The role of Cat -262C/T, GPX1 Pro198Leu and Sod1+35A/C gene polymorphisms in a development of primary open-angle glaucoma in a Polish population

Introduction

Around 70 million people currently suffer from glaucoma [1, 2] and although no comprehensive data exists, it is estimated that around 800.000 people in Poland are affected [3, 4]. Glaucoma is a dangerous, chronic, progressive eye disease characterized by optic neuropathy leading to complete vision loss. It occurs as a result of impaired outflow of aqueous humor caused by an increase in intraocular pressure. This increased pressure can lead to the destruction of retinal ganglion cells and the optic nerve. Pressure is relative, but the development of glaucoma is determined by several factors, including genetic predisposition or risk of blood circulation disorders.
Glaucoma is the most common cause of blindness, and the leading cause of irreversible blindness worldwide [5, 6]. Primary open angle glaucoma (POAG) is the most common type of glaucoma. Its incidence depends on age and is characterized by progressive loss of retinal ganglion cells (RGCs) and their axons, leading to the pathognomonic cupping of the optic nerve head [7]. Recently, epidemiological studies have indicated that apart from elevated intraocular pressure (IOP) and age, the risk of POAG might also be associated with ethnic origin, the presence of diabetes mellitus and most significantly, genetic predisposition [8, 9, 10]. In addition, oxidative stress is a very dangerous condition that can lead to the development of glaucoma, together with many other diseases [11, 12]. Oxidative stress is defined as a shift in the pro-oxidant antioxidant balance in favor of the former caused by the production of inter alia reactive oxygen species (ROS) [13]. The increase in fluid volume causes an increase in intraocular pressure, which in turn results in the destruction of retinal ganglion cells and the optic nerve. Although the development of glaucoma is known to be associated with genetic predisposition and the risk of blood circulatory disorders, ROS production may also play a role. Increased levels of free radicals have been shown to lead to oxidative modification of proteins and lipid peroxidation in the circulatory system of the eye [14].
In addition, ROS and reactive nitrogen levels have been found to be elevated in various parts of the eye during glaucoma, indicating that free radical damage is associated with the progressive deterioration of the optic nerve in open angle glaucoma [15].
As the antioxidant enzyme pathway is considered the most important mechanism involved in the repair of ROS-induced damage, the present study examines the possible association between polymorphisms of superoxide dismutase (SOD1), catalase (CAT), and glutathione peroxidase (GPX1) genes and the development of age-related glaucoma [16]. These significant genetic variations related to oxidative stress have already been studied extensively, including the single nucleotide polymorphisms (SNP) 35 A/C of the SOD1 gene (rs2234694), -262C/T in the promoter region of the CAT gene (rs1001179), and GPX1 Pro198Leu gene (rs1050450). SOD1 35A/C, CAT -262C/T and GPX1.
The Pro198Leu polymorphisms can significantly influence the levels and activity of most common antioxidant enzymes, which can lead to reduced protection against oxidative stress [17, 18, 19, 20, 21].
The SOD1-gene has five exons. The +35A/C polymorphism (rs2234694) is adjacent to the splicing point (exon3/intron3) [16], being related to the SOD1-activity – AA-genotype having the higher SOD1-activity [22].
GPX represent one of the most important defenses of enzymatic antioxidants [23]. They serve to protect cells against oxidative damage by reducing hydrogen peroxide and a wide range of organic peroxidases to H2O with reduced glutathione [24]. This enzyme is encoded by the GPx1 gene, which is located at chromosome 3p21 and contains two exons within a 1.42 kb region [25]. A transition of C to T (rs:1050450) is known to exist at nucleotide 594 in exon 2 of the GPx1 gene, corresponding to an amino acid change from proline (Pro) to leucine (Leu) at codon 198 (Pro198Leu) [26]. Selenium enhances GPX1 expression and increases cellular antioxidant capacity.
Catalase (CAT, EC 1.11.1.6), another component of the antioxidant system, is a tetrameric enzyme weighing 240 kDa [27]. CAT reacts very efficiently with H2O2, converting it to water and molecular oxygen [28]. This enzyme is largely located within cells in peroxisomes and is most abundant in erythrocytes, hepatocytes and kidney tissue [25]. The CAT gene itself is located on chromosome 11p13 and contains 13 exons [29, 30]. A frequently-occurring polymorphism is often present in the promoter region, consisting of a C to T (rs1001179) substitution at position -262 in the 50 region. This polymorphism influences transcription factor binding, reporter gene transcription and is correlated with blood CAT levels [30, 31].
It is assumed that polymorphic variations in these antioxidant genes modify the risk of glaucoma, especially when oxidative stress is increased and non-enzymatic antioxidants are deficient [32]. The purpose of the study was to evaluate the possible association between SOD1 35A/C, CAT -262A/T and GPX1 Pro198Leu polymorphisms and the risk of age-related glaucoma in a Polish population.

