SOD2 Genes, SNPs & Factors that May Increase/Decrease It

Association of SOD2 Mutation (c.47T > C) with Various Primary Angle Closure Glaucoma Clinical Indices

SOD2 Genes, SNPs & Factors that May Increase/Decrease It


We investigated whether the c.47T > C polymorphism (SNP rs4880) in the manganese superoxide dismutase (SOD2) gene is a risk factor for primary angle closure glaucoma (PACG) in the Saudi population. Among cases (n = 139), the prevalence of various genotypes were 25.9%, 46.8% and 27.

3% for T/T, C/T and C/C genotypes respectively. This trend was similar in the controls (n = 403); 22.6%, 50.1% and 27.3% for T/T, C/T and C/C respectively. The differences in genotype distribution were not statistically significant (p = 0.391 and 0.682 respectively). The minor allele frequency was 50.

7% in cases and 52.4% in controls; this difference was not statistically significant (p = 0.676).

Investigating the potential association between this SOD2 polymorphism and different clinical indices, there was a statistically significant difference among different genotype groups in terms of three important clinical indices for PACG; Mean age at onset, duration of onset to and the mean LogMAR visual acuity (p = 0.

041, 0.018 and 0.033 respectively). The three markers are highly associated prognostic factors to diseases severity. If our results are proven in larger cohort and in various populations, then this SNP may have potentiality to be used as an indicator for PACG severity.

Primary angle-closure glaucoma (PACG) is a type of glaucoma characterized by a narrow iridocorneal angle resulting in a blockage of the aqueous outflow structures. It seems that there is an anatomical and physiological predisposition to PACG. Eastern Asian ascendance, hyperopia and female gender significantly predispose to this disease.

It has been estimated that in Saudi Arabia, 40% of glaucoma patients belong to the PACG type.1 Although a hereditary component for PACG exists, causative genes had not been identified until recently where a significant association at three new loci: rs11024102 in PLEKHA7 [P = 5.33 × 10(−12)], rs3753841 in COL11A1 [P = 9.

22 × 10(−10)] and rs1015213 located between PCMTD1 and ST18 on chromosome 8q [P = 3.29 × 10(−9)] were reported.2 The three SNPs may explain in part some aspects of the PACG pathogenesis, but not all. Oxidative stress has been implicated to cause increased IOP by triggering TM degeneration and thus contributing to alterations in the aqueous outflow pathway.

Indeed, treatment with hydrogen peroxide (H2O2) impairs TM cell adhesion to the extracellular matrix and causes rearrangement of cytoskeletal structures. In humans, in vivo experiments have demonstrated that oxidative DNA damage is significantly more abundant in the TM cells of glaucoma patients.

Additionally, both increased IOP and visual field damage were significantly related to the amount of oxidative DNA damage affecting TM cells. Superoxide dismutase (SOD) is a major antioxidant enzyme, which plays a vital role in clearance of reactive oxygen species (ROS).

Among its isoforms is the manganese superoxide dismutase (SOD2) which plays an important role as a primary mitochondrial antioxidant enzyme.3 Previous studies had shown that a polymorphism at c.47T > C (p.16 Val>Ala) in the SOD2 gene (Gene Reference Sequence NM_00636.

2; SNP rs4880) was a risk factor for a range of diseases and conditions such as sepsis, sensorineural hearing loss, medulloblastoma, obstructive pulmonary disease, and pancreatic cancer.

Because of: (1) the pivotal role of mitochondria in retinal ganglion cell survival in diseases glaucoma4; (2) SOD2 is found in human mitochondria and plays an important role in preventing oxidative stress status; (3) accumulated evidence of oxidative stress involvement in glaucoma, and (4) our recent study which showed the association of this polymorphism with various clinical indices important for POAG,5 we decided to investigate whether this polymorphism is a risk factor for PACG in the Saudi population and investigate if there is a link between this polymorphism and various clinical indices important for PACG.

