No association between synapsin III gene promoter polymorphisms and multiple sclerosis in German patients

We investigated whether the polymorphisms rs133946 and rs133945 in the promoter region of the synapsin III (SYN3) gene are associated with multiple sclerosis in German patients. Association of the SYN3 variations and haplotypes with MS is not evident in German MS patients - in contrast to a MS cohort from Italy, as reported previously. Received in revised form: 23 February 2006     

Association between Synapsin III gene promoter polymorphisms and multiple sclerosis

Although multiple sclerosis (MS) is considered to be an inflammatory demyelinating disease, increasing evidence indicates that it is also an axonal pathology; indeed, studies of experimental allergic encephalitis showed that several neuronal proteins such as synapsins take part in the pathogenesis of the axonal dysfunction. Synapsins are a family of abundant neuron-specific phosphoproteins with crucial roles in synaptogenesis and neuronal plasticity. Distinct genes encode the three different isolated proteins (I, II and III); of interest, the gene of synapsin III (SYN3) is located in the chromosome 22q12-q13, a locus close to one of the candidate susceptibility regions (22q13.1) for MS. In the present study we selected two polymorphisms (g.-631C > G and g.-196A > G) within the SYN3 5'-promoter region because of the protein's role and genetic location; we analysed the allele and genotype distributions of these polymorphisms in a selected MS population of southern Italy. An inverse association between MS and the g-631C > G polymorphism was found; indeed, the two polymorphisms were in almost complete linkage disequilibrium and the haplotype analysis showed that the C631/A196 haplotype seemed to confer a significant protection against MS.     

Genetic association between polymorphisms in the ADAMTS14 gene and multiple sclerosis

ADAMTS14 is a novel member of the ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 modules) metalloproteinase family which processes extracellular matrix proteins. In the present study we performed a comprehensive investigation of the ADAMTS14 as a candidate gene for susceptibility to multiple sclerosis (MS). Eight single nucleotide polymorphisms (SNPs) were analyzed in a case-control study of 287 patients with MS [192 with relapsing-remitting MS (RRMS) and 95 with primary-progressive MS (PPMS)], and 285 age- and sex-matched controls. Allele and genotype frequencies were compared between controls and the MS subgroups, and gene-based haplotypes were reconstructed by computational procedures. Pairwise linkage disequilibrium values (D') suggested that three locus pairs (SNPs 3 through 5) had alleles in strong disequilibrium and constituted a haplotype block spanning 14 kb. Overall comparisons of allele and genotype frequencies showed association for SNPs 3 and 6 with MS. Stratification of MS patients according to major clinical forms revealed an increased frequency of both allele C (p = 0.006) and CC homozygosity (p = 0.008) at SNP6 in RRMS patients compared with controls. PPMS was associated with allele A at SNP2 compared with RRMS (p = 0.003) and controls (p = 0.009), and with CG heterozygosity at SNP3 compared with controls (p = 0.005). Haplotype frequency comparisons showed significant association between PPMS and the AGGGC haplotype compared with controls (p = 0.0004), and negative association between RRMS and the GGAGT haplotype compared with controls (p = 0.0026). No association was detected between different genotypes and disease severity measured by the Multiple Sclerosis Severity Score (MSSS). These findings suggest a potentially important role for the ADAMTS14 gene in predisposition to MS.     

ICOS基因多态性与中国南方汉族人群多发性硬化的相关性

目的探讨可诱导协同刺激分子(inducible costimulate,ICOS)基因多态性与多发性硬化(Multiple sclerosis,MS)遗传易感性。方法以来自中国南方汉族人群的83名确诊MS患者和110名非自身免疫性疾病的患者及健康志愿者为研究对象,利用PCR-RFLP技术监测ICOS基因-2394/2119位点酶切多态性。结果 ICOS-2394位点TT基因型频率MS组明显高于对照组(MS33.7%VS对照组10.9%,P<0.001),携带T等位基因可增加MS患病危险(OR=3.482,P<0.001),ICOS-2119位点TT基因型MS组明显低于对照组(MS4.8%vs对照组15.5%,P<0.05)。结论中国南方汉族人群ICOS基因多态性与MS发病相关,该基因可能是MS的易感基因。     

