Skip to main content
  • Research article
  • Open access
  • Published:

NQO1gene rs1800566 variant is not associated with risk for multiple sclerosis

Abstract

Background

A possible role of oxidative stress in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis has been suggested. The detoxification enzyme NAD(P)H dehydrogenase, quinone 1 (NQO1) has been found up-regulated in MS lesions. A previous report described an association between the SNP rs1800566 in the NQO1 gene and the risk for MS in the Greek population. The aim of this study was to replicate a possible influence of the. SNP rs1800566 in the NQO1 gene in the risk for MS in the Spanish Caucasian population.

Methods

We analyzed allelic and genotypic frequency of NQO1 rs1800566 in 290 patients with MS and 310 healthy controls, using TaqMan Assays.

Results

NQO1 rs1800566 allelic and genotypic frequencies did not differ significantly between MS patients and controls, and were unrelated with age of onset of MS, gender, and clinical type of MS.

Conclusions

Our results indicate that NQO1 rs1800566 does not have an effect on MS disease risk.

Peer Review reports

Background

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder with axonal degeneration of the central nervous system. Although the etiology of MS is not well understood, the interplay of both genetic and environmental factors is the most likely hypothesis [15]. With regard to the role of genetic factors, genome-wide association studies (GWAS) have confirmed more than 100 loci with genome-wide significance [68]. According to the most recent GWAS, approximately 22% of signals overlapped at least one other autoimmune disease signal [8], However, all loci except HLA showed modest odds-ratio (OR) in the range of 1.1-1.3 [9]. In particular the association between MS and the HLA-DRB1*15:01 haplotype has been shown to be strong.

A number or reports have suggested a possible role of oxidative stress and lipid peroxidation in the inflammatory processes and in the pathogenesis of MS [1040]. Reactive oxygen species (ROS) generated in excess primarily by macrophages and microglia, have been implicated as mediators of demyelination and axonal damage [10]. The main results of studies on oxidative stress markers in the brain, spinal cord, and CSF, both in MS patients and in experimental autoimmune encephalomyelitis (EAE) are summarized in a table included as an Additional file 1: Table S1.

NAD(P)H dehydrogenase, quinone 1 (NQO1) is a phase II detoxification enzyme that catalyzes the one-electron reduction of endogenous and exogenous quinones, preventing their participation in redox cycling and subsequent generation of reactive oxygen species. This enzyme is encoded by the NQO1 gene (chromosome 16q22.1, Gene Identity 1728) (link http://www.ncbi.nlm.nih.gov/gene/1728). The enzymatic activity of NQO1 depends fundamentally on a single nucleotide polymorphism (SNP) at the NQO1 locus, rs1800566 (C609T), which produces a proline-to-serine substitution at amino acid 187 (P187S) (link http://www.ncbi.nih.gov/pubmed/9000600). Individuals with rs1800566TT genotype completely lack NQO1 activity, whereas those with rs1800566C/T genotype present approximately threefold decreased enzyme activity [41].

Although NQO1 polymorphisms are not mentioned among the possible susceptibility genes in GWAS studies, the possible role of oxidative stress in the pathogenesis of MS makes it reasonable to analyse the possible relationship between NQO1 gene polymorphisms and the risk of MS. Moreover, NQO1 has been found to be markedly up-regulated in active demyelinating MS lesions [13, 14] Stavropoulou et al. [42], in a case–control association study involving 231 MS patients and 380 controls, reported an association between the rs1800566CT and TT genotypes and the risk of developing MS, and a higher incidence of rs1800566CT genotype in patients with primary progressive MS. The aim of the present study was to replicate the findings by Stavropoulou et al. [42] in the Spanish population.

Methods

Patients and controls

We studied 290 unrelated Caucasian Spanish patients who fulfilled McDonald’s criteria for definite MS [43], with no other previous neurological diseases. MS patients were recruited from the “Multiple Sclerosis Association of Madrid” (n = 165 cases), the Health Areas of the La-Mancha-Centro Hospital (Alcázar de San Juan, Ciudad Real, n = 65 cases), and University Hospitals “Doce de Octubre” (Madrid, n = 30 cases), and “Príncipe de Asturias” (Alcalá de Henares, Madrid, n = 30 cases). Most of these patients had participated in previous studies of genetic association with MS risk [4448]. The control group was composed of 310 healthy unrelated Caucasian Spanish individuals (students or professors from the University of Extremadura) gender and age-matched with the patients. Ethnicity and geographical origin for cases and controls was self-reported. All the participants were included in the study after giving written informed consent. Table 1 summarizes the characteristics of the individuals included in the study. The protocol was approved by the Ethics Committees of the University Hospitals “Príncipe de Asturias” and “Infanta Cristina” (Badajoz). The study was conducted according to the principles expressed in the declaration of Helsinki.