We recruited 139 Saudi PACG patients (cases) who satisfied strict clinical criteria for PACG which includes at least three of the following: (1) clinical documentation of angle closure, defined as the presence of appositional or synechial closure of the anterior chamber angle involving at least 270° by gonioscopy in either eye; (2) intraocular pressure elevated to a level ≥21 mmHg as measured by Goldmann applanation tonometry; (3) evidence of characteristic glaucomatous optic disk damage with excavation of the disc causing a cup-to-disk ratio (c/d) vertically of at least 0.70 in at least one eye; and (4) characteristic peripheral visual field loss including nerve fiber bundle defects (nasal step, arcuate scotoma, paracentral scotoma) or advanced visual field loss (central and/or temporal island of vision) as tested by Humphrey Field Analyzer in those patients with vision better than 20/200 or Goldmann Manual Perimetry in those with worse vision. Exclusion criteria included: (1) secondary angle closure glaucoma; (2) presence of pseudoexfoliation syndrome even if coexistent with angle closure; (3) another cause of optic nerve injury affecting either eye; (4) significant visual loss in both eyes not associated with glaucoma; (5) inability to visualize the fundus for optic disk assessment; or (6) refusal to participate.

Patients were recruited from the glaucoma clinic at King Abdulaziz University Hospital (KAUH) after signing an informed consent form approved by the institutional review board (proposal number # 08-657).

A second group (n = 403) of healthy Saudi Arabs controls (Control group) free from glaucoma by examination were recruited. Entry criteria for those subjects were age >40, normal IOP range (≥6 and ≤21 mmHg), open angles on gonioscopy, and normal optic nerves on examination.

DNA was extracted from blood samples from patients and controls and genotyped for SNP rs4880 of the SOD2 genes as described previously.5

Among our 139 cases, only 12 (9.2%) had a family history of glaucoma. Meanwhile, around one third of them; 36 (27.7%) were diabetic and one fourth; 33 (25.4%) were hypertensive. On the other hand, among our control group, 138 (34.2%) were diabetic and 128 (31.8%) were hypertensive.

Consequently, there were no statistically significant difference between cases and controls neither in terms of the prevalence of diabetes mellitus nor in hypertension [p = 0.069; 95% CI: (−0.165 – 0.007)] and 0.074; 95% CI: (−0.159 – 0.008) for diabetes mellitus and hypertension respectively (Table 1). However, only 17 (13.

1%) of them were found to be aware of having glaucoma. the 139 glaucoma cases, 136 (97.7%) were bilateral and three (2.3%) were unilateral.

Among cases, the prevalence of the wild type allele “T/T” was 36 (25.9%) while the heterozygous mutated genotype “C/T” was more dominant; 65 (46.8%) and the homozygous fully mutated genotype “C/C” was 38 (27.3%). This trend was almost similar to the genotype distribution in controls which was 91 (22.6%); 202 (50.1%) and 110 (27.

3%) for “T/T”; “C/T” and “C/C” respectively. There was no statistically significant difference between cases and controls in terms of genotype distribution on both heterozygous mutants [OR: 0.81, (95% CI: 0.493–1.355), p = 0.391] and homozygous mutant [OR: 0.87, (95% CI: 0.495–1.544), p = 0.

683] respectively compared to the wildtype allele distribution (Table 2).

Investigating potential association between SOD polymorphism and different glaucoma indices, our findings show that there was an overall difference in “age at onset” across groups (p = 0.

041), however, there were no significant associations between age at onset and different types of polymorphism in the pairwise analysis; (p = 0.141 and 0.145) for “C/T” and “C/C” specifically.

Nevertheless, looking at the mean duration from onset to presentation to the hospital, it was found that there is a clear decreasing trend between such duration and the genotype of the polymorphism where the mean (±SD) duration to presentation was 64.8 (±54.1), 60 (±42) and 16.2 (±18.8) for “T/T”, “C/T”, and “C/C” respectively.

Moreover, this descending trend was statistically significant across groups (p = 0.018) and in comparing the homozygous variant “C/C” to the wildtype homozygous genotype “T/T”; p = 0.021 which indicates that the difference between these two groups is the source of overall variation.

With regards to the glaucoma clinical indices, the intraocular pressure (IOP) didn’t show any statistically significant differences either across groups (p = 0.848) or in pairwise comparisons (p = 0.703 and 0.866) for “C/T” and “C/C” respectively.

For the cup/disc ratio, there was a recognized ascending trend in severity of cupping directly proportional to the variant genotype whereas the mean (±SD) was 24.3 (±36.5) in the “T/T” genotype group while it increased to 28.9 (±35.4) and 29.5 (±37.4) in both “C/T” and “C/C” groups respectively.

However, these differences did not reach statistical significance either for all groups comparison (p = 0.744) or for the pairwise comparisons (p = 0.453, and 0.548) for both “C/T” and “C/C” groups compared to the “T/T” group respectively.

As regards the mean number of medications, there was a similar ascending trend such as in the mean CDR, where it increased from 1.4 (±1.1) in the “T/T” group to 1.5 (±1.1) and 1.7 (±1.2) in both “C/T” and “C/C” groups respectively. However, this trend was not significant in the across groups or the between group’s analyses.

