Association of tumor necrosis factor‐α and matrix metalloproteinase‐3 gene variants with stroke

Background and purpose: There is increasing evidence that the genetic variation in the genes coding for pro‐inflammatory markers and matrix metalloproteinase may play an important role in the pathogenesis of various human diseases including stroke. The aim of this study was to evaluate the association of genetic variants within the genes encoding tumor necrosis factor‐α (TNF‐α) and matrix metalloproteinase‐3 (MMP‐3), with stroke. Methods: Five hundred and twenty‐five ischemic stroke patients and 500 age‐ and sex‐matched controls were included in this study. We analyzed +488 G/A polymorphism in TNF‐α gene and −1612 5A/6A polymorphism in MMP‐3 gene. The genotypes were determined by Amplification Refractory Mutation System PCR. The strength of association between genotypes and stroke was measured by the odds ratio with 95% confidence interval (CI) and chi‐squared analysis. Results: Allelic and genotypic frequencies of TNF‐α G/A polymorphism differed significantly between patients and healthy controls (P < 0.001). A stepwise logistic regression analysis confirmed these findings (P < 0.001). Further, evaluating the association of this polymorphism with stroke subtypes, we found significant association with intracranial large artery atherosclerosis, extracranial large artery atherosclerosis, and stroke of undetermined etiology. As far as MMP‐3−1612 5A/6A polymorphism is concerned, there was no significant difference in genotypic distribution and allelic frequency between the patients and healthy controls (P = 0.5 and 0.9, respectively). We tested the gene–gene interaction between TNF‐α and MMP‐3 genes using the logistic regression model. However, there was no evidence for a gene–gene interaction between TNF‐α and MMP‐3. Conclusion: TNF‐α +488 G/A variant is an important risk factor for ischemic stroke in the South Indians from Andhra Pradesh, whereas MMP‐3−1612 5A/6A polymorphism is not associated with stroke in the same population.     

Paraoxonase 1 (PON1) polymorphisms and risk for essential tremor

Background: The polymorphic enzyme human serum paraoxonase 1 (PON1), encoded by the gene PON1 (chromosome 7q21.3), plays a major role in the metabolism of organophosphorus compounds. We investigated the possible association between the PON1 genotype and allelic variants of the polymorphisms Leu55Met and Glu192Arg, and the risk for essential tremor (ET). Methods: We studied the frequency of the PON1 genotypes and allelic variants in 201 patients with ET and 220 healthy controls using a PCR‐RLFP method. Results: The frequencies of the PON1 genotypes and allelic variants of the polymorphisms Leu55Met and Gln192Arg did not differ significantly between patients with ET and controls. These polymorphisms were unrelated with the age of onset of ET. Conclusions: PON1 polymorphisms are not related with the risk for ET.     

Dopamine receptor 3(DRD3) polymorphism and risk for migraine

Background/objectives: Dopamine has been implicated in the pathogenesis of migraine. We investigated the possible association between the polymorphism 312G>A (rs6280) in the DRD3 gene(essential tremor 1‐ETM1‐ locus, chromosome 3q13) and the risk for migraine and for triggering migraine attacks by alcohol. Methods: We studied the frequency of the DRD3 genotypes and allelic variants in 197 patients with migraine and 282 healthy controls using a polymerase chain reaction and MlsI‐restriction fragment length polymorphisms method. Results: The frequencies of the DRD3 genotypes and DRD3Gly9 were similar in patients with migraine and controls and were unrelated to the age of onset of migraine, gender, family history of migraine and triggering of migraine attacks by alcohol. The frequency of the genotype DRD3Gly9Gly9 was significantly higher in patients with migraine with aura when compared with patients with migraine without aura, but not with controls. Conclusion: DRD3 genotype and allelic variants were not related to the risk for migraine in Caucasian Spanish people.     

The Nonsynonymous Thr105Ile Polymorphism of the Histamine <Emphasis Type="Italic">N</Emphasis>-Methyltransferase is Associated to the Risk of Developing Essential Tremor

Objective We analyzed in patients with essential tremor (ET) the Thr105Ile polymorphism of the Histamine N-methyltransferase (HNMT) enzyme that is associated to Parkinson’s disease (PD) risk. Methods Leukocytary DNA from 204 ET patients and a control group of 295 unrelated healthy individuals was studied for the nonsynonymous HNMT Thr105Ile polymorphism by using amplification-restriction analyses. Results Patients with ET showed a higher frequency of homozygous HNMT 105Thr genotypes leading to high metabolic activity (p < 0.015) with a statistically significant gene-dose effect, as compared to healthy subjects. These findings were independent of gender, and of tremor localization, but the association of the HNMT polymorphism is more prominent among patients with late-onset ET (p < 0.007). Conclusion These results, combined with previous findings indicating alterations in the frequency for the HNMT Thr105Ile polymorphism in patients with PD, suggest that alterations of histamine homeostasis in the SNC are associated with the risk of movement disorders.     

