NQO1gene rs1800566 variant is not associated with risk for multiple sclerosis

Agúndez, José A. G.; García‐Martín, Elena; Martı́nez, Carmen; Benito‐León, Julián; Millán-Pascual, Jorge; Calleja, Patricia; Díaz‐Sánchez, María; Pisa, Diana; Turpín-Fenoll, Laura; Alonso‐Navarro, Hortensia; Ayuso‐Peralta, Lucía; Torrecillas, Dolores; Plaza-Nieto, José Francisco; Jiménez‐Jiménez, Félix Javier

doi:10.1186/1471-2377-14-87

Cited by 12 publications

(11 citation statements)

References 45 publications

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“…The methodology is similar to that used to detect other SNP allelic variants. 1 Hardy-Weinberg equilibrium was analyzed using DeFinetti software (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). The allelic and genotypic frequency analyses were performed using SPSS software, ver.…”

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The GSTP1 gene variant rs1695 is not associated with an increased risk of multiple sclerosis

et al. 2014

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We analyzed the allelic and genotypic frequencies of the glutathione-S-transferase P1 (GSTP1) rs1695 single nucleotide polymorphism (SNP) in 290 patients with multiple sclerosis (MS) and in 310 healthy controls. We found no significant association between the rs1695 variant and MS. Among MS patients, there was no relationship between the rs1695 variant and either gender, clinical type of MS or the age of onset of MS. These results suggest that the GSTP1 rs1695 polymorphism is not a risk factor for MS.Genome-wide association studies in samples from MS patients have identified more than 100 loci with genome-wide significance, but most of these loci had a modest odds ratio (OR) in the range of 1.1-1.3; only HLA (especially the HLA-DRB1*15:01 haplotype) had a strong association with MS risk. Glutathione S-transferases (GSTs) are a superfamily of dimeric phase 2 metabolic enzymes that catalyze the conjugation of reduced glutathione with electrophilic groups of carcinogens, herbicides/pesticides, and other compounds. GSTP1 also plays a role in inflammatory processes (http://www.ncbi.nlm.nih.gov/ pubmed/23596995). In humans, the GSTs are divided into a number of major classes that have distinct substrate specificities and tissue distributions. Polymorphisms in the GSTM1, GSTP1 and GSTT1 genes are known to alter gene function. The rs1695 variant of the GSTP1 gene (chromosome 11q13; Gene identity 2950, MIM 134660; http://www.ncbi.nlm.nih.gov/gene/2950) causes an amino-acid substitution and reduces the catalytic activity of the enzyme (http://www.ncbi.nlm.nih.gov/pubmed/ 9600848, http://www.ncbi.nlm.nih.gov/pubmed/16488119 and http://www.ncbi.nlm.nih.gov/pubmed/22401947). The rs1695 variant is the only non-synonymous polymorphism of the GSTP1 gene with a significant allele frequency in human populations and minor allele frequencies ranging from 17% to 44% (http://browser.1000genomes.org/Homo_sapiens/Variation/ Population?db5core;r511:67352189-67353189;v5rs1695;vdb 5variation;vf521985). The frequency of the GSTP1 rs1695 variant is nearly 35% in the Spanish population. 2Although GSTP1 polymorphisms were not identified as possible susceptibility genes by genome-wide association studies, we explored a possible relationship between GSTP1 polymorphisms and allelic gene variants and the risk of MS due to the possible role of oxidative stress and lipid peroxidation in the pathogenesis of MS 1 and the upregulation of GSTP1 gene expression found in active demyelinating MS lesions.3 Although two preliminary studies did not find a relationship between polymorphisms in either GSTM1 4,5 or GSTT1 5 and the risk for MS, another recent study showed an association between GSTT1 deletion and MS susceptibility 6 . Another study reported a relationship between GSTM1, GSTM3 and GSTP1, but not GSTT1, and the degree of disability in MS. Alexoudi et al.8 reported a similar distribution of GSTP1 genotypes in MS patients and controls but a higher frequency

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The GSTP1 gene variant rs1695 is not associated with an increased risk of multiple sclerosis

et al. 2014

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“…Along with Nrf2-HO1, NQO1 was increased in the brain as a protective mechanism against lead toxicity (Ye et al, 2016). To the contrary, Agúndez et al (2014) reported that the NQO1 gene does not show a significant correlation in comparison between MS patients and healthy controls. These inconsistent NQO1 results suggest the possibility of site-dependent differences in NQO1 expression or Nrf2independent changes in NQO1 expression in the spinal cord.…”

