Association between polymorphisms of OGG1, EPHA2 and age-related cataract risk: a meta-analysis

In this meta-analysis, we totally identified six articles concerning three genetic polymorphisms. Our results showed that CG genotype and GG+CG genotype of OGG1 rs1052133 were associated with increased the risk of ARC, in particular with cortical cataract. This significant relationship was not found in EPHA2 polymorphisms (rs7543472 and rs11260867), however, subgroup analysis by phenotypes of cataract showed that only in cortical cataract, the genotypes of rs7543472 under the allele model, homogenous model and recessive model; genotypes of rs11260867 under the heterogenous model and dominant model were associated with ARC risk. This was the first meta-analysis concerning these three SNPs in ARC risk.

Cataract is the single largest contributor to blindness in the world. Age is the major risk factor for cataract. Even though several measures have been identified as a solution for cataract treatment [35, 36], there is no obvious therapeutic benefits, and established medical treatment for better prevention and treatment of cataract was not built [37]. Moreover, this disease has a strong genetic component. Therefore, understanding of genetic polymorphisms within the lens may provide an insight into the process of cataract onset.

OGG1 is involved in multiple vital processes. Recent studies showed that OGG1 was highly expressed in the embryonic brain, and lack of OGG1 might cause severe brain defects in brain integrity, balance and mobility [38]. The acetylation of OGG1 was shown to play an important etiologic role in regulating its function in response to DNA damage [39], and could be one of the mechanisms for ARC development [40]. Xu et al. proved that OGG1 might increase in lens epithelium cells with ARC, and the alteration of OGG1 level was associated with the location and opaque degrees of lens [41]. Wang et al. proved that the reduced OGG1 expression was correlated with hypermethylation of a CpG island of OGG1 in lens cortex of ARC [42]. In addition, OGG1 mutations might delay the repair of oxidative DNA damage, and be associated with increased disease risk [43]. Ali et al. showed that OGG1 mutation may prove to be a good candidate of better diagnosis, treatment, and prevention of breast cancer [44]. Zhang et al. suggested that OGG1 Ser326Cys polymorphism might be associated with increased risk of ARC [31]. While Su et al. did not find a correlation between OGG1 variants and ARC risk in Han Chinese from the Jiangsu Eye Study [45].

EPHA2 is an epithelial cell tyrosine kinase, and was shown to be enriched in adult tissues [46]. It is highly expressed in aggressive human cancers. During tumor progression, EPHA2 receptor can gain ligand-independent pro-oncogenic functions due to Akt activation and reduced ephrin-A ligand engagement [47]. Moreover, EPHA2 can function as a therapeutic target for antibody therapy of cancers and diseases [48, 49]. Dunne et al. found that EPHA2 was a key driver of invasion and migration and a synthetically lethal target in KRASMT colorectal cancer, indicating that EPHA2 was a poor prognostic marker [50]. Kato et al. showed a promising role for EPHA2 as a target for antibody treatment in melanoma and enhanced the therapeutic effect as an agonistic antibody to EPHA2 [51]. Genetic and pharmacological inhibition of EPHA2 induces apoptosis and abrogates tumorigenic growth of tumor cells [52]. Recent studies have identified EPHA2 as a surprisingly abundant plasma membrane component in cells of the ocular lens [53]. Mutations in EPHA2 have been shown to underlie inherited forms of cataract in humans [54, 55]. Common variants in EPHA2 have been associated with the much more prevalent age-related form of cataract. Dave et al. showed that mutations in EPHA2 accounted for 4.7 % of inherited cataract cases in South-Eastern Australia, and a rare variant rs139787163 was potentially associated with increased susceptibility to cataract, providing a link between congenital and age-related cataract [56]. Furthermore, the cytoprotective and antiapoptotic function of EPHA2 in lens epithelial cells was abolished by the functional polymorphisms [52]. These results indicated the potential role of EPHA2 in maintaining lens clarity during aging by promoting cell viability.

Several limitations were presented in this meta-analysis. First of all, the number of included studies for each SNP was small, future large-scale researches with more ethnicities are needed to further evaluate the relationship. Secondly, between-study heterogeneity was presented in several comparisons. Thirdly, we did not conduct the subgroup analysis by ethnicities due to the less data, which should be concerned in the future. Lastly, gene-gene and gene-environment interactions were not addressed in our meta-analysis.