Paraoxonase 1 (PON1) polymorphisms and risk for migraine

The polymorphic enzyme human serum paraoxonase 1 (PON1), encoded by the gene PON1 (chromosome 7q21.3) plays a role as an antioxidant molecule through several mechanisms. Because oxidative stress has been implicated in the pathogenesis of migraine, we have investigated the possible association between the nonsynonymous polymorphisms 55LM and 192QR in the PON1 and the risk for migraine. We studied the frequency of the PON1 genotypes and allelic variants in 197 patients with migraine and 220 healthy controls using a TaqMan single nucleotide polymorphism analysis. The frequencies of the PON1 genotypes and PON1 allelic variants did not differ significantly between patients with migraine and controls, and were unrelated with gender, family history of migraine, and presence or absence of aura. The frequencies of the genotype PON1 192QQ and the allelic variant PON1 192Q were significantly higher in patients with earlier onset of migraine. The results of the present study suggest that PON1 polymorphisms are not related with the risk for migraine in Caucasian Spanish people, although PON1 192Q/Q genotype and PON1 192Q allelic variant should be related with an earlier onset of migraine.     

Association of HLA‐DRB1*15 allele and CSF oligoclonal bands in a Spanish multiple sclerosis cohort

Background and objective: The HLA‐DRB1*15 allele is consistently associated with multiple sclerosis (MS) susceptibility in most studied populations. This study investigated the association between HLA‐DRB1 alleles and the presence of oligoclonal immunoglobulin G bands (OCB) in the cerebrospinal fluid (CSF) in a Spanish population with MS. Methods: The HLA‐DRB1 typing was performed in 268 patients with sporadic MS and the detection of OCB in CSF. HLA‐DRB1 allelic frequencies were compared between OCB‐positive and OCB‐negative patients, and both groups were also compared with 1088 unrelated healthy controls. Moreover, we correlated the various HLA‐DRB1 genotypes, considering all the combinations of both parental alleles found with the presence or absence of OCB. Results: We found 206 OCB‐positive and 62 OCB‐negative patients. The HLA‐DRB1*15 allele in OCB‐positive patients had a higher frequency when compared with OCB‐negative patients (39.3% in OCB‐positive vs. 16.1% in OCB‐negative, OR = 1.38 95% CI = 1.18–1.61, P < 0.001). The other alleles did not show differences. When we compared with controls, the HLA‐DRB1*15 allele was associated with the disease only in the OCB‐positive patients group. None of the 55 genotypes found showed any association with the presence or absence of OCB. Conclusions: HLA‐DRB1*15 allele is associated with OCB‐positive patients with MS when studying a Spanish MS population.     

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.     

Common polymorphisms of chemokine (C‐X3‐C motif) receptor 1 gene modify amyotrophic lateral sclerosis outcome: A population‐based study

Introduction: In the brain, the chemokine (C‐X3‐C motif) receptor 1 (1CX3CR1) gene is expressed only by microglia, where it acts as a key mediator of the neuron–microglia interactions. We assessed whether the 2 common polymorphisms of the CX3CR1 gene (V249I and T280M) modify amyotrophic lateral sclerosis (ALS) phenotype. Methods: The study included 755 ALS patients diagnosed in Piemonte between 2007 and 2012 and 369 age‐matched and sex‐matched controls, all genotyped with the same chips. Results: Neither of the variants was associated with an increased risk of ALS. Patients with the V249I V/V genotype had a 6‐month‐shorter survival than those with I/I or V/I genotypes (dominant model, P = 0.018). The T280M genotype showed a significant difference among the 3 genotypes (additive model, P = 0.036). Cox multivariable analysis confirmed these findings. Discussion: We found that common variants of the CX3CR1 gene influence ALS survival. Our data provide further evidence for the role of neuroinflammation in ALS. Muscle Nerve 57 : 212–216, 2018     