Table 1 Characteristics of the individuals included in the study

Genotyping of rs1800566 polymorphism

Genotyping for rs1800566 was performed in genomic DNA obtained from venous blood samples of participants using TaqMan Assays (C___2091255_30, Life Technologies, Alcobendas, Madrid, Spain). Detection was carried out by qPCR in an Eppendorf realplex thermocycler. The amplification conditions were as follows: after a denaturation time of 10 min at 96°C, 45 cycles of 92°C 15 sec 60°C 90 sec were carried out and fluorescence was measured at the end of each cycle and at endpoint. All samples were determined in triplicate and genotypes were assigned both by gene identification software (RealPlex 2.0, Eppendorf, Madrid, Spain) and by analysis of the reference cycle number for each fluorescence curve, calculated by the use of the CalQPlex algorithm (Eppendorf, Madrid, Spain).

Statistical analysis

Hardy-Weinberg equilibrium (HWE) both in MS patient and control groups was analyzed by the DeFinetti software (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). Allele and genotype frequency analysis was performed with SPSS ver. 17.

For categorical variables the intergroup comparison values were calculated using the chi-square or Fisher’s exact tests when appropriate. For continuous variables, the Kolmogorov-Smirnoff test was used to analyze normality in the distribution. Then, the Student two sample t test was used for variables that followed a normal distribution (age and age at onset); the Mann–Whitney test was used for the duration of disease and the severity scores expanded disability status scale and progression index, because no normal distribution was observed for this parameter. The association between the genotypes and the risk of developing MS was assessed by two-way contingency table analysis (http://statpages.org/ctab2x2.html). Statistical power was calculated for the sample size of this study (this was determined from allele frequencies with a genetic model analyzing the frequency for carriers of the disease gene with Odds ratio (OR) = 1.5, p = 0.05 [49]). Two-tailed and one-tailed associations of the risk with the variant allele for ORs of 1.5; 1.4; 1.3; 1.2; and 1.1; were, respectively: 84.6% and 90.9%; 68.9% and 79.0%; 47.4% and 59.8%; 25.6% and 36.6%; and 9.9% and 16.56%.

Results

The frequencies of NQO1 rs1800566 genotypes and allelic variants in patients diagnosed with MS did not differ from those of controls (Table 2). The genotype and allele frequencies in MS patients and healthy subjects were in Hardy-Weinberg’s equilibrium. Mean age at onset of MS did not differ significantly between patients carrying NQO1 rs1800566 C/C (mean ± SD = 32.1 ± 10.2 years, reference), C/T (mean ± SD = 33.5 ± 11.6 years, p = 0.220) and T/T (mean ± SD = 32.4 ± 12.0 years, p = 0.270). Association between the rs1800566 variant and MS risk was not observed when analyzing gender separately (Table 2). The distribution of the NQO1 rs1800566 genotype and allelic frequencies did not differ between each MS clinical evolutive type and controls (Table 3) or in the severity scores: Expanded Disability Status Score or EDSS (p = 0.508 and p = 0.370 for heterozygous and homozygous carriers of the minor allele, respectively, as compared with homozygous carriers of the major allele) or progression index (p = 0.872 and p = 0.673 for heterozygous and homozygous carriers of the minor allele, respectively, as compared with homozygous carriers of the major allele).

Table 2 NQO1 rs1800566 genotype and allelic variants of patients with multiple sclerosis (MS) and healthy volunteers
Table 3 NQO1 rs1800566 genotype and allelic variants in patients with multiple sclerosis (MS), and relation with the clinical evolutive type of MS

Discussion

In contrast with the findings in the study by Stavropoulou et al. [42], we did not find significant differences either in the frequencies of rs1800566 genotypes, or in the frequencies of the allelic variants of this polymorphism in patients with MS when compared with healthy controls. In addition, rs1800566 polymorphism was neither associated with age at onset of MS, nor with clinical type of MS. Patient sample size and statistical power are higher in our study than in the study by Stavropoulou et al. [42].

