An association study of a functional catalase gene polymorphism, −262C→T, and patients with Alzheimer's disease

doi:10.1016/S0304-3940(02)00780-2

Neuroscience Letters

Volume 330, Issue 2, 20 September 2002, Pages 210-212

https://doi.org/10.1016/S0304-3940(02)00780-2 Get rights and content

Abstract

According to the oxidative stress hypothesis which has been proposed as one of a number of possible mechanisms underlying pathogenesis of Alzheimer's disease (AD), accumulation of hydrogen peroxide in the brain of affected individuals, due to overproduction and/or insufficient detoxification, can trigger a cascade of neurotoxic events, thus contributing to the neuronal damage characteristic of the disease. The upregulation of enzymes that are able to neutralize hydrogen peroxide (catalase, peroxidases) would then be conceivably able to offer at least some protection from the damaging effects of this agent. In this study we examined the distribution of a functional polymorphism in the gene for catalase, −262C→T, in an independent population of 137 AD patients and 130 control individuals. The presence of the polymorphism, which results in the elimination of a SmaI restriction site, was tested with a PCR amplification/SmaI digestion-based assay. No significant difference has emerged from the comparison of either genotype or allele frequencies (P>0.5). We conclude that the catalase gene −262C→T polymorphism does not confer a protective effect with respect to AD.

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Acknowledgements

This work was supported by grants AG 06786 and AG 16574 to the Mayo Foundation.