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confidence: 99%

Changes in Nrf2 Expression in the Spinal Cord in Mouse Model of Experimental Autoimmune Encephalomyelitis

Nam¹

2019

PVJ

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In this study, we investigated the expression of nuclear factor erythroid-derived 2related factor 2 (Nrf2) in the spinal cord using an experimental autoimmune encephalomyelitis (EAE) model. MOG35-55 was injected into female mice to induce an autoimmune response. Clinical scoring and a behavioral rotarod test were conducted to assess the successful modeling of EAE. Animals were sacrificed 1, 2, and 3 weeks after immunization. Spinal cords were prepared for morphometry, immunohistochemistry, and western blotting. Multifocal demyelination was observed in the white matter. Nrf2 immuno-reactivity was detected in astrocytes and neurons in spinal cord. Nrf2 immuno-reactive neurons and astrocytes had increased by 2 weeks after immunization, and their up-regulation was maintained until 3 weeks after immunization. Additionally, time-dependent up-regulation of Nrf2 in the spinal cord was investigated by western blotting. The level of NAD(P)H quinine oxidoreductase-1 protein, an Nrf2 target gene, was not changed during week 1, but showed a significant decrease 2 and 3 weeks after immunization. Parallel to upregulated Nrf2, heme oxygenase-1, another target gene of Nrf2, was significantly augmented until 3 weeks after immunization. We conclude that Nrf2 expression in neurons is involved in an autoimmune attack in the spinal cord in an EAE model.

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“…The study, which was conducted in accordance with the principles of the Helsinki declaration of 1975, was approved by the Ethics Committees of Clinical Investigation of the University Hospital “Príncipe de Asturias” (University of Alcalá, Alcalá de Henares, Madrid, Spain), the Infanta Cristina University Hospital (Badajoz, Spain), and Clínica Universitaria de Navarra (Pamplona, Spain). Most of the patients recruited had participated in other previous studies of genetic association with MS risk 1 24 25 26 27 28 29 30 .…”

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“…Despite Genome-wide association studies (GWAS) in MS confirmed more than 100 loci with genome-wide significance (most of them with modest odds-ratio-OR), only HLA (in particular the HLA-DRB1*15:01 haplotype) showed a strong association with the risk for MS 1 . Many studies of oxidative stress markers in the brain, spinal cord, and cerebrospinal fluid of patients diagnosed with MS, and in the experimental model of autoimmune encephalomyelitis (EAE), suggested a possible role of oxidative stress and lipid peroxidation in the pathogenesis of MS (revised in 1 ).…”

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“…HMOX1 acts as a heat shock protein, and is induced by oxidative stress. The possible role of oxidative stress in the pathogenesis of MS 1 , together with the previously mentioned data regarding HMOX1 in MS and in the EAE model makes that analysis of a possible relationship between HMOX polymorphisms and MS risk could seem reasonable, despite HMOX polymorphisms have not been mentioned among the possible susceptibility genes in GWAS. Recently, Zborníková et al .…”

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Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Multiple Sclerosis

Agúndez

García‐Martín

Martı́nez

et al. 2016

Sci Rep

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Several neurochemical, neuropathological, and experimental data suggest a possible role of oxidative stress in the ethiopathogenesis of multiple sclerosis(MS). Heme-oxygenases(HMOX) are an important defensive mechanism against oxidative stress, and HMOX1 is overexpressed in the brain and spinal cord of MS patients and in experimental autoimmune encephalomyelitis(EAE). We analyzed whether common polymorphisms affecting the HMOX1 and HMOX2 genes are related with the risk to develop MS. We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations(CNVs) of these genes in 292 subjects MS and 533 healthy controls, using TaqMan assays. The frequencies of HMOX2 rs1051308AA genotype and HMOX2 rs1051308A and HMOX1 rs2071746A alleles were higher in MS patients than in controls, although only that of the SNP HMOX2 rs1051308 in men remained as significant after correction for multiple comparisons. None of the studied polymorphisms was related to the age at disease onset or with the MS phenotype. The present study suggests a weak association between HMOX2 rs1051308 polymorphism and the risk to develop MS in Spanish Caucasian men and a trend towards association between the HMOX1 rs2071746A and MS risk.

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NQO1gene rs1800566 variant is not associated with risk for multiple sclerosis

Cited by 12 publications

References 45 publications

The GSTP1 gene variant rs1695 is not associated with an increased risk of multiple sclerosis

The GSTP1 gene variant rs1695 is not associated with an increased risk of multiple sclerosis

Changes in Nrf2 Expression in the Spinal Cord in Mouse Model of Experimental Autoimmune Encephalomyelitis

Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Multiple Sclerosis

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