María Díaz-Sánchez

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

Background Some epidemiological, genetic, and experimental data suggest a possible role of vitamin D in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis. Data on the possible contribution of several single nucleotide polymorphisms (SNP) in the vitamin D receptor (VDR) gene to the risk for MS are controversial. Several studies suggested an interaction between some SNPs in the VDR gene and HLADRB1*1501 in the risk for MS. Objectives The aim of this study was to investigate a possible influence of the SNPs rs2228570 and rs731236 in the VDR gene in the risk for MS. A secondary objective was to address the possible interactions between VDR genes and HLADRB1*1501. Methods We analyzed the allelic and genotype frequency of VDR rs2228570, rs731236, and HLADRB1*1501 (rs3135388) in 303 patients with MS and 310 healthy controls, using TaqMan Assays. We also conducted a meta-analysis, that was carried out by using the software Meta-Disc 1.1.1 (http://www.hrc.es/investigacion/metadisc.html; Unit of Clinical Statistics, Hospital Ramón y Cajal, Madrid, Spain). Heterogeneity between studies in terms of degree of association was tested using the Q-statistic. Results VDR rs2228570 and rs731236 allelic and genotype frequencies did not differ significantly between MS patients and controls, and were unrelated with the age of onset of MS, gender, and course of MS. HLADRB1*1501 showed a high association with the risk of developing MS 4.76(95% C.I.  = 3.14–7.27; p<0.0001). The meta-analysis, after excluding data of one study that was responsible of heterogeneity for rs731236 polymorphism, showed lack of relation of both SNPs with the risk for MS. HLADRB1*1501 showed lack of interaction with VDR rs2228570 and rs731236 in increasing MS risk. Conclusions These results suggest that VDR rs2228570 and rs731236 polymorphisms are not related with the risk for MS, and did not confirm interaction between these VDR SNPs and HLADRB1 in the risk for MS.

Application of the 2010 McDonald criteria for the diagnosis of multiple sclerosis in a Spanish cohort of patients with clinically isolated syndromes

Background: Recently the International Panel on Diagnosis of Multiple Sclerosis (MS) has proposed new magnetic resonance imaging (MRI) criteria for the diagnosis of MS in patients with clinically isolated syndromes (CIS). We aimed to evaluate the accuracy of these new criteria for lesions dissemination in space (DIS) and time (DIT), from a single MRI scan, to predict conversion from CIS to clinically definite MS. Methods: We studied 67 CIS patients with baseline MRI performed within the first 3 months after onset. The follow-up was of at least 24 months. The sensitivity, specificity and accuracy of Barkhof–Tintoré criteria and the new proposed MRI criteria for DIS and DIT were calculated with SPSS v.15.0. Results: The mean age for clinical onset was 30 years and 64% of patients were female. The overall conversion rate was 74%. In our cohort, Barkhof–Tintoré criteria showed a sensitivity of 71.43%, a specificity of 66.67%, with an accuracy of 73.1%. New DIS criteria showed a sensitivity of 85.71%, a specificity of 64.71% and an accuracy of 80.30%. We also evaluated the new DIT criteria with a single MRI scan in 54 patients with baseline scans that included gadolinium-enhanced images. The sensitivity of the test was 52.63% with a specificity of 75.00% and an accuracy of 59.26%. Conclusion: New DIS criteria are simpler and more sensitive than previous criteria. The sensitivity of DIT criterion using a single MRI scan was rather low, as other previous studies showed, reflecting its stringency, but it could improve the accuracy of early MS diagnosis in that group of patients with typical CIS and gadolinium-enhancing and non-enhancing lesions on their baseline scans. These results reinforce their use in MS diagnosis.

Most of the Quality of Life in Essential Tremor Questionnaire (QUEST) psychometric properties resulted in satisfactory values

OBJECTIVE This study sought to assess the psychometric attributes of the Quality of Life in Essential Tremor Questionnaire (QUEST) by undertaking an independent validation. STUDY DESIGN AND SETTING This was an observational, multicenter, cross-sectional study carried out in Neurology Departments of general hospitals. The following assessments were applied: Louis Rating Scale, Clinical Assessment of Tremor, Clinical Global Impression of Severity (CGI-ET), Hospital Anxiety and Depression Scale (HADS), EQ-5D, and QUEST (Spanish version). RESULTS One hundred and eighteen consecutive patients were included. According to the CGI-ET, most of patients had mild (42.4%) or moderate (43.2%) impact of tremor on performing daily activities. Fully computable QUEST data were 60.2%. The QUEST Summary Index (QUEST-SI) displayed marginal floor or ceiling effect. On the whole, QUEST internal consistency and reproducibility were satisfactory (Cronbachs alpha values: 0.73-0.86; QUEST-SI intraclass correlation coefficient: 0.77). Factor analysis identified eight factors (73.6% of the variance) that could be grouped into six, relatively coincident with the questionnaires dimensions. The QUEST-SI correlated moderately with the EQ-5D index (r(S)=-0.40), HADS-Depression (r(S)=0.39), and CGI-ET (r(S)=0.39), and strongly with the QUEST scale for self-evaluation of tremor severity (r(S)=0.63). The standard error of measurement was 8.00. CONCLUSION Apart from a substantial problem of acceptability, most of the tested psychometric attributes of the QUEST resulted satisfactory.