Additionally, looking at the mean value of LogMAR visual acuity, there was a significant difference across the different genotype groups (p = 0.033). Moreover, the source of this variation was due to the significant difference between the heterozygous mutant allele group and the wildtype allele group: 0.5 (±0.7) compared to 0.8 (±0.9); p = 0.009.

Overall, it was recognized that all clinical indicators show their highest average levels among the homozygous fully mutated group “C/C” compared to the overall mean values of the whole group of cases.

Despite the fact that this increase was not always statistically significant, it may still be used as an indicator for PACG severity (Table 3). If these results are proven in a larger cohort and in various populations, then this SNP (c.

47T > C) in the SOD2 gene has the potential to be used as a marker for PACG severity.

The authors would to thank the Glaucoma Research Chair at the Department of Ophthalmology, College of Medicine, King Saud University for funding this research. The authors would to express deep thanks and appreciation to Ms Priscilla W. Gikandi at the Department of Ophthalmology for formatting this manuscript.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

TABLE 1. Cases and controls distribution by demographic and systemic co-morbidity.DemographicsCases (n = 139) Mean (SD)Controls (n = 403) Mean (SD) p Value 
Age63.1 (9.4)61.1 (10.8)0.052
n (%)n (%)OR95% CIp Value
 Male85 (61.2)121 (30.0)
 Female54 (38.8)282 (70.0)3.7[2.454–5.484] C) with various POAG clinical indices. Ophthalmic Genet 2013 [Google Scholar]


Role of two common SNPs of superoxide dismutase 2 gene in the development of primary open angle glaucoma

SOD2 Genes, SNPs & Factors that May Increase/Decrease It

Research Article – Biomedical Research (2017) Volume 28, Issue 17

Yeye Chang1,2 and Hezheng Zhou3*

1Southern Medical University, Guangzhou, PR China

2Inner Mongolia People's Hospital, Hohhot, PR China

3Wuhan General Hospital of Guangzhou Military, Wuhan, PR China

*Corresponding Hezheng ZhouWuhan General Hospital of Guangzhou Military

Wuhan,PR China

Accepted date: August 04, 2017

Visit for more related articles at Biomedical Research


Oxidative stress is considered as risk factors for the development of POAG. SOD2 plays an important role in many biological processes caused by ROS.

We performed a study to investigate the association of two common SNPs in SOD2 (rs2842980 and rs4880) with the risk of POAG, and the interaction between SOD2 polymorphisms and environmental factors. 170 patients with POAG and 340 matched healthy controls were collected into this study without blood relationship.

Genotyping of SOD2 rs2842980 and rs4880 was conducted in a 384-well plate format on the sequenom MassARRAY platform. The association between SOD2 rs2842980 and rs4880 and risk of POAG was analyzed by logistic regression analyses.

Compared with the TT individuals, individuals with the TC and CC genotypes have a substantial increased susceptibility for POAG incidence, and adjusted ORs (95% CI) were 1.63 (1.03-2.58) and 6.92 (2.12-22.62), respectively. Moreover, the C allele displayed a 2.

09 folds risk of POAG in comparison to the T allele (adjusted OR: 2.09, 95% CI: 1.43-3.06). We found that the rs4880 showed interaction with age. In conclusion, our study suggests a significant association between rs4880 polymorphism and risk of POAG in the Chinese population. SOD2 rs4880 polymorphism could be a susceptibility biomarker for POAG.


Superoxide dismutase 2 (SOD2), rs2842980, rs4880, Primary open angle glaucoma (POAG)


Glaucoma is the leading cause of irreversible blindness, and this disease has become one of the important public health issues worldwide [1,2]. It is estimated that about 60.5 million people with primary glaucoma by 2010, which may increase to 79.6 million by 2020 with bilateral blindness, in which 5.

9 million are Primary Open Angle Glaucoma (POAG) [3]. Almost half of the world’s glaucoma population occurs in Asian counties. A recent study suggested that POAG prevalence is about 0.7% in mainland China [4].

The etiology of developing POAG is still uncertain, but it is well known that many environmental and lifestyle factors contribute to the development of this disease, such as intraocular pressure, age, alcohol drinking, cigarette smoking, high body mass index, systemic hypertension [5].

However, many cases suffering from POAG are not related to these risk factors, suggesting that genetic factors contribute to the development of this disease.

