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30 January 2023: Clinical Research  

Polymorphisms in and Genes Contribute to the Susceptibility to High Myopia-Induced Cataract in Han Chinese Population

Bo Ma1ABDEF, Wenpei Zhang2BC, Xiaochen Wang2BC, Huili Jiang3BF, Li Tang3BF, Wen Yang3BF, Qianyan Kang4A*, Juan Cao3BF

DOI: 10.12659/MSM.937702

Med Sci Monit 2023; 29:e937702

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Abstract

BACKGROUND: Myopia has been shown to be associated with many pathological complications including cataracts, and previous evidence supported that high myopia facilitates the formation of cataracts. However, no studies have identified a link between the genetic susceptibility of high myopia-induced cataracts (HMC) and the underlying genetic mechanisms. Our study aimed to determine how the TRIB2 and CAPRIN2 genes correlate to the risk of HMC.

MATERIAL AND METHODS: In total, we successfully recruited 3162 participants, including 1026 participants with high myopia and cataracts and 2136 controls with high myopia only. For genotyping, 22 tag single nucleotide polymorphisms (SNPs) in TRIB2 and CAPRIN2 genes were chosen. Single marker association analysis and functional effects of significant SNPs were carried out.

RESULTS: Strong correlation signals were captured for SNP rs890069 (χ²=22.13, P=2.55×10–6) in TRIB2 and SNP rs17739338 (χ²=16.07, P=6.10×10-5) in CAPRIN2. In patients with high myopia, the C allele at SNP rs890069 was strongly linked to cataract risk (OR [95% CI]=1.36 [1.20-1.55]). In patients with high myopia, the T allele at SNP rs17739338 was significantly related to a lower risk of cataract (OR [95% CI]=0.54 [0.40-0.74]). In different types of human tissues, SNPs rs890069 and rs17739338 were found to be significantly correlated to the levels of TRIB2 and CAPRIN2 gene expression.

CONCLUSIONS: Our study indicated that both TRIB2 and CAPRIN2 genes conferred the susceptibility to cataract in patients with high myopia and Chinese Han ancestry. Future research remains necessary for fully understanding the pathogenic mechanisms and genetic characteristics of cataract.

Keywords: Case-Control Studies, Disease Susceptibility, Polymorphism, Single Nucleotide, Humans, East Asian People, Haplotypes, Myopia, Genetic Predisposition to Disease, Cataract, Genotype, RNA-Binding Proteins, Calcium-Calmodulin-Dependent Protein Kinases

Background

Cataracts leads to great harm of vision and disability in patients, accounting for more than 33.3% of blindness worldwide [1–3]. Other than being affected by risk factors such as age-related degenerative changes in the crystalline lens [4–6], the development of cataracts is strongly influenced by hereditary factors, as shown by twin and genealogy research [7,8]. The heritability of cataracts is approximately 35% to 58% [9]. Although previous studies have uncovered many risk gene variants for cataracts [10], the genetic underpinnings of the pathogenesis of cataracts remain confusing. Myopia affects hundreds of millions of people worldwide, and it has become more commonplace in recent years. According to a recent study, myopia prevalence would increase to 49.8% and high myopia prevalence to 9.8% by 2050 [10]. Myopia has been shown to be associated with many pathological complications, including cataracts [11]. Previous evidence supported that high myopia facilitates the formation of cataracts [12]. Myopia is also coregulated by genetic and environmental factors [13]. Thus, genetic factors are indicated to contribute to the pathogenesis of high myopia-induced cataracts (HMC). However, to date, few studies have revealed the association between the genetic susceptibility of HMC and the underlying genetic mechanisms.

Caprin Family Member 2 (CAPRIN2) is a type of RNA binding protein. CAPRIN2 is implicated in RNA transportation and cell differentiation and was shown to activate the Wnt pathway, suggesting that it is involved in the development of hepatoblastoma [14]. In addition, CAPRIN2 was found to be located at the rim of the lens vesicles and to be implicated in eye development and disease. In animal models, Caprin2 has been shown to be a component of RNA granules of the lens and contributes to the posttranscriptional regulation of gene expression in eye morphogenesis. Mice with Caprin2 gene knockout showed abnormal compact lens nuclei and developmental defectsin the lens [15]. In flies, the Drosophila ortholog of Caprin2 was associated with RNA granules and eye sizes [16,17]. Thus, the CAPRIN2 gene may constitute a liability in the development of cataracts. Single nucleotide polymorphism (SNP) rs17739338 in the CAPRIN2 gene was recently reported to be significantly correlated with susceptibility to cataracts in Europeans [9].