Accuracy of MRI criteria for dissemination in space for the diagnosis of multiple sclerosis in patients with clinically isolated syndromes

The MRI Barkhof—Tintoré criteria have proved to be highly specific for predicting conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes (CIS), but lacked an optimal sensitivity. In order to improve the accuracy of early multiple sclerosis diagnosis, new imaging criteria have been proposed by Swanton et al. We aimed to evaluate the accuracy of both MRI criteria for dissemination in space to predict conversion from CIS to clinically definite multiple sclerosis. We studied 79 CIS patients with baseline MRI performed within the first 3 months after onset. The sensitivity and specificity of both MRI criteria to predict conversion to clinically definite multiple sclerosis were analysed. The time to develop clinically definite multiple sclerosis from CIS onset, according to each imaging criteria, was studied by Kaplan—Meier survival curves. The overall conversion rate was 75.7% with a median follow-up of 57 months. Barkhof— Tintoré’s criteria showed a sensitivity of 71.9% and a specificity of 77.2%. Swanton’s criteria had a sensitivity of 91.2% and a specificity of 68.1%. Both MRI criteria identified CIS patients with higher risk and faster conversion to clinically definite multiple sclerosis. Swanton’s criteria are simpler and more sensitive than Barkhof—Tintoré‘s criteria, with a slight decrease in specificity. These results reinforce their use in multiple sclerosis diagnosis.

Paraoxonase 1 Polymorphisms Are Not Related with the Risk for Multiple Sclerosis

It has been suggested a possible role of oxidative stress and lipid peroxidation in the inflammatory processes and in the pathogenesis of multiple sclerosis. Human serum paraoxonase 1 is a polymorphic enzyme encoded by the gene PON1, located in chromosome 7q21.3, that plays a major role in the metabolism of organophosporus compounds, and in the protection against oxidative stress. Paraoxonase-1 activity has been found decreased in the plasma of multiple sclerosis patients. An association between PON1 polymorphism and the risk of multiple sclerosis has been described in Italians. To investigate the possible association between the PON1 genotype and allelic variants of the polymorphisms L55M and Q192R and the risk for multiple sclerosis in the Spanish Caucasian population; we studied the frequency of the PON1 genotypes and allelic variants in 228 patients with multiple sclerosis and 220 healthy controls using a PCR-RLFP method. The frequencies of the PON1 genotypes and allelic variants did not differ significantly between patients and controls, and were unrelated with gender, age of onset, and course of the disease. The OR (95% confidence intervals) for the variant alleles PON1-55L and PON1-192R were 0.96 (0.73–1.26) and 1.01 (0.76–1.35), respectively. The results of the present study suggest that PON1 polymorphism is not related with the risk for multiple sclerosis in our population.

LINGO1 rs9652490 and rs11856808 polymorphisms are not associated with risk for multiple sclerosis.

BackgroundSome recent experimental data suggest a possible role of LINGO-1 in the pathogenesis of multiple sclerosis (MS). In an attempt to identify genetic biomarkers related to MS susceptibility, we genotyped two common SNPs in the LINGO1 gene which have been associated to other neurological conditions, in patients with MS and in healthy subjects. These SNPs are linked to several SNPs within the LINGO1 gene, especially in individuals of Oriental or Caucasian descent.MethodsWe analyzed the allelic and genotype frequency of two LINGO1 variants (rs9652490 and rs11856808) in 293 patients with MS and 318 healthy controls, using KASPar assays.ResultsLINGO1 rs9652490 and rs11856808 allelic and genotype frequencies did not differ significantly between MS patients and controls. The minor allele frequencies for rs9652490 were 0.171 (95% CI = 0.140-0.201) and 0.167 (95% CI = 0.138-0.196 for cases and controls respectively (p = 0.853). For rs11856808 the minor allele frequencies were 0.317 (95% CI = 0.280-0.355) and 0.310 (95% CI = 0.274-0.346) for cases and controls, respectively (p = 0.773). Allele and genotype frequencies were unrelated with the age of onset of MS, gender, and clinical course of MS. In addition, haplotype analyses did not reveal any putative risk related to haplotypes.ConclusionsThese results suggest that LINGO1 rs9652490 and rs11856808 polymorphisms are not related with risk for MS. This study adds to other published evidence indicating that, to date, the LINGO1 SNPs studied here could be useful risk biomarkers of developing essential tremor, but not other movement disorders.

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

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.

NQO1 gene rs1800566 variant is not associated with risk for multiple sclerosis

BackgroundA 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.MethodsWe analyzed allelic and genotypic frequency of NQO1 rs1800566 in 290 patients with MS and 310 healthy controls, using TaqMan Assays.ResultsNQO1 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.ConclusionsOur results indicate that NQO1 rs1800566 does not have an effect on MS disease risk.

MAPT gene rs1052553 variant is not associated with the risk for multiple sclerosis.

BACKGROUND/OBJECTIVES Some experimental data suggest a possible role of tau protein in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis. The aim of this study was to investigate a possible influence of the SNP rs1052553 in the MAPT gene in the risk for relapsing bout onset (relapsing-remitting and secondary progressive) MS. METHODS We analyzed the allelic and genotype frequency of MAPT rs1052553, which has been associated with some neurodegenerative diseases, in 259 patients with relapsing bout onset MS and 291 healthy controls, using TaqMan Assays. RESULTS MAPT rs1052553 allelic and genotype frequencies did not differ significantly between relapsing bout onset MS patients and controls, and were unrelated with the age of onset of MS or gender. CONCLUSIONS These results suggest that MAPT rs1052553 polymorphism is not related with the risk for relapsing bout onset MS.

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

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.