It is estimated that about 29 genetic variations have been defined by linkage studies on the development of POAG, and about 4% of the glaucoma patients have genetic variation in any one of the potential risk genes [6,7]. Therefore, understood of the role of genetic factors in POAG risk could early predict the high risk individuals of POAG.

Oxidative stress is on behalf of the imbalance of Reactive Oxygen Species (ROS) in human body, and it is considered as a risk factor for the development of POAG [8]. As a second messenger, ROS involves in signal transduction, vascular function and protein regulation, and retinal ganglion cell death signaling pathway [9,10].

The low activity of anti-oxidative enzymes and low molecular weight of antioxidants reveal the oxidative stress in the pathogenesis of POAG [11,12]. Superoxide Dismutase (SOD) is an antioxidant enzyme with a high activity on catalytic dismutation of superoxide radical anion, and plays an important role in many biological processes caused by ROS [13].

Three types of SOD were observed, including SOD1, SOD2 and SOD3. SOD has been reported to have a protective role in cells and extracellular components from damages related to inflammatory process in the pathogenesis of many diseases [14,15]. Previous studies have reported that the expression of SOD2 was changed in the aqueous humor of POAG patients [16,17].

Genetic polymorphisms of SOD genes have been widely investigated, and reported to be involving in many diseases [18,19]. Three previous studies have been reported the association between SOD2 polymorphisms and risk of POAG, but the results are inconsistent [20-22].

In this study, we performed a study to investigate the association of two common SNPs in SOD2 (rs2842980 and rs4880) with the risk of POAG, and interaction between SOD2 polymorphisms and environmental factors.

Materials and Methods

Ethics statement

The protocol of this study was approved by the Institutional Review Board of the Inner Mongolia Autonomous Region People’s Hospital, Hohhot, China. The informed consent was obtained from all subjects prior to enrolment.

Patients and controls

In this study, 170 patients with POAG were collected into this study without blood relationship. Patients were enrolled from the Inner Mongolia Autonomous Region People’s hospital between May 2013 and 2016.

All the patients were primarily diagnosed by the following criteria: I) Appearance of the disc or retinal nerve fiber layer; II) Visual field loss in line with optic nerve damage; III) Glaucomatous optic nerve damage with cup-to-disc ratio>0.

5; IV) Intraocular pressure above 21 mmHg in any one eye, and visual acuity


SOD2 Genes, SNPs & Factors that May Increase/Decrease It

SOD2 Genes, SNPs & Factors that May Increase/Decrease It

SOD2 is an intriguing enzyme. Scientists think it may affect mitochondrial health and cellular stress. What happens when this enzyme is active and what when it’s blocked? Read on to find out what scientists have discovered, including SOD2 genes and SNPs.

The SOD Family

Superoxide dismutases are enzymes that transform the superoxide (O2-) radical into either ordinary oxygen (O2) or hydrogen peroxide (H2O2) [1].

Superoxide is produced as a by-product of oxygen metabolism. If left be, it can cause widespread cell damage. Thus, SOD is an important part of antioxidant defense in all cells exposed to oxygen [1].

Hydrogen peroxide is also damaging, but less so. On the upside, it can also be degraded by other enzymes such as catalase [1].

Scientists think that SOD plays a protective role against oxidative stress, ionizing radiation, and inflammatory cytokines [1, 2].

SOD Types

There are three types of SOD: SOD1, SOD2, and SOD3 [2].

SOD1 is located in the cellular fluid, SOD2 in the mitochondria, and SOD3 outside the cell [2].

Superoxide – the harmful molecule SOD neutralizes – is one of the main reactive oxygen species in the cell. That’s why SOD serves as a key antioxidant [2].

SOD2 (also called MnSOD) is often viewed as the most important form of SOD in humans, especially in the brain. As its name suggests, SOD2 requires manganese (Mn) to work [2, 1].

What SOD2 Does

SOD2 transforms superoxide produced by the mitochondria into the less toxic hydrogen peroxide and oxygen. This allows SOD2 to clear mitochondrial reactive oxygen species (ROS) and confer some protection against cell death [2, 1].

Proposed Health Effects

Mutations in the SOD2 gene have been associated with idiopathic cardiomyopathy (IDC) and sporadic motor neuron disease. Low activity of this enzyme has been linked with stroke, Alzheimer’s and Parkinson’s disease, and several aging-related diseases [1].

Mice lacking Sod2 die shortly after birth, amid massive oxidative stress [3].