Tribbles pseudokinase 2 (TRIB2) is one of the pseudokinase proteins in the serine/threonine kinase superfamily. TRIB2 is involved in the processes of cell growth, proliferation, and differentiation in the contexts of normal development and in stressful stimuli [18]. TRIB2 is an upstream molecule of PI3K/AKT/MAPK signaling, and dysfunction of TRIB2 has been shown to be related to many tumors [19,20]. In addition, with a potential role in cell development in the ocular region, the TRIB2 gene may also be associated with ophthalmic diseases such as cataracts. A current meta-analysis of genome-wide association studies in cataracts found for the first time that SNP rs890069 near the TRIB2 gene was positively related to the risk of cataracts in Europeans.

Together, the CAPRIN2 and TRIB2 genes were reported to be positively related to HMC in Europeans, but those positive signals lack precise biological interpretation, leaving the genetic basis of the HMC unexplained and urgently in need of clarification. The CAPRIN2 and TRIB2 genes are 2 significant options for identifying the risk genetic variations in HMC, given the effects of genetic and environmental factors on the pathogenesis of HMC. Therefore, the purpose of our study was to assess the association between both genes and HMC susceptibility in the Chinese Han population.

Material and Methods

STUDY PARTICIPANTS:

We enrolled 1026 high myopia patients with cataracts and 2136 controls (age-matched) with only high myopia from Xi’an Fourth Hospital (Figure 1). All participants were high myopia patients and unrelated Han Chinese individuals (at least all 3 generations were of Han descent and had no history of migration). All participants were examined by detailed ophthalmic assessments. According to the spherical equivalent (SE) of both eyes, high myopia was defined by SE ≤−6.0 dioptres (D). Those having both eyes meeting the criteria were included. Those with prior ocular surgery, ocular trauma, strabismus, corneal or ocular surface diseases, corneal scar, uveitis, glaucoma, or other major eye diseases affecting the accuracy of refraction were excluded from the study. Ocular lens opacification and best-corrected visual acuity less than 20/40 were used to diagnose cataracts. According to the lens opacity area of the enrolled patients, cataracts were divided into 4 types: cortical cataracts, nuclear cataracts, posterior subcapsular cataracts, and mixed cataracts. If the enrolled patient had at least 1 eye with more than 1 type of cataract or 2 eyes with different types, he or she was defined as the mixed type. Patients meeting the following criteria were included in the case group: (1) lens opacity; (2) under 50 years old (excluding age-related cataracts); (3) best-corrected visual acuity below 20/40; and (4) no other clear causes of cataracts. Patients with complicated cataracts caused by diabetes or other known causes, as well as with pseudophakia or aphakia in either eye, were also excluded from the study.

The study participants’ peripheral blood samples were drawn, conserved, and used in subsequent genotyping. Table 1 displays the clinical features and demographic data of the study participants that were gathered through questionnaires and medical records. Each participant provided their written informed consent. The Medical Ethics Committee of Xi’an Fourth Hospital approved the study.

SNP SELECTION AND GENOTYPING:

SNPs in TRIB2 and CAPRIN2 genomic regions were extracted for genotyping experiments. For the TRIB2 gene region, 43 SNPs with minor allele frequency ≥0.02 were screened from 1000 Genomes data. Among these SNPs, 9 tag SNPs were selected using r2=0.5 as criteria. A similar SNP selection strategy was applied to the CAPRIN2 gene region. A total of 101 SNPs with minor allele frequency ≥0.02 were extracted, and 13 tag SNPs were selected. Finally, 22 tagging SNPs were chosen in total to be genotyped (Table 2).

DNA extractions were carried out from the collected peripheral blood by genomic DNA kits (Axygen Scientific Inc, USA). All screened tag SNPs were detected by the Sequenom MassARRAY platform. Further data processing was conducted using a Typer Analyzer. Technicians were blinded to the sample labels throughout the experiments.