A possible reason for the discrepancies between the study by Stavropoulou et al. [42] and the present one is the fact that the genotype distribution in the control group of the Stavropoulou et al. [42] study was in Hardy-Weinberg’s disequilibrium (Pearson’s p = 0.0086). The Hardy-Weinberg’s disequilibrium was attributable to the female control group of the study by Stavropoulou et al. [42]. Another putative difference is that in the study by Stavropoulou et al. [42] the genotyping analysis was carried out by using qPCR melting curves, whereas in our study TaqMan genotyping was used.

Several SNPs have been described within the NQO1 gene. It should be noted that most association studies on NQO1 focusing on the SNP analyzed in this study show a relatively high minor allele frequency (about 20% for Caucasian populations according to 1000 genomes). The rs1800566 analyzed in this study is common in Caucasian individuals; in fact it occurs in all human populations, and is classified as a pathogenic allele related with altered susceptibility to benzene toxicity and response to chemotherapy (see http://browser.1000genomes.org/Homo_sapiens/Variation/Phenotype?db=core;r=16:69744645–69745645;v=rs1800566;vdb=variation;vf=1366399).

The present study has some limitations. First, the size of the analyzed cohorts may not be sufficient for strict conclusions about the role of NQO1in MS (though adequate to detect an OR as small as 1.5, a more modest association would not be detected). Secondly, because the cohort study included MS patients with different degrees of severity, it is not adequate for the investigation of the influence of NQO1 genotypes on disability or severity of MS. The ideal study for this purpose should be prospective, including the genotyping of patients with a recent diagnosis of MS and a re-examination of the same patient cohort after similar long-term follow-up periods to establish evolutive type).

Conclusions

Taking in account the limitations of the present study, the results suggest that, in contrast with the Stavropoulou et al. [42] report, NQO1 rs1800566 genotypes and allelic variants are not associated with the risk for MS in Caucasian Spanish people. The fact that this particular SNP showed lack of association with MS risk in the present study does not exclude the possibility that other SNPs in the NQO1 gene could be associated with a modification in the risk of this disease.

References

  1. Giordano M, D'Alfonso S, Momigliano-Richiardi P: Genetics of multiple sclerosis: linkage and association studies. Am J Pharmacogenomics. 2002, 2: 37-58. 10.2165/00129785-200202010-00004.

    Article  CAS  PubMed  Google Scholar 

  2. Dyment DA, Ebers GC, Sadovnick AD: Genetics of multiple sclerosis. Lancet Neurol. 2004, 3: 104-110. 10.1016/S1474-4422(03)00663-X.

    Article  CAS  PubMed  Google Scholar 

  3. Ramagopalan SV, Deluca GC, Degenhardt A, Ebers GC: The genetics of clinical outcome in multiple sclerosis. J of Neuroimmunol. 2008, 201–202: 183-199.

    Article  Google Scholar 

  4. Pugliatti M, Harbo HF, Holmøy T, Kampman MT, Myhr KM, Riise T, Wolfson C: Environmental risk factors in multiple sclerosis. Acta Neurol Scand. 2008, Suppl 188: 34-40.

    Article  Google Scholar 

  5. Duque B, Sepulcre J, Bejarano B, Samaranch L, Pastor P, Villoslada P: Memory decline evolves independently of disease activity in MS. Mult Scler. 2008, 4: 947-953.

    Article  Google Scholar 

  6. Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, Dilthey A, Su Z, Freeman C, Hunt SE, Edkins S, Gray E, Booth DR, Potter SC, Goris A, Band G, Oturai AB, Strange A, Saarela J, Bellenguez C, Fontaine B, Gillman M, Hemmer B, Gwilliam R, Zipp F, Jayakumar A, Martin R, Leslie S, Hawkins S, Giannoulatou E, et al: Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011, 476: 214-219. 10.1038/nature10251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Patsopoulos NA, Bayer Pharma MS Genetics Working Group, Steering Committees of Studies Evaluating IFNβ-1b and a CCR1-Antagonist, ANZgene Consortium, GeneMSA, International Multiple Sclerosis Genetics Consortium: Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Ann Neurol. 2011, 70: 897-912. 10.1002/ana.22609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A, Cotsapas C, Shah TS, Spencer C, Booth D, Goris A, Oturai A, Saarela J, Fontaine B, Hemmer B, Martin C, Zipp F, D'Alfonso S, Martinelli-Boneschi F, Taylor B, Harbo HF, Kockum I, Hillert J, Olsson T, Ban M, Oksenberg JR, Hintzen R, Barcellos LF, Agliardi C, Alfredsson L, Alizadeh M, International Multiple Sclerosis Genetics Consortium (IMSGC), et al: Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet. 2013, 45: 1353-1360. 10.1038/ng.2770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gourraud PA, Harbo HF, Hauser SL, Baranzini SE: The genetics of multiple sclerosis: an up-to-date review. Immunol Rev. 2012, 248: 87-103. 10.1111/j.1600-065X.2012.01134.x.

