0.984; pheterogeneity = 0.465; p = 0.017). Similar trends were detected in the rs4395927 site (e.g., T vs. C; OR = 0.791; 95% CI, 0.670–0.935; pheterogeneity = 0.199; p = 0.006) and rs6469937 site (e.g., A vs. G; OR = 0.811; 95% CI, 0.697–0.944; pheterogeneity = 0.030; p = 0.007). Furthermore, high myopia patients carrying the SNTB1 rs6469937 AA+AG genotypes exhibited pronounced increases in serum levels of SNTB1 compared to the GG genotype (p < 0.01) but showed an opposite trend compared to genotype-matched normal controls (p < 0.05).
Conclusions: The current study suggested that the SNTB1 rs4455882, rs4395927, and rs6469937 polymorphisms may be potential influencing factors of high myopia. Furthermore, the rs6469937 polymorphism may offer value as a candidate variant requiring validation that can aid in the early identification and prognostic evaluation of high myopia.
High myopia (typically defined as ≤–6.00 diopters) is a severe refractive error marked by excessive axial elongation of the eyeball. It poses significant risks of vision-threatening complications and has become a global public health concern, especially in East Asia. In adults, its prevalence ranges from 0.5% to 9.8%, with considerable regional variations [1].
The etiology of high myopia is complex, involving interactions between genetic and environmental factors. Compared to low-to-moderate myopia, high myopia has a stronger genetic predisposition, while environmental factors play a modulating role. In contrast, the recent rapid increase in low-to-moderate myopia is largely attributed to environmental and lifestyle changes since the mid-20th century [2].
Before the genome-wide association study (GWAS) era, researchers used family linkage analyses and candidate gene approaches to identify high myopia–associated genes in families, twins, and offspring. These studies confirmed that individuals with high myopia in their parents are more likely to develop the condition, highlighting the role of genetic susceptibility [3,4].
GWASs have identified over 200 loci associated with high myopia, including PAX6 and GJD2 [5]. Recently, syntrophin beta-1 (SNTB1) has been widely linked to high myopia susceptibility. SNTB1 encodes a cytoskeleton-associated protein in the syntrophin family, which is involved in cell signaling and structural maintenance. In the retina, SNTB1 may interact with proteins such as the dystrophin complex to influence photoreceptor or retinal neuron stability. Some studies suggest a connection between SNTB1 and retinal development or diseases such as retinal degeneration, although the exact mechanisms remain unclear [6–11].
Currently, no meta-analysis has examined the association between SNTB1 gene polymorphisms and high myopia risk. Therefore, we performed pooled analyses of all available case-control studies, focusing on four common polymorphisms: rs4455882, rs4395927, rs7839488, and rs6469937. This aims to provide stronger evidence on whether these variants are significantly associated with high myopia [12–15]. Additionally, we explored the relationship between different rs6469937 genotypes and SNTB1 expression based on our single-center data.
At the beginning, the PubMed and Wanfang databases were searched for articles published as of June 1, 2025, using the keywords SNTB1 or syntrophin beta-1, polymorphism, and myopia or shortsightedness. No language or publication year restrictions were imposed on the search. The references of retrieved articles and reviews were additionally manually searched for relevant studies.
Eligible studies were those that (a) evaluated correlations between high myopia risk and one or more of the selected polymorphisms, (b) were case-control studies, (c) included age- and gender-matched control groups, and (d) had an available full-text manuscript. Studies were excluded if they (a) lacked a control population, (b) did not provide genotype frequencies, (c) were duplicate studies, or (d) exhibited clear evidence of bias. Literature search results were reviewed by two investigators. Collected data from identified studies included first author, publication year, country, ethnicity, genotypes in the case and control groups, source of controls, Hardy–Weinberg equilibrium analyses of controls, and genotyping methods (polymerase chain reaction, Sequenom MassARRAY System, San Diego, CA, sequencing).
Odds ratios (ORs) and 95% confidence intervals (CIs) were used to examine the association between SNTB1 polymorphisms and the risk of high myopia based on genotypic frequency levels in cases and control subjects. Subgroup analyses were initially conducted based on the source of control subjects, separately assessing population-based and hospital-based studies.