Cognitive impairment in patients with multiple sclerosis: association with the APOE gene and promoter polymorphisms

BACKGROUND: Studies examining the epsilon4 allele of the APOE gene as a factor affecting the severity of multiple sclerosis (MS) have yielded conflicting results. The focus of these studies on physical disability to the neglect of cognitive impairment is surprising in light of the associations between the epsilon4 allele and other dementia conditions. Only two studies examine the relationship between the epsilon4 allele and cognitive impairment. METHODS: A neuropsychological test battery was administered to 263 MS patients, and their current disability status was evaluated. Genotypes were determined for APOE epsilon and for two promoter region polymorphisms (-219 G/T and -491 A/T). RESULTS: Although effects were generally weak, female patients with the -491 AA genotype had a later age of disease onset, lower disability scores, and somewhat higher scores on the cognitive battery. Male patients with the epsilon2 allele had lower disability and higher scores on the cognitive battery. The epsilon4 allele was not related to physical disability, and there was no difference between epsilon4+ and epsilon4--patients in overall cognitive performance. However, when patients with severe cognitive impairment were identified, a greater proportion (52%) of these patients had the epsilon4 allele than those in the unimpaired group (27%). CONCLUSION: An association with the epsilon4 allele was evident in this study, but only in cases of severe cognitive impairment.     

Genetic association between polymorphisms in the BTG1 gene and multiple sclerosis

In the present study, we investigated the B-cell translocation gene 1 (BTG1) as a candidate for multiple sclerosis (MS) susceptibility. BTG1 is a member of a family of genes involved in the apoptotic process. We genotyped two SNPs of the BTG1 gene (rs731652 and rs12694) in 550 MS patients and 548 controls. For SNP rs731652, significant associations with relapse-onset MS were found at the allele and genotype levels when compared with controls. We identified a risk haplotype associated with relapse-onset MS. These findings support the hypothesis that BTG1 polymorphisms may influence genetic predisposition for MS, especially in relapse-onset MS patients.     

No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis

An association has previously been reported between susceptibility to multiple sclerosis and the rare mutant alleles of the CYP27B1 gene responsible for autosomal recessive vitamin D–dependent rickets type 1 (VDDR1). In an attempt to replicate this finding, we screened 495 multiplex families and 2,092 single affected families, together with 4,594 cases and 3,583 controls (a total of 17,073 individuals) but were unable to find any evidence supporting this putative association. Our data do not indicate that mutations responsible for VDDR1 influence the risk of developing multiple sclerosis. ANN NEUROL 2013;73:430–432     

An assessment of the association between IL-2 gene polymorphisms and Japanese patients with multiple sclerosis

Castleman's disease (CD) is a rare lymphoproliferative disorder that may be associated with a neuropathy. In a recent report, the presence of human herpesvirus type 8 (HHV-8) DNA sequences were detected in an HIV-negative patient with polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) associated with the multicentric hyaline vascular variant of CD. It was proposed that the presence of these sequences may have a role in the pathophysiology of the neuropathy.We describe an HIV-negative woman with the multicentric plasma cell form of CD who presented with a disabling neuropathy. In addition to a severe demyelinating polyneuropathy, she had some of the other features of POEMS including an IgA lambda gammopathy and lymphadenopathy. We were unable to detect the presence of either HHV-8 DNA or proteins in this patient. The significance of our results and the relationship between CD, POEMS and neuropathy are discussed.     