Glutathione-S-transferase P1 polymorphism and risk for essential tremor

Glutathione- S -transferases (GST) are polymorphic enzymes that participate in the metabolism of carcinogens (including those of tobacco smoke) and pesticides. We investigated the possible association between the GSTP1 genotype and allelic variants and the risk for essential tremor (ET). We studied the frequency of the GSTP1 genotypes and allelic variants in 200 patients with ET and 220 healthy controls using PCR-RFLP method. The association between GSTP1 polymorphism and the exposure to some environmental factors (agricultural work, pesticides, well-water and smoking-cigarettes habit) was also studied in a subgroup of patients. The frequencies of the GSTP1 genotypes and allelic variants did not differ significantly between patients with ET and controls or between patients with ET exposed to agricultural work, well water and cigarette smoking versus those non-exposed. Mutated allelic variants were significantly more frequent in patients with ET exposed to pesticides versus those non-exposed. GSTP1 polymorphism was unrelated with the age of onset of ET. GSTP1 genotypes and allelic variants were not related with the risk for ET with the possible exception of those patients exposed to pesticides.     

Insulin‐like growth factor (IGF)‐I and IGF‐binding protein‐3 serum levels in relapsing–remitting and secondary progressive multiple sclerosis patients

Background: Insulin‐like growth factor (IGF)‐I has a role in remyelination, and insulin‐like growth factor‐binding protein‐3 (IGFBP‐3) might reduce its bioavailability. A role of IGFBP‐3 in multiple sclerosis (MS) progression was hypothesized in patients with primary progressive (PP) MS. Objective: To evaluate serum levels of IGF‐I and IGFBP‐3 in patients with relapsing–remitting (RR) and secondary progressive (SP) MS and their correlations with disease activity and progression. Methods: Sixty‐three (41 RR and 22 SP) ‘naive’ MS patients and 60 age‐matched healthy controls were enrolled. Patients were assessed through clinical [Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), number of relapses] and laboratory investigations. IGF‐I and IGFBP‐3 were measured by ELISA. Results: Levels of IGF‐I and IGFBP‐3 were similar in the two MS groups. IGFBP‐3 levels were higher in patients with MS than in controls (P < 0.001), with a reduction in IGF‐I/BP3 ratio (P < 0.001). Patients showing IGFBP‐3 levels higher than 2SD of the normal population had a higher EDSS (mean EDSS 3.7 vs. 2.8, P = 0.021). MSSS was not related to IGF‐I or IGFBP‐3 serum levels. Conclusions: Our patients showed high IGFBP‐3 serum levels respect to controls and higher serum levels were associated with a higher EDSS, despite of comparable disease duration. Therefore, MS and higher disability seem to be associated with a reduction in bioavailability of IGF‐I. MSSS score was not related to IGFBP‐3 levels, suggesting that IGFBP‐3 might not have the pathogenetic role previously suggested for PP MS, in the mechanism of progression in the SP form of disease.     

Association of intronic polymorphism rs3773364 A>G in synapsin‐2 gene with idiopathic epilepsy

In epilepsy, there is a tendency towards recurrent unprovoked seizures. Seizures result due to the excessive electrical misfiring in the brain between neurons and disturbance in neurotransmitter release. Several gene products affect the behavior of these neurons by regulating neurotransmission via several mechanisms. One such gene, Synapsin‐2 (SYN2), involved in synaptogenesis is also reported to regulate the neurotransmitter release. We hypothesized that SYN2 gene and its polymorphisms could affect the process of epileptogenesis and therapeutic response in humans. In this hospital‐based study, we enrolled 372 patients with epilepsy and 199 control subjects. We selected rs3773364 A>G polymorphism in SYN2 gene and analyzed its distribution in north Indian patients with epilepsy and control subjects. Genotyping was carried out by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method. According to the results obtained, SYN2 “AG” genotype frequency was significantly higher in patients with epilepsy versus control subjects in north Indian population (P = 0.02, OR = 1.55, 95% CI = 1.06–2.26). After subclassification, we observed higher frequency of AG genotype in idiopathic patients as compared to control subjects (P = 0.01, OR = 1.67, 95% CI = 1.08–2.56). There were no significant differences in genotypic (AG: OR = 0.80, P = 0.377; GG: P = 0.628, OR = 1.17) or allelic (P = 0.86, OR = 1.03) frequency distributions in patients with multiple drug resistance versus patients with drug‐responsive epilepsy. Results from our study indicate the involvement of SYN2 gene polymorphism in conferring risk to epilepsy; however, the genetic variant does not seem to modulate drug‐response in epilepsy pharmacotherapy. Synapse 64:403–408, 2010. © 2009 Wiley‐Liss, Inc.     