    Article  PubMed  Google Scholar 

  10. LeVine SM: The role of reactive oxygen species in the pathogenesis of multiple sclerosis. Med Hypotheses. 1992, 39: 271-274. 10.1016/0306-9877(92)90121-R.

    Article  CAS  PubMed  Google Scholar 

  11. Newcombe J, Li H, Cuzner ML: Low density lipoprotein uptake by macrophages in multiple sclerosis plaques: implications for pathogenesis. Neuropathol & Appl Neurobiol. 1994, 20: 152-162. 10.1111/j.1365-2990.1994.tb01174.x.

    Article  CAS  Google Scholar 

  12. Haider L, Fischer MT, Frischer JM, Bauer J, Höftberger R, Botond G, Esterbauer H, Binder CJ, Witztum JL, Lassmann H: Oxidative damage in multiple sclerosis lesions. Brain. 2011, 134: 1914-1924. 10.1093/brain/awr128.

    Article  PubMed  PubMed Central  Google Scholar 

  13. van Horssen J, Schreibelt G, Bö L, Montagne L, Drukarch B, van Muiswinkel FL, de Vries HE: NAD(P)H:quinone oxidoreductase 1 expression in multiple sclerosis lesions. Free Radic Biol Med. 2006, 41: 311-317. 10.1016/j.freeradbiomed.2006.04.013.

    Article  CAS  PubMed  Google Scholar 

  14. van Horssen J, Schreibelt G, Drexhage J, Hazes T, Dijkstra CD, van der Valk P, de Vries HE: Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic Biol Med. 2008, 45: 1729-1737. 10.1016/j.freeradbiomed.2008.09.023.

    Article  CAS  PubMed  Google Scholar 

  15. Bizzozero OA, DeJesus G, Callahan K, Pastuszyn A: Elevated protein carbonylation in the brain white matter and gray matter of patients with multiple sclerosis. J Neurosci Res. 2005, 81: 687-695. 10.1002/jnr.20587.

    Article  CAS  PubMed  Google Scholar 

  16. Zheng J, Bizzozero OA: Decreased activity of the 20S proteasome in the brain white matter and gray matter of patients with multiple sclerosis. J Neurochem. 2011, 117: 143-153. 10.1111/j.1471-4159.2011.07182.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Langemann H, Kabiersch A, Newcombe J: Measurement of low molecular-weight antioxidants uric acid tyrosine and tryptophan in plaques and white matter from patients with multiple sclerosis. Eur Neurol. 1992, 32: 248-252. 10.1159/000116835.

    Article  CAS  PubMed  Google Scholar 

  18. van Horssen J, Drexhage JA, Flor T, Gerritsen W, van der Valk P, de Vries HE: Nrf2 and DJ1 are consistently upregulated in inflammatory multiple sclerosis lesions. Free Radic Biol Med. 2010, 49: 1283-1289. 10.1016/j.freeradbiomed.2010.07.013.

    Article  CAS  PubMed  Google Scholar 

  19. Wilhelmus MM, van der Pol SM, Jansen Q, Witte ME, van der Valk P, Rozemuller AJ, Drukarch B, de Vries HE, Van Horssen J: Association of Parkinson disease-related protein PINK1 with Alzheimer disease and multiple sclerosis brain lesions. Free Radic Biol Med. 2011, 50: 469-476. 10.1016/j.freeradbiomed.2010.11.033.

    Article  CAS  PubMed  Google Scholar 

  20. McMahon JM, McQuaid S, Reynolds R, FitzGerald UF: Increased expression of ER stress- and hypoxia-associated molecules in grey matter lesions in multiple sclerosis. Mult Scler. 2012, 18: 1437-1447. 10.1177/1352458512438455.

