Purpose. To determine the association between plasma 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels, a marker for oxidative DNA damage, and patients with primary open-angle glaucoma (POAG) or its clinical phenotypes. Furthermore, we also examined the utility of plasma 8-OHdG as a potential biomarker in POAG. Materials and Methods. In a retrospective case-control study, plasma samples were obtained from 50 POAG cases and 45 glaucoma-free controls matched for age, sex, and ethnicity. 8-OHdG levels were measured in duplicate using an enzyme-linked immunosorbent assay (ELISA) on an automated ELISA analyzer. Results. There was no significant difference in age, sex, and systemic disease distribution between POAG cases and controls. Both mean and median 8-OHdG levels were significantly elevated in POAG cases and male subjects. The area under the receiver operating characteristic (ROC) curve value for plasma 8-OHdG was 0.653 (95% confidence interval = 0.54–0.76, p=0.010). The cutoff values based on quartile distribution and ROC curve analysis showed that elevated plasma 8-OHdG significantly increased the risk of POAG by more than 4-folds. Plasma 8-OHdG had a sensitivity of 78% and specificity of 53%. In logistic regression analysis, 8-OHdG showed a significant effect on POAG outcome (p=0.016) independent of age, sex, smoking, and systemic diseases. However, no significant correlation was observed between 8-OHdG and specific clinical markers of glaucoma such as intraocular pressure (p=0.699), cup/disc ratio (p=0.213), and the number of antiglaucoma medications (p=0.603). Conclusion. The study shows that there is a significant association between elevated plasma 8-OHdG and POAG, supporting the role of systemic oxidative stress-induced DNA damage in POAG pathogenesis. However, with a high rate of false-positivity, plasma 8-OHdG may lack the ability to serve as a potential biomarker in POAG. Further studies in a much larger cohort are needed to confirm these findings.

Background: To investigate whether SNP rs4986790 in toll-like receptors (TLRs) is a risk factor for primary open angle glaucoma (POAG) in a Saudi population. Materials and methods: A cohort of 85 unrelated POAG patients and 95 unrelated control subjects from Saudi Arabia were genotyped utilizing Taq-Man® assay. The association between mutant genotypes and various clinical indices important for POAG was investigated. Results: Among cases, the normal pattern (A/A) was detected in 70 (82.4%) of the subjects, A/G in 14 (16.5%) and G/G in one subject only (1.2%). Among controls, prevalence of the genotype (A/A) was detected in 86 (90.5%), the (A/G) genotype in 8 (8.4%) and homozygous mutated genotype (G/G) in 1 (1.1%) subjects. Comparing cases to controls, the odds ratio of having heterozygous mutation (A/G) was 2.15 [95% CI: 0.853–5.417], which was not significant (p = 0.114). The odds ratio of having homozygous mutation (G/G) was 1.22 [95% CI: 0.075–19.99], which was statistically non-significant (p = 0.568). Likewise, the presence of the mutated allele (G) was non-significantly different between cases and controls (p = 0.154). Comparing cases to controls as regards co-morbidity with other systemic diseases, there were no statistically significant differences between groups in all assessed diseases except for a family history of glaucoma (p = 0.014) Conclusions: In conclusion, we could not detect any direct link between genotypes or allele frequencies of SNP rs4986790 in the TLR4 gene and POAG. In contrast, genotype (A/A) may be protective against POAG especially among individuals with no family history of glaucoma.

Background: Glaucoma is a polygenic neurodegenerative disease and the second most common cause of blindness in Saudi Arabia. To test the hypothesis that genetic variants in the genes involved in the bone morphogenic protein (BMP) signaling pathway may be associated with glaucoma, we investigated the association between 3′ untranslated region variants, rs12997 in ACVR1 and rs1043784 in BMP6, and primary angle-closure glaucoma (PACG) and pseudoexfoliation glaucoma (PXG). Methods: In a case-control study, TaqMan® real-time PCR-based genotyping was done in 444 subjects consisting of 250 controls, 101 PACG and 95 PXG cases, and tested for genetic association with glaucoma-types and other clinical phenotypes. Results: Rs12997[G] allele in ACVR1 exhibited significant 2-fold increased risk of PACG (p = 0.005) in women but not in men. Similarly, genotype analysis also showed that subjects carrying rs12997[G/G] genotype were at > 2-fold risk of PACG that remained significant after adjustment for age, sex, and Bonferroni correction in the recessive model. Furthermore, this effect was also significant in women only. In PXG, the rs12997[G/G] genotype showed a significant trend towards increased risk of the disease (OR = 2.04, 95% CI = 0.99–4.18, p = 0.049) but did not survive the Bonferroni correction. Regression analysis showed that rs12997[G/G] genotype was a significant predictor of PACG independent of age, sex, and rs1043784 genotypes. Likewise, age and rs12997[G/G] genotype showed significant effect on PXG outcome. The rs12997[A/G] genotype showed significant association with cup/disc ratio as compared to wild-type (p = 0.005) in PXG. Genotype and allele frequencies of rs1043784 in BMP6 did not show any significant association either with PACG or PXG. Conclusions: Our results suggest that the polymorphism rs12997 in the ACVR1 gene involved in the BMP signaling pathway is significantly associated with PACG and PXG in a Saudi cohort. This is the first study to associate this variant/gene with PACG and PXG. However, further studies would be needed to replicate these findings in a large population-based cohort.