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Due to the retrospective nature of our study it was not possible to collect relevant data of maternal factors, such as medication taken during pregnancy, as they are possible confounders which could be addressed if our study had been performed prospectively. Taking in consideration that regional differences in vulnerability of brain to HIE exist26 and that CAT in the brain tissue is presented in rather low levels,27 while glutathione is the most prevalent antioxidant in most brain cells,28 it may be appropriate to consider also other antioxidant enzyme polymorphisms. Despite major advances in technology with therapeutic hypothermia during the last decade, HIE remains a serious condition that causes significant mortality and long-term morbidity.
Hypoxic-ischaemic perinatal brain injury leads to the formation of reactive oxygen species (ROS) and the resultant cell and tissue damage may cause neurological sequelae such as cerebral palsy and/or epilepsy. A decrease in the capacity for defending against ROS may increase the susceptibility to cerebral palsy. The aim of this study was to investigate the impact of common functional polymorphisms in the antioxidant genes SOD2, GPX1 and CAT, associated with a decreased capacity for defending against ROS, in patients with perinatal hypoxic-ischaemic encephalopathy (HIE).
80 patients previously diagnosed with perinatal HIE were included. Genomic DNA was isolated from buccal swabs and genotyped for SOD2 rs4880, GPX1 rs1050450 and CAT rs1001179 using real-time PCR-based methods.
Among patients with neonatal HIE, carriers of at least one polymorphic CAT rs1001179 T allele were significantly associated with development of cerebral palsy compared to non-carriers (univariate logistic regression, p = 0.026; OR = 3.36; 95% CI = 1.16–9.76). This difference remained statistically significant after accounting for prematurity. The investigated SOD2 and GPX1 polymorphisms were not associated with cerebral palsy after perinatal HIE.
CAT rs1001179 polymorphism could be used to identify children that have a higher susceptibility to cerebral palsy after perinatal HIE.
rs2070424 of the SOD1 gene is associated with risk of alzheimer's disease
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There are only few studies evaluating the importance of ADS gene single nucleotide polymorphisms (SNPs) as risk factors of AD. So far, there were two studies evaluating the significance of one SNP of the catalase gene (rs1001179) [4,5], one – the significance of four SNPs of the SOD2 gene (rs2758346, r4880, rs2855116 and rs5746136) [6] and another one evaluating the significance of the rs1050450 SNP of the GPx-1 gene [7]. Only the study on the SOD2 gene, yielded positive results.
Oxidative stress plays an important role in Alzheimer's disease (AD) etiopathogenesis. There were several studies that showed impaired antioxidant defense system (ADS) enzymes expression or activity in AD patients. There are only few studies evaluating the importance of ADS gene single nucleotide polymorphisms (SNPs) as risk factors of AD. We evaluated association between chosen SNPs of the enzymes of the ADS and risk of AD.
We included 400 AD patients and 402 healthy controls. We studied rs1041740, rs4998557 and rs2070424 of the SOD1 gene, rs2855116, rs5746136 and rs4880 of the SOD2 gene and rs3448, rs1050450 and rs1800668 of the GPx-1 gene (real time PCR). To determine the APOE gene common polymorphism, two single-nucleotide polymorphisms (SNPs; NCBI SNPs rs429358 and rs7412) were genotyped (TaqMan assays, Applied Biosystems [ABI], Foster City, CA, USA). The genotype and gender frequencies were compared between the studied groups by the χ² test and mean age by the t-Student test.
Among all studied SNPs only rs2070424 of the SOD1 gene was a protective factor for AD in an additive (OR = 0.47; 95% CI = 0.30–0.74, p = 0.001) and recessive (OR = 0.47; 95% CI = 0.30–0.75, p = 0.002) models including age, gender and APOE gene status.
rs2070424 polymorphism of the SOD1 gene is a risk factor for AD in Polish population. Allel G and genotype AG and GG are protective factors for AD.
Relationships between single nucleotide polymorphisms of antioxidant enzymes and disease
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In contrast, a Russian study reported no direct association between the C-262T SNP and asthma, although an indirect association between the C allele and asthma due to a positive linkage disequilibrium with the A-21T SNP was speculated (Polonikov et al., 2009). Finally, there was no association between the C-262T polymorphism and Alzheimer's disease (Goulas et al., 2002), depressive illness (Galecki et al., 2009), systemic lupus erythematosus (D'Souza et al., 2008), chronic kidney disease and its progression (Crawford et al., 2011, in press), and acute renal failure (Perianayagam et al., 2007). Studies investigating the associations between genotypes from the catalase C-262T SNP and disease in humans have been equivocal.
The presence and progression of numerous diseases have been linked to deficiencies in antioxidant systems. The relationships between single nucleotide polymorphisms (SNPs) arising from specific antioxidant enzymes and diseases associated with elevated oxidative stress have been studied with the rationale that they may be useful in screening for diseases. The purpose of this narrative review is to analyse evidence from these studies. The antioxidant enzyme SNPs selected for analysis are based on those most frequently investigated in relation to diseases in humans: superoxide dismutase (SOD2) Ala16Val (80 studies), glutathione peroxidise (GPx1) Pro197Leu (24 studies) and catalase C-262T (22 studies). Although the majority of evidence supports associations between the SOD2 Ala16Val SNP and diseases such as breast, prostate and lung cancers, diabetes and cardiovascular disease, the presence of the SOD2 Ala16Val SNP confers only a small, clinically insignificant reduction (if any) in the risk of these diseases. Other diseases such as bladder cancer, liver disease, nervous system pathologies and asthma have not been consistently related to this SOD SNP genotype. The GPx1 Pro197Leu and catalase C-262T SNP genotypes have been associated with breast cancer, but only in a small number of studies. Thus, currently available evidence suggests antioxidant enzyme SNP genotypes are not useful for screening for diseases in humans.
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Genomic DNA was extracted from 0.15 mL of K3EDTA-anticoagulated blood with a QIAamp DNA Mini Kit (QIAGEN). The polymorphisms −262C/T in the CAT gene, 239+34A/C in the SOD1 gene and 47C/T in the SOD2 gene were analyzed using the PCR-RFLP methods as previously described (14,15). For genotyping of C599T (Pro200Leu) polymorphism in the GPX1 gene (rs1050450) genomic DNA was amplified by PCR with primers flanking polymorphic region: 5′-GCCGCCGCTTCCAGACCAT-3′ as a sense primer, and 5′-CCCCCCGAGACAGCAGCACT-3′ as an anti-sense primer.
Post-transplant diabetes mellitus (PTDM) is a metabolic disorder that develops in response to a relative insulin deficiency in patients after organ transplantation treated with immunosuppressive drugs. Several studies have suggested that oxidative stress may be associated with diabetes and its complications. The aim of this study was to examine the association of polymorphisms in superoxide dismutase, catalase and glutathione peroxidase genes with PTDM in patients after kidney transplantation.
The study included 159 patients receiving kidney transplants. PTDM was diagnosed in 21 patients.
Analyzing the C599T (Pro200Leu) polymorphism in the GPX1 gene PTDM was diagnosed in 8.45% of patients with CC genotype, 13.43% with CT and in 28.57% with TT. Allele T was significantly more frequent among patients with PTDM compared to patients without PTDM (OR = 2.14, 95% CI = 1.11–4.12, p = 0.024). There were no associations between SOD1, SOD2 and CAT polymorphisms and PTDM.
The present results suggest that Pro200Leu polymorphism of the GPX1 gene may be associated with the risk of PTDM development in renal graft recipients.
Blood selenium, glutathione peroxidase activity and antioxidant supplementation of subjects exposed to arsenic via drinking water
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These claims need further research and more solid substantiation. The present catalase −262C>T genotype distributions were similar to previously published data from USA and Sweden (Goulas et al., 2002), although the C allele was somewhat more frequent in this study (81.5% vs 76.6%). Ahsan et al. (2003) reported almost identical distribution in a Bangladeshi population.
This work investigated serum selenium (Se) and glutathione peroxidase (GPx) levels in 25 Croatian subjects exposed to high levels of As from drinking water (median As level in urine: 620.74 μg/g creatinine) and 25 controls (32.98 μg/g creatinine). The exposed group had lower (p < 0.001) median serum Se and GPx levels (Se: 82.34 μg/l vs 59.02 μg/l; GPx: 45.99 U/g hemoglobin vs 38.38 U/g hemoglobin). A subsample of 20 exposed subjects took part in a 2-month antioxidant supplementation trial which increased median GPx activity from 30.71 to 40.98 U/g hemoglobin (p = 0.041) and reduced total urinary As median from 680.15 to 501.96 μg/g creatinine (p = 0.051). The effect of selected catalase (−262C>T) and GPx1 (−593C>T) gene polymorphisms was also examined. The low Se status and GPx activity may heighten risk of adverse health effects, especially in genetically predisposed individuals. The outcome of antioxidant treatment indicates modulation of As metabolism and oxidative stress, relevance of which needs further research.

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An association study of a functional catalase gene polymorphism, −262C→T, and patients with Alzheimer's disease

Abstract

Section snippets

Acknowledgements

Neurosci. Lett.

Blood Cells Mol. Dis.

Arch. Biochem. Biophys.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Free Radic. Biol. Med.