Material and methods

The study analyzes SOD1 35A/C, CAT -262A/T and GPX1 Pro198Leu polymorphisms in patients with age-related glaucoma and healthy age-matched controls. In total, a group of 400 unrelated subjects were included in the study. Peripheral blood samples were taken, and the material for DNA tests was isolated from the lymphocytes (Table I). The study group consisted of 209 unrelated patients with diagnosed POAG (79 males and 130 females; mean age 64 ±11) and a control group of 191 unrelated patients without glaucoma symptoms (90 males and 101 females; mean age 66 ±15). All patients and controls were matched on age. All subjects underwent ophthalmic examination, including best-corrected visual acuity, intraocular pressure, slit-lamp examination, gonioscopy, and fundus examination using non-contact and fundus contact lenses with a slit lamp. In the group of glaucomatous patients, the diagnosis of POAG was stated prior to enrolment, in accordance with the guidelines of European Glaucoma Society (Terminology and Guidelines for Glaucoma, Second Edition, Dogma, Savona 2003, Italy). The patients with POAG at the time of enrolment in the study were treated topically with typical anti-glaucoma medication, such as beta blockers (Timolol), prostaglandin analogs (Latanoprost), carbonic anhydrase inhibitors (Dorzolamide) or a2 agonists (Brimonidine), either alone or in combination.
Participants were enrolled from the Department of Internal Medicine, Chair of Clinical Ophthalmology of the Medical University of Warsaw, Poland. All subjects included into the study were Caucasian and had been recruited from the Warsaw area. This project was approved by the Ethics Committee of the Medical University of Lodz. In accordance with the Declaration of Helsinki, each subject was informed of the detailed study protocol, and gave their informed consent to take part.

Polymorphism analysis

DNA was extracted from peripheral blood lymphocytes using DNA Blood Mini Kits (A&A Biotechnology, Gdynia, Poland). Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). PCR was carried out in a volume of 25 µl. The reaction mixture consisted of 100 ng of genomic DNA, 1U Taq polymerase (Thermo Scientific), 1.5 mmol MgCl2, 200 µmol dNTPs, and 0.5 µmol of each primer [33, 34]. PCR conditions were as follows. SOD1+35A/C: initial denaturation two minutes at 94°C, 32 cycles – 40 s at 94°C, 40 s at 55°C, 40 s at 72°C, ending with a final elongation of one minute at 72°C. RFLP was performed in a 20 μl total reaction containing 5 U of HhaI (Fermentas) Samples CAT -262C/T initial denaturation two minutes at: 94°C for 30 s, 68°C –0.5 for 45 s, 72°C for one minute, 17 cycles, then 94°C for 30 s, 60°C for 45 s, 72°C for one minute, 25 times. The final extension step was 10 minutes at 72°C. RFLP was performed in a 20 μl total reaction containing 10 U of Sma I (Fermentas). The PCR cycling for GPX1 Pro198Leu initial denaturation two minutes at 95°C for three minutes, followed by 35 cycles at 95°C for 30 s, 58°C for 30 s, and 72°C for 90 s, with a final extension step at 72°C for 10 minutes. RFLP was performed in a 20 μl total reaction containing 10 U of Apa I (Fermentas). After digestion, the products were separated on a 2% agarose gel stained with ethidium bromide. The primers, length of PCR products and restriction enzymes are summarized in Table II.