Purpose. To investigate systemic oxidative stress-induced DNA damage in patients with pseudoexfoliation glaucoma (PXG), we estimated plasma levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) as a marker for oxidative DNA damage in comparison to controls. In addition, we also examined a combined effect of lysyl oxidase-like 1 (LOXL1) polymorphism status and 8-OHdG levels on PXG risk. Materials and Methods. A retrospective case-control study was performed to estimate plasma levels of 8-OHdG in 41 PXG patients and 45 nonglaucomatous controls using the enzyme-linked immunosorbent assay (ELISA). The assay was performed in duplicate on an automated ELISA analyzer. Two common polymorphisms (rs1048661 and rs3835942) in LOXL1 gene were genotyped by Sanger sequencing. Results. The mean and median levels of 8-OHdG were significantly increased in the PXG cases (p=0.032) and male subjects (p=0.041). Subjects with levels greater than the third quartile (75% percentile) exhibited a significant increased risk of PXG (odds ratio = 4.06, 95% confidence interval (CI = 1.11–14.80, p=0.029)). Within- and between-group comparisons showed that the mean levels were higher in individuals carrying the LOXL1 risk variant (G/G), but not statistically significant. In logistic regression analysis, both 8-OHdG (p=0.044) and rs3835942 (p=0.012) showed a statistically significant effect on the PXG outcome. However, the effect was lost when age, sex, and rs1048661 were included. A significant positive correlation was observed between 8-OHdG levels and intraocular pressure (R=0.284, p=0.008) and cup/disc ratio (R=0.233, p=0.031). Furthermore, in receiver operating characteristic analysis, the area under the curve was statistically significant (p=0.032) with a value of 0.635 (95% CI = 0.518–0.751). Conclusion. The study demonstrates an association of increased plasma levels of 8-OHdG in patients with PXG, supporting the role of oxidative stress, and increased oxidative DNA damage in PXG development.

We investigated whether polymorphism rs7555523 (A > C) in human transmembrane and coiled-coil domain 1 (TMCO1) gene is a risk factor for primary open angle glaucoma (POAG) in a Saudi cohort. A cohort of 87 unrelated POAG cases and 94 control subjects from Saudi Arabia were genotyped using Taq-Man® assay. The association of genotypes with POAG and other glaucoma specific clinical indices was investigated. The genotype and allele frequency of polymorphism rs7555523 at TMCO1 did not show any statistically significant association with POAG as compared to controls. The minor allele frequency was 0.103 in cases and 0.085 in controls. Except for awareness of glaucoma (p = 0.036), no significant association of genotypes were seen with glaucoma specific clinical indices such as intraocular pressure (IOP), cup/disc ratio and number of anti-glaucoma medications used. Binary logistic regression analysis (adjusted for age and gender) showed that age was a significant indicator for the development of glaucoma in this group (adjusted odds ratio = 1.2; 95 % confidence interval = 1.078–1.157; p < 0.001). Our study was unable to replicate the findings of previously reported association for polymorphism rs7555523 in TMCO1 with POAG and related clinical indices such as IOP and cup/disc ratio indicating that this variant is not a risk factor for POAG in the Saudi cohort.

Polymorphism rs13334190 in the zinc finger protein 469 gene has been suggested to predispose toward a “thin” cornea, which then becomes keratoconic or is directly pathogenic. Thus, we genotyped polymorphism rs13334190 in 127 unrelated keratoconus cases and 168 control subjects from Saudi Arabia using Taq-Man^® assay. The genotype frequency distribution did not deviate significantly from the Hardy–Weinberg equilibrium (p > 0.05). Overall, both the genotype and allele frequencies were not significantly different between cases and controls. A minor allele frequency of 0.068 was comparable to the aggregate rates ranging from 0.060 to 0.086 observed in other populations. Binary logistic regression analysis was performed to ascertain the effects of age, gender and genotype on the likelihood of having keratoconus. The analysis indicated that increased age was statistically significant (p = 0.000) and that females have a 2.19-fold increased risk (p = 0.018) of developing keratoconus. The genotype frequencies did not differ between the sporadic or familial keratoconus cases. Polymorphism rs13334190 is not an independent risk factor for keratoconus in the Saudi cohort.