Meta-analysis of the IL23R and IL12B polymorphisms in multiple sclerosis

Purpose: Polymorphisms in the genes encoding interleukin-23 receptor (IL23R) and the p40 subunit of IL-12/23 (IL12B) have been implicated in multiple sclerosis (MS) risk. However, results of different studies are inconsistent. Our aim was to perform a meta-analysis on this topic. Methods: We assessed two variants (rs10889677 and rs7517847) of IL23R and the A1188C polymorphism (rs3212227) of IL12B. Electronic databases (PubMed, Web of Science and Scopus) were searched for eligible studies published until September 2014. Odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of association in dominant, recessive, homozygote and allelic comparison models. Results: Seven case–control studies with 2250 MS patients and 2320 controls were included in this meta-analysis. The pooled results showed no association of rs10889677 and rs7517847 with MS risk in any of the genetic models. Although the pooled analysis showed an association between rs3212227 and MS in all study subjects in dominant (OR = 0.81, 95% CI: 0.66–0.99, P_h = 0.480, P_z = 0.044) and allelic comparison (OR = 0.84, 95% CI: 0.72–0.98, P_h = 0.967, P_z = 0.030) models, subgroup analysis based on ethnicity did not suggest an association between rs3212227 and MS risk in Caucasians in any of the genetic models, and there was no association between rs3212227 and MS risk in an Asian group. Conclusions: The IL23R polymorphisms rs10889677, rs7517847, and the IL12B polymorphism rs3212227 are not associated with MS risk.     

The interleukin‐1 cluster gene region is associated with multiple sclerosis in an Italian Caucasian population

Background: Polymorphisms of the interleukin‐1 (IL‐1) gene family have been proposed as potential variants for different diseases including multiple sclerosis (MS). With respect to MS, IL‐1 beta (?511 C/T; rs16944), IL‐1 beta (+3954 C/T; rs1143634), IL‐1 alpha (?889 C/T; rs1800587), IL‐1 alpha (+4845 G/T; rs17561), and the variable number of tandem repeats in intron 2 of the IL‐1 receptor antagonist (IL‐1RN) gene polymorphisms have been studied in different ethnic groups, leading to conflicting results. Methods: This study investigates the association between IL‐1 genes and MS by means of 70 markers spanning the 1.1 Mb region where the IL‐1 genes map and exploring both the linkage disequilibrium (LD) and the haplotype structure in a case–control design including 410 subjects (160 patients and 250 controls). Results: From allelic/genotypic tests, significant association was found for several polymorphisms including the IL‐1 beta (?511 C/T) variant (P‐adjusted = 4.5 × 10^?4) and some polymorphisms around the IL‐1RN gene. The ‘block‐step’ pattern obtained from both the LD map and pairwise analysis identifies four LD regions. Region 1 showed a significant association with MS for the global test (P < 0.0001) and haplotypes containing the IL‐1 beta (?511 C/T) variant still demonstrate highly significant association with disease (P‐value range: 9.9 × 10^?5 to 0.02). Conclusions: Our findings support the existence of a causative variant for MS within this candidate region in a representative Italian Caucasian population and, in particular, the role of the IL‐1 beta (?511 C/T) variant warrants further investigation.     

Synergistic effect of two oxidative stress‐related genes (heme oxygenase‐1 and GSK3β) on the risk of Parkinson’s disease

Background: Oxidative stress is a central factor in the pathogenesis of Parkinson’s disease (PD). Heme oxygenase‐1 (HO‐1) is an antioxidant protein expressed in response to oxidative challenge, and its expression levels are inversely correlated with glycogen synthase kinase‐3β (GSK3β) activity. Underexpression of HO‐1 in concert with an upregulation of GSK3β would result in a less effective antioxidant response and might increase the risk of PD. Methods: We examined two functional polymorphism in the promoter regions of HO‐1 (?413, rs2071746) and GSK3β (?157, rs6438552) in a group of 251 Spanish patients with PD and 234 controls. Results: Subjects carrying both the HO‐1 (?413, rs2071746) TT genotype and the GSK3β (?157, rs6438552) TT genotype had a four times higher risk of developing PD than subjects without these genotypes (adjusted by age and sex OR = 4.12; 95% CI = 1.45–11.71; Bonferroni corrected P = 0.024). Conclusions: Considering synergistic effects between polymorphisms in oxidative stress‐related genes may help in determining the risk profile for PD.     