Pooled OR significance was assessed using the z test [16]. The χ2-based Q tests were used to assess heterogeneity, with p < 0.05 being indicative of significant heterogeneity, in which case pooled ORs were analyzed with a random-effects model [17], whereas a fixed-effects model [18] was otherwise employed [19,20]. For the rs4455882, rs4395927, rs7839488, and rs6469937 polymorphisms in the SNTB1 gene, associations between genotype and high myopia risk were assessed using dominant, heterozygote comparison, allelic contrast, homozygote comparison, and recessive genetic models. Begg’s and Egger’s tests were used to evaluate funnel plot asymmetry to detect publication bias [21], with p < 0.05 as the cutoff to define significance. The Pearson χ2 test for goodness of fit was used to detect departures from Hardy–Weinberg equilibrium with respect to the frequencies of SNTB1 polymorphisms, using p < 0.05 as the cutoff to define significance. Stata v11.0 (StataCorp LP, College Station, TX) was used to conduct statistical analyses.
Minor allele frequency reports for these four polymorphisms were assessed in six global populations using the 1000 Genomes Browser, which shows different ratios across races for each polymorphism (https://www.ncbi.nlm.nih.gov/snp/). In addition, the genomic locations of the four SNTB1 polymorphisms (rs4455882, rs4395927, rs7839488, and rs6469937) were visualized using the National Center for Biotechnology Information (NCBI) database. Finally, haplotype analysis was applied, using the LDBlockShow software; the linkage disequilibrium (LD) between single-nucleotide polymorphisms (SNPs) in some gene region was calculated (using the R2 statistic), and the Solid Spine of LD method (BlockType 2) was employed to identify haplotype blocks.
SNTB1 gene polymorphism genotyping has been performed with a range of techniques across studies, including polymerase chain reaction, the Sequenom MassARRAY System, and sequencing. For the present study, SNTB1rs6469937 polymorphism genotypes were assessed with the TaqMan assay using the approach documented by Castro et al. [22]. The power of our study was calculated by the PS: Power and Sample Size Calculation.
This cross-sectional study recruited 120 treatment-naive patients with high myopia (spherical equivalent ≤−6.00 D) at the Affiliated Hospital of Jiangnan University between April 2023 and December 2024. An age-matched control cohort (n = 120) with emmetropia (spherical equivalent −0.50 to +1.00 D) was concurrently enrolled from routine health screenings. Participants underwent a comprehensive ophthalmic evaluation to exclude confounding pathologies: ocular exclusions, including keratoconus, glaucoma, cataracts, macular degeneration, prior intraocular/refractive surgery, corneal opacities, or strabismus; systemic exclusions, including conditions potentially compromising visual function; and additional exclusions, including an unwillingness to participate or conditions affecting refractive assessment accuracy [23]. Peripheral blood samples (3 ml) were obtained from all participants after written informed consent. The study protocol (Ethical Approval Code: LS202221) received institutional review board approval at Jiangnan University and adhered to the principles of the Declaration of Helsinki.
Blood samples were collected in anticoagulant-free tubes, after which serum separator tubes were used and samples were allowed to clot overnight at 4 °C or at room temperature for 2 h. Samples were then centrifuged (1,000 ×g, 15 min), after which serum was collected and immediately assessed or stored at −20 °C or −80 °C for future analyses, minimizing repeated freezing and thawing. Serum levels were detected with an ELISA kit (Yuhengfeng Co. Ltd., Beijing, China). Absorbance at 450 nm was assessed, with correction at 540 or 570 nm. For further details, see the manufacturer’s website (ELISA).
Our systematic search strategy retrieved 15 potentially relevant articles from PubMed and Wanfang databases. After rigorous evaluation based on predefined inclusion criteria, four high-quality studies were selected for meta-analysis (Figure 1), including three case-control studies for rs4455882, three case-control studies for rs4395927, four case-control studies for rs6469937, and three case-control studies for rs7839488. The detailed characteristics of the included studies are presented in Table 1.
Minor allele frequency reports for these four polymorphisms were assessed in six global populations using the 1000 Genomes Browser, which shows different ratios across races for each polymorphism (SNP; Figure 2). In addition, through comprehensive database mining, these four polymorphisms (rs4455882, rs4395927, rs7839488, and rs6469937) were located within the promoter region of the SNTB1 gene (Figure 2).
An LD heatmap was then generated, with four SNPs of interest (rs4455882, rs4395927, rs7839488, and rs6469937) annotated in Figure 3. Through the LD plot, we can intuitively visualize the LD structure among SNPs in the target region. rs4395927 and rs7839488 may have an LD relationship. The LD patterns of the four annotated SNPs with surrounding SNPs help elucidate the genetic structure of this region and provide clues for subsequent gene mapping and functional studies.