However, mice 50% deficient in SOD2 have a normal lifespan and minimal defects but do suffer increased DNA damage and increased the incidence of cancer [3].

In flies and yeast, higher production of Sod2 has been suggested to increase lifespan, but this hasn’t been proven in humans. We can’t apply findings from simple organisms fruit flies to humans, so we have yet to see to what extent this enzyme affects longevity in people [4].

On the other hand, scientists point out that superoxide has a few positive functions in the body: clearing infections, cellular communication, creating new mitochondria, and destroying cancer- cells [5].

Also, researchers are investigating whether certain cancer cells overproduce SOD2 to become more invasive – at least in test tubes. This hasn’t yet been looked at in humans [6].

On the whole, though, superoxide is seen as more damaging than helpful. Its harmful effects have been linked to one scientific theory that says oxidative stress contributes to many chronic diseases. Still, whether or not superoxide can directly cause these diseases remains unclear [5].

When to See a Doctor

If your goal is to increase SOD2 because you have a chronic health problem, it’s important to talk to your doctor, especially your symptoms are significantly impacting your daily life.

Your doctor should diagnose and treat any underlying conditions causing your symptoms.


Supplements have not been approved by the FDA for medical use and generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective.

Additionally, supplement-drug interactions can be dangerous and, in rare cases, even life-threatening. That’s why it’s so important to consult your healthcare provider before supplementing and let them know about all drugs and supplements you are using or considering.

Dosage may also matter and different doses will have different effects on antioxidant defense. Safe supplement doses should not be exceeded.

Finally, have in mind that none of these strategies should replace what your doctor recommends or prescribes.

Research Limitations

Remember that the existing evidence did not verify that low SOD2 causes any disorder, with the exception of some rare genetic disorders.

The potential health effects of activating SOD2 in humans are still an area of research.

Additionally, changes in biochemistry are not something that people can change on their own with the approaches listed below.

Thus, we’re providing a summary of the existing research, which should guide further investigational efforts.

The studies listed in this section were mostly done in animals and should not be interpreted as supportive of health benefits in humans.

Please read through them having these important limitations in mind.

What May Increase SOD?

Scientists are investigating whether the following increases SOD enzymes:

The listed supplements, drugs, and pathways are theoretical and anecdotal. They aren’t backed up by solid science. Plus, some studies don’t distinguish which SOD (SOD1, SOD2, or SOD3) something increases.

What May Decrease the Superoxide Radical?

Theoretically, factors that decrease the superoxide radical mimic SOD. They might act as antioxidants. However, most are experimental and human data are lacking.

Hormones (Experimental)

The following hormones are highly experimental. Researchers are investigating them to better understand SOD2-related biochemical pathways.

Do not take any hormones or drugs without seeing a doctor.

Hormones (including progesterone, estrogen, and testosterone) and drugs ( corticosteroids) are available only with a doctor’s prescription. Taking hormones or other prescription medication without medical supervision can be extremely dangerous.

Additionally, Pregnenolone [49] and Androstenedione [48] were also researched for affecting SOD. Both should be avoided. Pregnenolone is classified by the FDA as an unapproved new drug with high potential for harm, while androstenedione is an illegal anabolic hormone.

What May Increase Superoxide?

These factors may disrupt antioxidant balance since the superoxide radical is a potentially harmful reactive oxygen species.


It’s always a good idea to avoid unhealthy habits – such as smoking, fast food, overeating, being under a lot of stress, and drinking too much – that can weaken your antioxidant defense. Look to get regular exercise, enough nutrients, sleep, and keep a healthy circadian rhythm.

Sleep apnea or intermittent hypoxia can cause superoxide buildup [50].


You should be aware that the following hormones may increase superoxide.

  • Thyroid hormones [51, 52]
  • Growth Hormone (HGH) [53]
  • Prolactin [53]

However, these hormones all play important roles in the body. The body requires them in normal amounts.

Remember, superoxide also has some good roles in the body. Scientists think that, in certain circumstances, balanced levels of these hormones help the superoxide radical kill bacteria [54].

Aside from naturally produced hormones, some researchers hypothesize that chronic Estrogen exposure (as in birth control, HRT) excessively increases superoxide, experiments in animals.

This hasn’t yet been confirmed in humans [55].


The SOD2 gene has many SNPs you can view in SelfDecode.

Most important SOD2 SNP:

Other SOD2 SNPs:

  1. RS10370 (SOD2) TT
  2. RS2758331 (SOD2) AA
  3. RS2758339 (SOD2) CC
  4. RS2758346 (SOD2) TT