    Article  CAS  PubMed  Google Scholar 

  21. Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J, Mahad D, Bradl M, van Horssen J, Lassmann H: NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain. 2012, 135: 886-899. 10.1093/brain/aws012.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Choi IY, Lee SP, Denney DR, Lynch SG: Lower levels of glutathione in the brains of secondary progressive multiple sclerosis patients measured by 1H magnetic resonance chemical shift imaging at 3 T. Mult Scler. 2011, 17: 289-296. 10.1177/1352458510384010.

    Article  CAS  PubMed  Google Scholar 

  23. Zheng J, Bizzozero OA: Accumulation of protein carbonyls within cerebellar astrocytes in murine experimental autoimmune encephalomyelitis. J Neurosci Res. 2010, 88: 3376-3385. 10.1002/jnr.22488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dasgupta A, Zheng J, Perrone-Bizzozero NI, Bizzozero OA: Increased carbonylation, protein aggregation and apoptosis in the spinal cord of mice with experimental autoimmune encephalomyelitis. ASN Neuro. 2013, 5: e00111-

    Article  PubMed  PubMed Central  Google Scholar 

  25. Li S, Vana AC, Ribeiro R, Zhang Y: Distinct role of nitric oxide and peroxynitrite in mediating oligodendrocyte toxicity in culture and in experimental autoimmune encephalomyelitis. Neuroscience. 2011, 184: 107-119.

    Article  CAS  PubMed  Google Scholar 

  26. Toshniwal PK, Zarling EJ: Evidence for increased lipid peroxidation in multiple sclerosis. Neurochem Res. 1992, 17: 205-207. 10.1007/BF00966801.

    Article  CAS  PubMed  Google Scholar 

  27. Calabrese V, Raffaele R, Cosentino E, Rizza V: Changes in cerebrospinal fluid levels of malondialdehyde and glutathione reductase activity in multiple sclerosis. Int J Clin Pharmacol Res. 1994, 14: 119-123.

    CAS  PubMed  Google Scholar 

  28. Ghabaee M, Jabedari B, Al-E-Eshagh N, Ghaffarpour M, Asadi F: Serum and cerebrospinal fluid antioxidant activity and lipid peroxidation in Guillain-Barre syndrome and multiple sclerosis patients. Int J Neurosci. 2010, 120: 301-304. 10.3109/00207451003695690.

    Article  CAS  PubMed  Google Scholar 

  29. Seven A, Aslan M, Incir S, Altıntaş A: Evaluation of oxidative and nitrosative stress in relapsing remitting multiple sclerosis: effect of corticosteroid therapy. Folia Neuropathol. 2013, 51: 58-64.

    Article  CAS  PubMed  Google Scholar 

  30. Greco A, Minghetti L, Puopolo M, Cannoni S, Romano S, Pozzilli C, Levi G: Cerebrospinal fluid isoprostanes are not related to inflammatory activity in relapsing-remitting multiple sclerosis. J Neurol Sci. 2004, 224: 23-27. 10.1016/j.jns.2004.05.016.

    Article  CAS  PubMed  Google Scholar 

  31. Mattsson N, Haghighi S, Andersen O, Yao Y, Rosengren L, Blennow K, Praticò D, Zetterberg H: Elevated cerebrospinal fluid F2-isoprostane levels indicating oxidative stress in healthy siblings of multiple sclerosis patients. Neurosci Lett. 2007, 414: 233-236. 10.1016/j.neulet.2006.12.044.

    Article  CAS  PubMed  Google Scholar 

  32. Sbardella E, Greco A, Stromillo ML, Prosperini L, Puopolo M, Cefaro LA, Pantano P, De Stefano N, Minghetti L, Pozzilli C: Isoprostanes in clinically isolated syndrome and early multiple sclerosis as biomarkers of tissue damage and predictors of clinical course. Mult Scler. 2013, 19: 411-417. 10.1177/1352458512457721.

    Article  CAS  PubMed  Google Scholar 

  33. Pennisi G, Cornelius C, Cavallaro MM, Salinaro AT, Cambria MT, Pennisi M, Bella R, Milone P, Ventimiglia B, Migliore MR, Di Renzo L, De Lorenzo A, Calabrese V: Redox regulation of cellular stress response in multiple sclerosis. Biochem Pharmacol. 2011, 82: 1490-1499. 10.1016/j.bcp.2011.07.092.