Polymorphism of the angiotensin-converting enzyme gene in patients with cerebral infarction in koreans

The relationship between cerebrovascular disease and an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene is still being debated. The frequency of the DD genotype of the ACE gene was significantly higher in subjects with than those without cerebral infarction in Japan. The aim of the present study was to assess the relationship between ACE gene polymorphism and the development of cerebral infarction in a population from Korea. We examined its possible role as a risk factor in patients with cerebral infarction. The association between ACE gene polymorphism and cerebral infarction was examined in 106 patients with cerebral infarction and 498 controls without cerebral infarction. Frequencies of the genotypes and alleles of the ACE gene were investigated. The ACE genotype was analyzed by the polymerase chain reaction (PCR). The frequency of D allele was 37.7% in patients and 39.1% in controls (X ²=0.128, p=0.720). The frequencies of the genotypes of the ACE gene were II:39.6%, ID:45.3%, and DD:15.1% in patients, and II:37.1%, ID:47.6%, and DD:15.3% in controls (X ²=0.127, p=0.721). There was no significant difference in the frequency of the DD genotype of the ACE gene, and we did not find any association between ACE polymorphism and cerebral infarction. These results indicate that ACE polymorphism is not a risk factor for the development of cerebral infarction in a Korean population.     

Re‐sequencing of ankyrin 3 exon 48 and case‐control association analysis of rare variants in bipolar disorder type I

Doyle GA, Lai AT, Chou AD, Wang M‐J, Gai X, Rappaport EF, Berrettini WH. Re‐sequencing of ankyrin 3 exon 48 and case‐control association analysis of rare variants in bipolar disorder type I. Bipolar Disord 2012: 14: 809–821. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Genome‐wide association studies (GWAS) recently identified ankyrin 3 (ANK3) as a candidate gene for bipolar disorder type I (BPD‐I). Because the GWAS suggested multiple common haplotypes associated with BPD‐I (with odds ratio ～1.3), we hypothesized that rare variants within these common haplotypes might increase risk for BPD‐I. Methods: We undertook a project in which the serine‐rich domain–tail domain (SRD‐TD)‐encoding exon of ANK3 was amplified from genomic DNA (gDNA) of 384 BPD‐I patients and re‐sequenced by next generation sequencing (NGS; SOLiD?). Results: We confirmed 18 novel mis‐sense rare variants and one novel insertion/deletion variant within the SRD‐TD exon, many of which change amino acid residues with extremely high evolutionary conservation. We genotyped most of these mis‐sense variants in ≥ 1000 BPD‐I and ≥ 1000 control individuals. We found no statistically significant association of any of the rare variants detected with BPD‐I. Conclusions: Thus, we conclude that rare variants within the re‐sequenced structural domains of ANK3 exon 48 do not contribute to BPD‐I.     

Different responses to interferon beta‐1b treatment in patients with neuromyelitis optica and multiple sclerosis

Background: Although the benefit of treatment for relapsing–remitting multiple sclerosis (MS) is firmly established, whether interferon beta‐1b (IFNB‐1b) therapy is efficacious for neuromyelitis optica (NMO) has been debated. Methods: We reviewed the responses to IFNB‐1b treatment in 18 patients with relapsing NMO and compared the results with those from 38 patients with relapsing–remitting MS. We compared clinical characteristics, the annualized relapse rate (ARR) and the probability of being relapse free before and after IFNB‐1b treatment in patients with NMO and MS. Results: The proportion of patients with more than 50% increase in the ARR after IFNB‐1b treatment was much higher in NMO than in MS (P = 0.046). ARR was significantly lower in patients with MS after IFNB‐1b administration than before (P = 0.015), but not in NMO. Kaplan–Meier and log‐rank statistical analyses revealed that relapse‐free rates were lower in NMO than MS after IFNB‐1b treatment (P = 0.032). The analyses also showed lower relapse‐free rates during the pre‐IFNB‐1b treatment period than the post‐IFNB‐1b treatment period in MS (P < 0.001), but not in NMO. Conclusion: IFNB‐1b treatment does not appear to be effective for preventing relapse in NMO likely because of differences between the immune‐pathogenesis of NMO and MS.     