The results of pooled analyses pertaining to the SNTB1rs4455882 polymorphism are presented in Table 2. A significant decrease in the association between this polymorphism and high myopia risk was detected in three genetic models (OR = 0.815; 95% CI, 0.688–0.964; pheterogeneity = 0.465; p = 0.017 for G-allele vs. A-allele, Figure 4; OR = 0.569; 95% CI, 0.359–0.903; pheterogeneity = 0.660; p = 0.017 for GG vs. AA; OR = 0.811; 95% CI, 0.658–0.999; pheterogeneity = 0.653; p = 0.049 for GG+GA vs. AA). Similar positive results were observed between the rs4395927 polymorphism and high myopia risk in four genetic models (e.g., OR = 0.791; 95% CI, 0.670–0.935; pheterogeneity = 0.199; p = 0.006 for T-allele vs. C-allele, Figure 5; OR = 0.544; 95% CI, 0.345–0.860; pheterogeneity = 0.775; p = 0.009 for TT vs. CC).
Another potential significant association was found between the rs6469937 polymorphism and high myopia risk in four genetic models in the total group (e.g., OR = 0.811; 95% CI, 0.697–0.944; pheterogeneity = 0.030; p = 0.007 for A-allele vs. G-allele, Figure 6; OR = 0.723; 95% CI, 0.588–0.889; pheterogeneity = 0.136; p = 0.002 for AA vs. GG), and the same associations were found when conducting subgroup analyses based on the source of control subjects both for population-based studies (e.g., OR = 0.824; 95% CI, 0.683–0.994; pheterogeneity = 0.027; p = 0.043 for A-allele vs. G-allele) and hospital-based studies (e.g., OR = 0.853; 95% CI, 0.780–0.932; pheterogeneity = 0.123; p = 0.017 for A-allele vs. G-allele, Figure 7; Table 2). For the three other SNTB1rs7839488 polymorphisms, no significant associations with overall high myopia risk were detected for different variant genotypes under the analyzed genetic models (Table 2).
The potential for publication bias was next evaluated with Begg’s funnel plots and Egger’s test. No publication bias was found in all four polymorphisms (data not shown).
The power of our study about rs6469937 was 0.238. In addition, our approach revealed that serum SNTB1 concentrations were significantly higher in high myopia patients harboring the AA+AG genotypes in rs6469937 as compared to the GG genotype (p < 0.01), but serum SNTB1 levels in high myopia patients with the AA+AG genotypes were also significantly lower as compared to levels in normal control subjects with the same genotypes (p < 0.05; Figure 8).
STRING database analysis identified 10 potential SNTB1-interacting genes, forming a complex regulatory network (Figure 9). Network topology analysis revealed 10 positive regulatory interactions (SNTB2, SNTG2, DAG1, DTNA, DTNB, UTRN, SGCG, SGCD, DMD, SGCA) with SNTB1. These interactions suggest potential combinatorial biomarker applications for early high myopia detection and provide valuable insights for future mechanistic studies.
High myopia affects approximately 2% to 5% of the global population, with prevalence exceeding 20% in East Asia [24]. This condition elevates the risk of sight-threatening complications, including retinal detachment (OR = 10.2), glaucoma (OR = 5.1), and myopic maculopathy, which has a 40% progression risk by age 60 [25].
GWASs have implicated over 25 susceptibility loci. For example, the PAX6 rs644242 polymorphism was associated with altered scleral remodeling (OR = 1.28; p = 3×10−11) [5]. The GJD2 rs634990 polymorphism may disrupt gap junction signaling (β = −0.57D; p = 4 × 10−10) [26]. Furthermore, the ZC3H11B rs4373767 polymorphism was a genetic risk factor for moderate and high myopia (OR = 1.42; p = 0.018) and was also associated with excessive axial length in children (β = 0.07; p = 0.002) [27]. Epistatic interactions between BMP2 and TGFBR1 variants can also amplify disease severity (p < 0.001) [28]. However, polygenic risk scores explain only 12% to 18% of the variance, suggesting that environmental factors play a significant role in the development of high myopia [29].
