A Multi-Locus Genetic Risk Score for Primary Open-Angle Glaucoma (POAG) Variants Is Associated with POAG Risk in a Mediterranean Population: Inverse Correlations with Plasma Vitamin C and E Concentrations

Abstract

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. The genetics of POAG are complex, and population-specific effects have been reported. Although many polymorphisms associated with POAG risk have been reported, few studies have analyzed their additive effects. We investigated, in a southern European Mediterranean population, the association between relevant POAG polymorphisms, identified by initial genome-wide association studies (GWASs) and POAG risk, both separately and as an aggregated multi-locus genetic risk score (GRS). Also, bearing in mind that oxidative stress is a factor increasingly recognized in the pathogenesis of POAG, we analyzed the potential association of the GRS with plasma concentrations of antioxidant vitamins (C and E). We carried out a case–control study including 391 POAG cases and 383 healthy controls, and analyzed four genetic polymorphisms (rs4656461-TMCO1, rs4236601-CAV1/CAV2, rs2157719-CDKN2B-AS1 and rs3088440-CDKN2A). An unweighted GRS including the four non-linked polymorphisms was constructed. A strong association between the GRS and POAG risk was found. When three categories of the GRS were considered, subjects in the top category of the GRS were 2.92 (95% confidence interval (CI): 1.79–4.77) times more likely to have POAG compared with participants in the bottom category (p < 0.001). Moreover, the GRS was inversely correlated with plasma vitamin C (p = 0.002) and vitamin E (p = 0.001) concentrations, even after additional adjustment for POAG status. In conclusion, we have found a strong association between the GRS and POAG risk in this Mediterranean population. While the additional correlation found between GRS and low levels of vitamins C and E does not indicated a causal relationship, it does suggest the need for new and deeper research into the effects of oxidative stress as a potential mechanism for those associations.

Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations

“…They found no association between PRS of myopia and POAG ( p = 0.81), VCDR ( p = 0.42), cup area ( p = 0.25), IOP ( p = 0.07), or RNFL thickness ( p = 7.7 × 10 −3 ), demonstrating that there is no evidence for overlap of genetic RFs between POAG and myopia [ 46 ]. Additionally, a 2017 PRS from a southern European Mediterranean population demonstrated a strong association between a PRS of 4 SNPs and POAG (OR: 2.92; 95%CI: 1.79–4.77, p < 0.001), while also showing an inverse correlation between the PRS and low levels of vitamin C ( p = 0.002) and vitamin E ( p = 0.001), suggesting a possible role for oxidative stress mechanisms in the pathogenesis of POAG [ 74 ].…”

Risk Stratification and Clinical Utility of Polygenic Risk Scores in Ophthalmology

“…The earliest studies have demonstrated significant but modest discriminatory powers for a glaucoma PRS. [40][41][42] In 2015, Tham et al 41 developed a glaucoma PRS combining seven IOP-associated and 18 VCDRassociated SNPs known at the time, and reported a modestly higher odds of developing POAG in the top tertile of the PRS relative to the bottom tertile in a multiethnic cohort from Singapore (IOP-PRS OR, 2.50; 95% confidence interval [CI], 1.54-4.02; VCDR-PRS OR, 2.31 [95% CI, 1.50-3.55]). Mabuchi et al 40 conducted an unweighted PRS utilizing nine IOPassociated SNPs in a Japanese cohort and reported a modest association with higher tension POAG (OR per risk allele = 1.12; 95% CI, 1.01-1.24).…”

Significance of the lncRNAs MALAT1 and ANRIL in occurrence and development of glaucoma

“…Genomic DNAs were extracted from venous blood samples of each participant, which were anticoagulated with ethylenediaminetetraacetic acid (EDTA), by applying approach of phenol‐chloroform extraction and ethanol precipitation. Then, DNA was amplified with the aid of a PCR kit (Takara), and SNPs in MALAT1 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 and ANRIL 14 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 were genotyped using the single‐base end extension (SNaPshot) method, a genetic analyzer (model: ABI3130), and Genemapper software from ABI.…”