Serum complement factor H and Tyr4O2 His gene polymorphism among Egyptians with multiple sclerosis

Abstract

Background and objectives:

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system. A contribution from complement has long been suspected. We investigated the association of complement factor H (CFH) Tyr402 His gene polymorphism and serum level in Egyptian patients with MS to examine whether complement might identify or predict specific pathological processes and outcomes in MS.

Design and setting:

This case-control study was performed during 2013 on MS subjects who attended the Department of Neurology, Cairo University Teaching Hospital.

Patients and methods:

The study included 86 subjects with MS and 74 healthy controls (HC). They were divided into two sets of patients: we measured serum CFH level in 42 patients and 34 HC, and CFH Tyr402 His gene polymorphism in 44 MS patients and 40 HC. Serum CFH was measured by an enzyme-linked immunosorbent assay. Complement factor H Tyr402 His gene polymorphism was detected using polymerase chain reaction followed by restriction fragment length polymorphism analysis.

Results:

Serum CFH levels were significantly higher in the MS group and subgroups (P?<?0.05) than those in the control group. There was no significant difference in the frequency of CFH Tyr402 His genotypes and alleles between MS patients and healthy controls.

Conclusion:

There was evidence that serum CFH level may be associated with disease risk. There was no evidence that CFH Tyr402 His gene polymorphism is associated with disease risk.     

The I/D polymorphism of the ACE1 gene is not associated with ischaemic stroke in Spanish individuals

Background: The angiotensin‐converting enzyme 1 (ACE1) gene has been extensively studied in stroke, yet generating conflicting results. The goal of our study was thus to clarify the influence of the ACE1 on the risk of suffering an ischaemic stroke (IS). Methods: We genotyped the rs4341 (in linkage disequilibrium with the I/D polymorphism) of the ACE1 gene in 531 patients with IS and 549 healthy controls, and the rs1799752 (I/D polymorphism) in a subset of 68 patients with IS and 27 controls. We also performed functional studies by measuring serum ACE protein levels and enzymatic activity in 27 controls, 68 patients with IS at baseline and 35 patients with IS 24 h after onset of stroke symptoms. Results: There was no association of the ACE1 variant with IS, although it affected ACE protein levels (P = 0.001). Indeed, patients with IS showed lower ACE levels than controls in the acute phase (115.9 ± 38.9 vs. 174.1 ± 56.1 ng/ml, P < 0.001), but not in the chronic phase (168.2 ± 51.2, P = 0.673), and ACE protein levels did not differ between IS etiologies. Similar results were found for ACE activity. Conclusions: The D allele of the ACE1 I/D and ACE protein levels was not associated with a higher risk of IS in Spanish individuals.     

Serum and CSF PDGF‐AA and FGF‐2 in relapsing‐remitting multiple sclerosis: a case–control study

Background and purpose: Fibroblast growth factor‐2 (FGF‐2) and platelet‐derived growth factor‐A (PDGF‐AA) are potent modulators of oligodendrocytes, the main responsible cells for myelin regeneration. We measured FGF‐2 and PDGF‐AA in the sera and cerebrospinal fluid (CSF) of patients with relapsing‐remitting multiple sclerosis (RR‐MS) and compared these values with control subjects. Methods: Twenty‐three patients with RR‐MS and 23 subjects without inflammatory and demyelinating diseases were included. Serum samples of the patients were collected in both relapse and remission phases and were analyzed with ELISA method. CSF was drawn during the relapse period. Blood and CSF were drawn from control subjects for comparison. Wilcoxon and Mann–Whitney U‐test and Spearman’s rank correlation were used for analysis. P values of <0.05 were considered significant. Results: Age and sex distribution were similar in both groups. Serum values of FGF‐2 were higher in relapse phase compared with remission phase, with a trend toward significance (P = 0.052). CSF PDGF‐AA showed significant negative correlation with disease duration (correlation coefficient = ?0.58, P = 0.004). Serum levels of PDGF did not differ between two phases significantly. There was no difference in serum and CSF values of these factors between patients and controls. When we compared patients with prolonged disease with controls, a significant difference between the CSF levels of PDGF‐AA was observed (mean ± SEM 2.78 ± 0.8 in controls vs. 0.55 ± 0.29 in patients with MS ≥ 2 years, P < 0.05). Conclusion: Our study was the first to show that CSF PDGF‐AA is related to disease duration. Supporting previous findings we showed that serum and CSF levels of these factors are weak indicators of disease severity.