    Article  CAS  PubMed  Google Scholar 

  34. Gonzalo H, Brieva L, Tatzber F, Jové M, Cacabelos D, Cassanyé A, Lanau-Angulo L, Boada J, Serrano JC, González C, Hernández L, Peralta S, Pamplona R, Portero-Otin M: Lipidome analysis in multiple sclerosis reveals protein lipoxidative damage as a potential pathogenic mechanism. J Neurochem. 2012, 123: 622-634. 10.1111/j.1471-4159.2012.07934.x.

    Article  CAS  PubMed  Google Scholar 

  35. Kalousová M, Havrdová E, Mrázová K, Spacek P, Braun M, Uhrová J, Germanová A, Zima T: Advanced glycoxidation end products in patients with multiple sclerosis. Prague Med Rep. 2005, 106: 167-174.

    PubMed  Google Scholar 

  36. Ljubisavljevic S, Stojanovic I, Vojinovic S, Stojanov D, Stojanovic S, Cvetkovic T, Savic D, Pavlovic D: The patients with clinically isolated syndrome and relapsing remitting multiple sclerosis show different levels of advanced protein oxidation products and total thiol content in plasma and CSF. Neurochem Int. 2013, 62: 988-997. 10.1016/j.neuint.2013.02.025.

    Article  CAS  PubMed  Google Scholar 

  37. Jiménez-Jiménez FJ, de Bustos F, Molina JA, de Andrés C, Gasalla T, Ortí- Pareja M, Zurdo M, Porta J, Castellano-Millán F, Arenas J, Enríquez de Salamanca R: Cerebrospinal fluid levels of alpha-tocopherol in patients with multiple sclerosis. Neurosci Lett. 1998, 249: 65-67. 10.1016/S0304-3940(98)00370-X.

    Article  PubMed  Google Scholar 

  38. de Bustos F, Navarro JA, de Andrés C, Molina JA, Jiménez-Jiménez FJ, Ortí-Pareja M, Gasalla T, Tallón-Barranco A, Martínez-Salio A, Arenas J: Cerebrospinal fluid nitrate levels in patients with multiple sclerosis. Eur Neurol. 1999, 41: 44-47.

    Article  CAS  PubMed  Google Scholar 

  39. Amorini AM, Petzold A, Tavazzi B, Eikelenboom J, Keir G, Belli A, Giovannoni G, Di Pietro V, Polman C, D'Urso S, Vagnozzi R, Uitdehaag B, Lazzarino G: Increase of uric acid and purine compounds in biological fluids of multiple sclerosis patients. Clin Biochem. 2009, 42: 2001-2006.

    Article  Google Scholar 

  40. Kastenbauer S, Kieseier BC, Becker BF: No evidence of Increased oxidative degradation of urate to allantoin in the CSF and serum of patients with multiple sclerosis. J Neurol. 2005, 252: 611-612. 10.1007/s00415-005-0697-z.

    Article  PubMed  Google Scholar 

  41. Kuehl BL, Paterson JW, Peacock JW, Paterson C, Rauth AM: Presence of a heterozygous substitution and its relationship to DT-diaphorase activity. Br J Cancer. 1995, 72: 555-561. 10.1038/bjc.1995.373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Stavropoulou C, Zachaki S, Alexoudi A, Chatzi I, Georgakakos VN, Terzoudi GI, Pantelias GE, Karageorgiou CE, Sambani C: The C609T inborn polymorphism in NAD(P)H:quinone oxidoreductase 1 is associated with susceptibility to multiple sclerosis and affects the risk of development of the primary progressive form of the disease. Free Radic Biol Med. 2011, 51: 713-718. 10.1016/j.freeradbiomed.2011.04.043.

    Article  CAS  PubMed  Google Scholar 

  43. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS: Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001, 50: 121-127. 10.1002/ana.1032.

    Article  CAS  PubMed  Google Scholar 

  44. Martínez C, García-Martín E, Benito-León J, Calleja P, Díaz-Sánchez M, Pisa D, Alonso-Navarro H, Ayuso-Peralta L, Torrecillas D, Agúndez JA, Jiménez-Jiménez FJ: Paraoxonase 1 polymorphisms are not related with the risk for multiple sclerosis. Neuromolecular Med. 2010, 12: 217-223. 10.1007/s12017-009-8095-9.