Statistical analysis

The allele frequencies were estimated by gene counting and genotypes were scored. The χ2 test was used to compare the observed numbers of genotypes with those expected for a population according to the Hardy-Weinberg equilibrium, and to test the significance of the differences of observed alleles and genotypes between groups. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.
The Pearson correction was used to calculate probability, and if the expected cell values were less than five, Fisher’s exact test was used. A P-value of < 0.05 was taken as statistically significant. The t-test was used to compare normally-distributed parameters between the two groups, and the Mann-Whitney test to compare non-normally distributed parameters. A p-value of < 0.05 was taken as statistically significant. STATISTICA 6.0 software (Statsoft, Tulsa, OK, USA) was used to perform the analyses.

Results

Analysis of polymorphisms

The genotype, allele frequency and odds ratios of the CAT -262C/T, GPX1 Pro198Leu and SOD1+35A/C gene polymorphisms in open angle glaucoma patients and controls are given in Tables III and IV. The observed genotype frequency of CAT -262C/T (p > 0.05: χ2 = 0.0052), GPX1 Pro198Leu (p > 0.05; χ2 = 0.0048) and SOD1 35 A/C (p > 0.05; χ2 = 0.86) in the control group were in agreement with the Hardy-Weinberg equilibrium (HWE).
The genotype distributions of the SOD1+35A/C polymorphism were 92%(A/A), 6%(A/C) and 1%(C/C) in patients, and 91%(A/A), 8%(A/C) and 1%(C/C) in controls. The allele frequencies of SOD1 for the +35A and +35C were 95% and 5% in controls, compared with 95% and 5% in patients (p = 0.92). The distribution of genotypes of the GPX1 Pro198Leu polymorphism were 50% (C/C), 43 % (C/T) and 7% (T/T) for patients, and 71% (C/C), 27% (C/T) and 3% (T/T) for controls. The respective allele frequencies for -198C and -198T were 72% and 28% in patients and 84% and 16% in controls (p < 0.0001). The distribution of genotypes of the Cat -262C/T polymorphism were 63% (C/C), 32% (C/T) and 5% (T/T) for patients, and 89% (C/C), 19% (C/T) and 1% (T/T) for controls. The allele frequencies for the -262C and -262T were 79% and 21% in patients and 90% and 10% in controls (p < 0.0001).
Logistical regression analysis was used to assess the relationship between all the investigated polymorphisms and the risk of developing glaucoma. Subjects carrying the +35A/C (OR = 0.77 [0.34-1.57]; p = 0.42) and = 35C/C (OR = 0.13 [0.03-2.91]; p = 0.35) genotypes of SOD1 had no significant risk of developing POAG. A significant relationship was found between the combined genotypes of CT/AA (OR = 0.37, 95% CI: 0.23-0.59), CT/CC SOD1+35A/C /GPx1 Pro198Leu (OR = 0.04, 95% CI: 0.005-0.29) and TT/AA (OR = 0.23, 95% CI: 0.11-0.45) SOD1+35A/C /GPx1 Pro198Leu. The genotype CC/AC SOD1+35A/C/CAT-262C/T was also observed (OR = 0.09, 95% CI: 0.036-0.25). We conclude that these genotypes reduce the risk of developing glaucoma.