This meta-analysis is the first to systematically evaluate the relationship between four SNTB1 polymorphisms and high myopia risk. Our pooled analysis included data from 670 cases and 1,015 controls for rs4455882, 691 cases and 1,022 controls for rs7839488, 2,176 cases and 2,753 controls for rs6469937, and 691 cases and 1,025 controls for rs4395927.
We found a significant association between the rs4455882, rs6469937, and rs4395927 polymorphisms and high myopia risk. However, these findings are based on currently limited sample sizes, and further research with larger cohorts is needed.
Notably, normal individuals with AA/AG genotypes of rs6469937 exhibited higher serum SNTB1 expression than both high myopia patients with the same genotypes and high myopia patients carrying the GG genotype. This suggested that the rs6469937 polymorphism could enable early risk assessment in the population, allowing for early interventions like promoting eye hygiene, avoiding prolonged eye use, and increasing participation in sports activities to reduce the incidence of high myopia.
Single genes often harbor multiple polymorphic loci that confer different disease susceptibilities. These loci can modulate disease risk independently or synergistically through distinct mechanisms: first, functional domain specificity: in the CFH gene, the rs1061170 variant increases age-related macular degeneration risk (OR = 2.5) by impairing Bruch’s membrane binding, while the rs800292 variant confers protection (OR = 0.6) via enhanced C3b cleavage [30]. Second, transcriptional versus coding effects: for IL6, the promoter SNP rs1800795 alters cytokine levels in atherosclerosis (β = 0.8 pg/ml; p = 1 × 10−6) [31], whereas the coding SNP rs2069845 affects chronic hepatitis C risk via receptor binding [32]. Third, allelic interaction patterns: in TP53, the rs1042522 variant enhances apoptosis in cancer (hazard ratio = 1.4), while the intronic rs17878362 variant influences messenger RNA splicing efficiency (ΔΨ = 0.21, p < 0.01) [33]. Fourth, spatial segregation: variants can occur in different regulatory regions (FTOrs1421085 [obesity] vs. rs9939609 [metabolic rate]) [34] and for the haplotype effects: CYP2D6 rs3892097 (poor metabolizer) negates rs1135840 (ultrarapid) [35]. Our study on SNTB1 reflects a similar complexity.
To investigate the mechanism of the SNTB1 protein, we used the STRING online system to identify potential interacting proteins. We detected 10 proteins that may contribute to myopia through syntrophin-mediated signaling, extracellular matrix (ECM) remodeling, and scleral biomechanics. Further research should explore their specific interactions in retinal dopamine signaling and scleral collagen regulation, which could reveal new therapeutic targets.
This study had several limitations. First, although we incorporated all relevant articles, the overall sample size remains relatively small. This limitation was compounded when stratifying data by age, sex, race, eye axis length, and myopia degree. Second, the risk of high myopia associated with these polymorphisms may be influenced by gene–gene, gene–environment, and other polymorphic interactions. Future efforts should aim to collect details data on these factors. Third, more in-depth research into the mechanisms by which these polymorphic loci lead to disease susceptibility is needed. Such research would strengthen the rationale for genetic testing, provide more convenient clinical detection methods, and offer potential intervention targets for treatment. Fourth, the generalizability of results is limited, as most included studies were from East Asian populations (Han Chinese, Singaporean Chinese). Finally, future directions should include longitudinal studies to assess whether these SNPs predict incident high myopia or its progression rate, expansion to multiethnic cohorts to determine whether the protective association holds across different genetic backgrounds, and larger, multicenter studies to increase statistical power and reduce sampling bias.
The results of the present meta-analysis support a potential link between the SNTB1rs4455882, rs6469937, and rs4395927 polymorphisms and an overall decrease in high myopia risk. The rs6469937 polymorphism was additionally established as a potential risk indicator/candidate variant requiring validation for high myopia. Large-scale studies with larger sample sizes and environmental factors will be essential to clarify the susceptibility of the SNTB1 gene to high myopia.
Author contributions: JP and JF completed the laboratory operations section and drafted the manuscript. YW and YD collected clinical data and helped draft the manuscript, and JL, YW and XC participated in the analysis and interpretation of the inspection results. All the authors have read and approved the final version of the manuscript. Ethics statement: The study was approved by the Affiliated Hospital of Jiangnan University, and all patients provided written informed consent before sample collection (the ethical code: LS202221). Funding: This article was supported by the Soft Science Research Project of Wuxi Science and Technology Association (KX-25-C261). Declaration of competing interest: None. Data availability: Data will be made available on request.