    Article  PubMed  Google Scholar 

  45. García-Martín E, Martínez C, Benito-León J, Calleja P, Díaz-Sánchez M, Pisa D, Alonso-Navarro H, Ayuso-Peralta L, Torrecillas D, Agúndez JA, Jiménez-Jiménez FJ: Histamine-N-methyl transferase polymorphism and risk for multiple sclerosis. European Jouirnal of Neurol. 2010, 17: 335-338. 10.1111/j.1468-1331.2009.02720.x.

    Article  Google Scholar 

  46. García-Martín E, Lorenzo-Betancor O, Martínez C, Pastor P, Benito-León J, Millán-Pascual J, Calleja P, Díaz-Sánchez M, Pisa D, Turpín-Fenoll L, Alonso-Navarro H, Ayuso-Peralta L, Torrecillas D, Lorenzo E, Plaza-Nieto JF, Agúndez JA, Jiménez-Jiménez FJ: LINGO1 rs9652490 and rs11856808 polymorphisms are not associated with risk for multiple sclerosis. BioMed Central Neurol. 2013, 13: 34-10.1186/1471-244X-13-34.

    Article  Google Scholar 

  47. García-Martín E, Agúndez JA, Martínez C, Benito-León J, Millán-Pascual J, Calleja P, Díaz-Sánchez M, Pisa D, Turpín-Fenoll L, Alonso-Navarro H, Ayuso-Peralta L, Torrecillas D, Plaza-Nieto JF, Jiménez-Jiménez FJ: Vitamin D3 receptor (VDR) gene rs2228570 (Fok1) and rs731236 (Taq1) variants are not associated with the risk for multiple sclerosis: results of a new study and a meta-analysis. Public Library of Sci One. 2013, 8: e65487-

    Google Scholar 

  48. Agúndez JAG, Garcia-Martin E, Martínez C, Benito-León J, Millán-Pascual J, Calleja P, Díaz-Sánchez M, Pisa D, Turpín-Fenoll L, Alonso-Navarro H, Ayuso-Peralta L, Torrecillas D, Plaza-Nieto JF, Jiménez-Jiménez FJ: MAPT gene rs1052553 polymorphism is not associated with the risk for multiple sclerosis. Hum Immunol. 2013, 74: 1705-1708. 10.1016/j.humimm.2013.07.008.

    Article  PubMed  Google Scholar 

  49. Pértegas Díaz S, Pita Fernández S: Cálculo del poder estadístico de un estudio. Cad de Atención Primaria. 2003, 10: 59-63.

    Google Scholar 

Pre-publication history

Download references

Acknowledgements

We are grateful to Prof. James McCue for assistance in language editing. This work was supported in part by Grants PI12/00241, PI12/00324 and RETICS RD12/0013/0002 from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain, and GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Union.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Félix Javier Jiménez-Jiménez.

Additional information

Competing interest

The authors declare that they have no competing interests.

Authors’ contributions

JAGA participated in the conception and design of the study, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, administrative, technical, and material support, supervision, and obtaining funding. EGM participated in the conception and design of the study, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, administrative, technical, and material support, supervision, and obtaining funding. CM participated in acquisition of data, analysis and interpretation of data, critical revision of the manuscript, administrative, technical, and material support. JBL participated in acquisition of data, and critical revision of the manuscript. JMP participated in acquisition of data, and critical revision of the manuscript. PC participated in acquisition of data, and critical revision of the manuscript. MDS participated in acquisition of data, and critical revision of the manuscript. DP participated in acquisition of data, and critical revision of the manuscript. LTF participated in acquisition of data, and critical revision of the manuscript. HAN participated in acquisition of data, analysis and interpretation of data, critical revision of the manuscript, administrative, technical, and material support. LAP participated in acquisition of data, and critical revision of the manuscript. DT participated in acquisition of data, and critical revision of the manuscript. JFPN participated in acquisition of data, and critical revision of the manuscript. FJJJ participated in the conception and design of the study, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, administrative, technical, and material support, and supervision. All authors read and approved the final manuscript

Electronic supplementary material

12883_2014_1003_MOESM1_ESM.doc

Additional file 1: Table S1: Results of studies of oxidative stress markers in the brain, spinal cord, and CSF of MS patients and in experimental autoimmune encephalomyelitis (EAE). (DOC 40 KB)

Rights and permissions

Open Access  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Agúndez, J.A.G., García-Martín, E., Martínez, C. et al. NQO1gene rs1800566 variant is not associated with risk for multiple sclerosis. BMC Neurol 14, 87 (2014). https://doi.org/10.1186/1471-2377-14-87

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1471-2377-14-87

Keywords