Discussion

The present study examines the relationship between the risk of glaucoma in a Polish population and the occurrence of the SOD1, CAT and GPX1-198 C/T gene polymorphisms. It also attempts to determine their influence on the activity of antioxidant enzymes, resulting in synergistic effects of glaucoma-induced oxidative damage. The CAT -262C/T, GPX1 Pro198Leu and SOD1 +35A/C polymorphisms were associated with an increased risk of glaucoma. These findings support the hypothesis that genetic variations in antioxidant defense may modify the risk of glaucoma among individuals with elevated oxidative stress or decreased antioxidant capacity [33, 34, 35, 36].
The present study examines the effect of serum SOD1, GPX and CAT1 level on the eye. The CAT gene encodes catalase, a common enzyme found in nearly all living organisms exposed to oxygen. It maintains the oxidative status of the body and plays an important role in protecting eukaryotic cells from entering premature apoptosis. Catalase is a heme aerobic cells. The enzyme is present in almost all paroxysms and reduces the toxic activity of hydrogen peroxide ROS by converting them to water and oxygen [37].
Recent studies indicate that free radicals play a crucial role of in the pathogenesis of many diseases, including such diseases of the eye as cataract, glaucoma and age-related macular degeneration. Free radicals are formed in trace amounts as by-products of metabolism and cause premature cell death. In addition, the amount of dangerous free radicals increases following trauma or neurodegenerative diseases [38, 39, 40, 41, 42].
Parkinson’s disease, Alzheimer’s or multiple sclerosis (MS) are some of the most common neurodegenerative diseases [43]. These are associated with progressive damage to the pigment cells of the substantial nigra midbrain: cells which are responsible for the synthesis of dopamine under physiological conditions, which they use as a neurotransmitter [44, 45, 46, 47, 48, 49]. Patients with Alzheimer’s and Parkinson’s disease are more likely to suffer from glaucoma than healthy people, and severe adverse reactions location biochemical, i.e. glycosylation, formation and carbonylation AEGs. During glycosylation, protein molecules bind to glucose molecules, leading to the formation of damaged and dysfunctional structures with reduced biological activity. Many age-related diseases such as hardening of the arteries, cataracts and neurological diseases arise, at least in part, due to glycosylation. The accumulation of protein in tissue is a clear sign of disease. An ideal supplement for people with an increased risk of such degenerative diseases, or who have suffered from them, is carnosine. It has been found to prevent the formation of these radicals, and is known to be effective against both oxidative stress and the resulting synuclein [50].
Izzotti et al. analyzed the frequency of mitochondrial (mtDNA) DNA damage in primary open angle glaucoma. Oxidative damage is known to play an important role in the pathogenesis of glaucoma, and their results indicate that mitochondria are targeted by the effects of glaucoma. These findings may be valuable for the development of new molecular biomarkers of glaucoma and to identify potential patients at high risk [51]. One of the most influential factors regarding individual susceptibility to complex diseases is represented by the presence of SNPs. Since ROSs have a high potential to interact with genetic material, SNPs in genes coding for antioxidant enzymes may have an important influence on individual differences in the ability to maintain the integrity of the human genome. Genetic polymorphisms in CAT, GPx1 and SOD have been associated with the potential to develop various diseases including cancer [46, 47, 48].
The presence of the C/T genotype (1-GPX1 Pro198Leu, 2-CAT C262T) was found to be associated with an increased risk of open angle glaucoma (OR = 2.24, p = 0.0001, OR = 2.16, p = 0.001). Our findings indicate that the combined genotypes CT/AA, CT/AC and CT/CC of Sod1+35A/C GPX1 Pro198Leu may be associated with a reduced risk of POAG among the Polish population. In addition, in contrast to earlier research, they indicate that the prevalent polymorphisms CAT -262C/T, GPX1 Pro198Leu and SOD1+35A/C in the Polish population have toxicogenetic effects.
There is currently a lack of research into the gene-gene interactions and the role of the SOD1-251A, CAT G/T and T-21A GPX1-198C polymorphisms of antioxidant enzymes in patients with open-angle glaucoma. Recent studies have indicated that the SOD1-251 A/G polymorphism is associated with reduced antioxidant capacity [52, 53]. Therefore, our findings indicate that individuals with impaired antioxidant activity may have a predisposition to diseases associated with oxidative stress. Our study provides a framework for future studies concerning the role of polymorphic variants of CAT, SOD1 and GPX1 antioxidant enzymes in the development of glaucoma associated with long-term exposure to free radicals. Most importantly, our findings indicate that the GPX1 Pro198Leu and SOD1+35A/C gene polymorphisms may play a protective role in the risk of glaucoma development in a Polish population.

The authors declare no conflict of interest.

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Address for correspondence

Katarzyna Malinowska
Department of Chemistry and Clinical Biochemistry
Medical University of Lodz
Hallera 1 square
90-647 Lodz, Poland
e-mail: modmal@wp.pl