Single nucleotide polymorphisms and functional analysis of MxA promoter region in multiple sclerosis

OBJECTIVE: Interferons (IFNs)-inducible myxovirus resistance protein A (MxA) has recently been used as an indirect marker of neutralizing antibody against IFN in patients with multiple sclerosis (MS). On the other hand, MxA inhibits the replication of viruses by means of modifying cellular function, including apoptotic pathway. Our objective is to investigate the genetic and pathological role of MxA in patients with MS. METHODS: We examined SNPs of MxA promoter region in 67 patients with MS. Moreover, to elucidate the functional roles of SNPs, we conducted Luciferase assay with pGL3-basic vector including patient-derived or artificially mutated MxA promoter region. RESULTS: A significantly higher frequency of the haplotype with -88T and -123A, which correlates with over-expression of MxA, was observed in MS. Moreover, we elucidated novel findings showing that nt -88 played a leading part with type I IFNs and that nt -123 played the same role independently without type I IFNs, respectively. CONCLUSION: SNPs on MxA promoter region may play an important role in the pathophysiology of MS and provide a novel strategy for the therapeutic resolutions of MS.     

白细胞介素23受体基因单核苷酸多态性与中国南方汉族人群多发性硬化的相关性

目的 探讨白细胞介素23受体(IL23R)基因单核苷酸多态性(SNPs)与中国南方汉族人群多发性硬化(MS)的相关性.方法 选取IL23R基因3个SNPs位点(rs2201841、rs10889677、rs7517847),采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测178例MS患者和221名健康对照者IL23R基因的多态性,分析其与MS的相关性,并采用SHEsis软件进行连锁不平衡和单倍型分析.结果 IL23R基因rs2201841[TT、TC、CC 3种基因型在病例组为5.7％(10/175)、45.7％(80/175)、48.6％(85/175),在对照组为7.4％ (16/217)、41.0％ (89/217)、51.6％ (112/217);x2=1.08,P=0.58]、rs10889677[AA、AC、CC 3种基因型在病例组为52.0％(89/171)、42.7％(73/171)、5.3％(9/171),在对照组为57.7％(123/213)、36.2％(77/213)、6.1％(13/213);x2=1.71,P=0.43]、rs7517847位点[GG、GT、TT3种基因型在病例组为16.9％(29/172)、51.7％(89/172)、31.4％(54/172),在对照组为14.4％(31/215)、49.3％(106/215)、36.3％ (78/215);x2=1.15,P=0.56]各基因型与等位基因频率分布在两组之间差异均无统计学意义;MS患者SNPs位点各基因型之间首次发病年龄、病程及扩展残疾状态评分比较差异均无统计学意义.IL23R基因rs2201841和rs10889677位点存在连锁不平衡关系(D’=0.614,r2=0.327),进一步分析发现各单倍体频率分布在病例组和对照组之间差异均无统计学意义.结论 在中国南方汉族人群中,IL23R基因3个单核苷酸位点(rs2201841、rs10889677、rs7517847)多态性与MS之间无相关性.     

CD24基因多态性与多发性硬化患病易感性研究

目的探讨CD24基因多态性与多发性硬化(multiple sclerosis,MS)的相关性。方法以来自中国南方汉族人群的83名确诊MS患者和110名非自身免疫性疾病的患者及健康志愿者为研究对象,利用PCR—RFLP 技术检测CD24 E2 226C／T位点酶切多态性。结果 CD24 E2 226位点T等位基因频率MS组明显高于对照组 (MS 44．6％ vs CON 33．2％,P=0．022)。未发现CD24基因型等位基因与性别、疾病发病年龄、MS临床类型及临床严重程度之间存在相关性。结论中国南方汉族人群CD24基因多态性与MS患病相关,该基因可能是MS的易感基因。     

Vitamin D receptor gene polymorphism in multiple sclerosis and the association with HLA class II alleles