STATISTICAL ANALYSIS:

Demographic and clinical information were compared between the case and control groups. The Hardy-Weinberg equilibrium test was carried out in the controls. Haploview was used to display the genotyped SNPs’ linkage disequilibrium pattern [21]. Single marker association analysis was carried out at the allelic and genotypic levels to assess the genetic relationship between 22 tag SNPs and HMC risk. The statistical significance was examined by χ2 and Fisher’s exact tests. Plink was used for genetic association analysis [22]. To adjust for multiple comparisons, Bonferroni correction was applied. To investigate the potential effects of population stratifications, a Q-Q plot was created. The P value cutoff was set at 0.05/22≈0.002 for single marker association analysis. Additionally, we performed an analysis to investigate the correlation of the clinical type of cataract with targeted SNPs.

Several bioinformatics tools were used to further examine the functional effects of the significant SNPs found in association analysis. In the Genotype-Tissue Expression database, the relationship between SNP genotypes and the levels of TRIB2 and CAPRIN2 gene expression in different human tissues was investigated [23]. The gene expression of CAPRIN2 and TRIB2 in mouse eyes was investigated using the iSyTE database (https://research.bioinformatics.udel.edu/iSyTE/). RegulomeDB was utilized for annotating the significant SNPs for their potential functional significance [24]. In addition, previous associations between the significant SNPs and other complex human traits were explored using the genome-wide association study catalog database [25].

Results

A total of 3162 patients with high myopia, including 1026 patients with both high myopia and cataracts (cases) and 2136 patients with high myopia only (controls), were recruited (Table 1). Comparisons between the case and control groups showed no differences in sex (P=1.00), age (P=0.73), or axial length (P=0.47). Among patients with HMC, 105 patients had cortical cataracts (10%), 498 patients had nuclear cataracts (49%), 134 patients had posterior subcapsular cataracts (13%), and 289 patients had mixed-type cataracts (28%). Distributions of age between the 2 groups are shown in Figure 2.

All SNPs were in accordance with the Hardy-Weinberg equilibrium in controls (Table 2). The LD plot constructed from the genotype data indicated no significant correlations (Figure 3). A positive association was identified for SNP rs890069 in TRIB2 at both genotypic (Table 3, χ2=22.97, P=1.03×10−5) and allelic levels (χ2=22.13, P=2.55×10−6). The C allele at SNP rs890069 was strongly linked with the risk of cataracts in patients with high myopia (odds ratio [OR] [95% CI]=1.36 [1.20–1.55]). In addition, a dosage-dependent pattern could be observed from the ORs of different genotypes. The OR values increased with increasing copies of the C allele. A strong association was found for SNP rs17739338 in CAPRIN2 at both genotypic (Table 3, P=1.03×10−5) and allelic levels (χ2=16.07, P=6.10×10−5). The T allele at SNP rs17739338 was significantly related to a lower risk of cataract in patients with high myopia (OR [95% CI]=0.54 [0.40–0.74]). In Table 4, the complete outcomes of the single marker association analysis are presented. The locations of both significant SNPs and the gene structures for CAPRIN2 and TRIB2 are shown in Figure 4.

The Q-Q plot showed that no significant inflations could be identified from the results of the association analysis (Figure 5). This indicated that the confounding effects of population stratifications were limited. The significant SNP genotypes and the different clinical types of cataracts did not significantly differ from one another (Table 5). Some positive expression quantitative trait loci (eQTL) associations for rs890069 in the TRIB2 gene were found in 22 out of 47 types of human tissues (Table 6, Figure 6A). The most significant signal was obtained from cultured fibroblast cells (NES=−0.11, T statistic=−6.30, P=8×10−10). In 34 of the 47 different types of human tissues, there were significant eQTL associations for the rs17739338 in CAPRIN2 gene (Table 7, Figure 6B). Thyroid tissue had the strongest association signal (NES=−0.49, T statistic=−13.0, P=2.10×10−32). The expression patterns of Caprin2 (upregulated) and Trib2 (downregulated) are significantly enriched in the lens during the eye development process of mice. It indicates that both genes might play important roles for pathogenesis of eye-related diseases (Table 8).

Discussion

We found 2 significant SNPs in the present study, rs890069 in TRIB2 and rs17739338 in CAPRIN2, which are linked to the incidence of cataracts in patients with high myopia in the Chinese Han population. In a recent multi-ethics meta-analysis, both SNPs were identified to be significantly linked to cataract risk [9]. Although the effect size was smaller in the present study than it was in the prior publication, the effect directions of both SNPs were the same. Our findings can be considered as a successful confirmation of these earlier findings in the Chinese Han population.

Since both SNPs were in intronic regions, they could not change the amino acid sequence of the encoded protein to alter its molecular structure. Nevertheless, bioinformatics analysis using data from publicly available databases has shown that both SNPs are significantly associated with their mapped genes. Both SNPs showed widespread eQTL signals across many human tissue types. This result suggested that both SNPs may affect gene expression and therefore have functional effects. The Genotype-Tissue Expression database does not include any information on the targeted tissues of cataracts; thus, we need to be wary of these bioinformatics findings.

TRIB2 is one of the pseudokinase proteins in the serine/threonine kinase superfamily. These loci have been linked to some human diseases and traits in previous genome-wide association studies, such as blood components [26], body fat percentage [27], and dental caries [28]. Interestingly, a recent genome-wide association study indicated that the TRIB2 gene was related to optic cup area measurement [29]. This measurement describes optic nerve morphology and may be related to glaucoma pathogenesis mechanisms [29]. To date, no report has been published on supporting shared genetic architecture between cataract and primary open-angle glaucoma. Our findings may shed light on the hypothesis of a genetic overlap between the 2 typical eye diseases.

CAPRIN2 is a type of RNA binding protein. Unlike TRIB2, to which very limited evidence of eye-related diseases or traits has been linked, multiple lines of evidence have linked CAPRIN2 with eye-relevant traits in model animals [15,17,30–32]. The RNA binding proteins were believed to be involved in the post-transcriptional regulation process through mediating spatiotemporal expression of key factors related to the cell cycle [33]. This locus has been connected to some human diseases and traits in previous genome-wide association studies, including of body height [34] and waist-hip ratio [34]. What is more interesting is that these loci were found to be linked with facial morphology in a recent genome-wide association study [35]. The facial feature of the vertical position of the orbits relative to the midface was found to be strongly correlated with genetic CAPRIN2 polymorphism [35].

For most gene association mapping scenarios, associated SNPs could be surrogates of certain underlying polymorphisms that have true effects. For the present study, although both SNPs have been reported in at least 2 independent studies, we believe that it is quite likely that both SNPs identified in the present study are just surrogates, because limited evidence has been reported for their functional consequences. Rare or low-frequency DNA variations have been demonstrated to significantly increase the susceptibility of complex diseases in a number of sequencing-based genetic studies owing to the emergence of next-generation sequencing technology [36]. A recent study indicated that 2 key eye diseases, myopia and glaucoma, might primarily be influenced by rare and low-frequency DNA variants [37]. It is likely that a collection of numerous low-frequency or rare genetic variants is the source of the association signals of common genetic variants. Examining how low-frequency or rare variations on the genetic level contribute to cataract risk is outside the scope of the current investigation. Genetic research based on sequencing will be required in the future to detect the genetic characteristics of cataracts.

With the rapid development of omics technology, future analysis integrating multi-omics data is expected to elucidate the molecular mechanisms of complex diseases on the basis of understanding multidimensional molecular interactions [38–43]. Therefore, it is worth mentioning some limitations of our study. The selected SNPs only cover the gene region of candidate loci. Neither 3′ nor 5′ untranslated regions were included. This SNP selection strategy might raise concern for the genetic information coverage of the present study because both untranslated regions have been proven to be important genomic regions containing regulatory elements for genes. Myopic individuals were included in this study, which may make it difficult to generalize the findings. A comparison of the magnitude of the risk for cataracts conferred by these gene variants in patients with high myopia versus patients without high myopia might enable us to identify noteworthy discoveries in the future.

Conclusions

In summary, our study showed that both TRIB2 and CAPRIN2 conferred genetic susceptibility to cataracts in patients with high myopia with Chinese Han ancestry, offering new targets or indicators for the prevention and treatment of HMC and aiding in deepening our understanding of the genetic roots of the illness. Future research is still required to fully understand the pathogenic mechanisms and genetic characteristics of cataracts.

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