We have previously reported that the association between Bsm I polymorphism, one of the vitamin D receptor genes (VDRG) polymorphism, and multiple sclerosis (MS). In this report, we investigated the further possible role or relevance of VDRG in the pathogenesis of MS. Apa I polymorphism was detected by PCR-RFLP from the DNA of 77 conventional MS patients and 95 healthy controls. The study of the Bsm I and Apa I haplotypes was carried out by employing previously reported Bsm I data. The AA genotype and the [A] allele in the profiles were significantly more prevalent in MS patients than in controls (P=0.0070 and P=0.0321, respectively). In the [A] allele-positive MS patients, the positive rate of DPB1*0501 in HLA was significantly higher than that of the [A] allele-positive controls and that of the [A] allele-negative MS patients even when the corrected P value (P(corr)) was applied (P(corr)=0.0220 and P(corr)=0.0077, respectively). The frequency of DRB1*1501 was higher in the [A] allele-positive patients than in the [A] allele-positive controls and the [A] allele-negative patients (P(uncorr)=0.0431 and P(uncorr)=0.0089, respectively), but the P values did not reach statistical significance after P corrections. The rate of Bsm I and Apa I haplotypes was much higher in bA/bA-positive MS patients than in the controls (P=0.0003), and in the bA positive MS patients, the positive rate of DPB1*0501 was higher than that of the bA-positive controls and that of the bA-negative MS patients (P(corr)=0.0308 and P(corr)=0.0033, respectively). These results indicate that VDRG polymorphism may be associated with susceptibility to MS, and HLA alleles may correlate with risk for MS together with VDRG.     

Molecular cloning and expression of the rat monocyte chemotactic protein-3 gene: a possible role in stroke.

Using the suppression subtractive hybridization (SSH) strategy for differential gene cloning, we identified the induced expression of a rat homologue to murine and human monocyte chemotactic protein-3 (MCP-3) in ischemic brain. The 2.4-kilobase rat MCP-3 gene features high homology in gene structure and sequence to murine MCP-3. The temporal expression of MCP-3 mRNA was examined in brain tissue rendered ischemia by permanent or temporary occlusion of the middle cerebral artery (MCAO). A marked increase in MCP-3 mRNA was observed 12 h post-ischemia, with 49-fold and 17-fold increase (n=4, p<0.01) over control in the permanent or temporary MCAO, respectively. Significant induction of MCP-3 in the ischemic cortex was sustained up to 5 days after ischemic injury. The profile of MCP-3 mRNA induction paralleled leukocyte infiltration and accumulation that occur after focal stroke, suggesting a role for MCP-3 in recruiting these inflammatory cells into the ischemic tissue. Molecular cloning of rat MCP-3 should provide a valuable tool, as demonstrated in the present work, for the investigation of MCP-3 expression and function in rat disease models.     

Interleukin-10 promoter polymorphisms in patients with multiple sclerosis

The expression level of interleukin-10 (IL-10) is related to polymorphisms -1082 (G/A), -819 (T/C) and -592 (A/C) in the promoter region of the IL-10 gene. The distribution of these polymorphisms was analyzed to determine whether they could influence disease susceptibility or clinical course in multiple sclerosis (MS). The -1082 (G/A), -819 (T/C) and -592 (A/C) genotypes were similarly distributed between MS patients and the controls. The primary progressive MS patients with the low IL-10 expression haplotype showed a trend towards a worse clinical outcome than did patients with medium- or high-expression haplotypes (P = 0.056). The polymorphisms did not influence the clinical course in patients with relapsing-remitting MS.     

可诱导协同刺激分子、CD28、CD24基因多态性与多发性硬化的相关性

目的探讨可诱导协同刺激分子（ICOS）、CD28、CD24基因多态性与多发性硬化（multiple sclerosis，MS）遗传易患性的相关性。方法以来自中国汉族人群的83例确诊MS患者和110例非自身免疫性疾病的患者及健康志愿者为研究对象，利用聚合酶链．限制性长度多态性分析（PCR-RFLP）技术检测3个基因扩增产物酶切多态性。结果ICOS-2394位点TT基因型频率MS组明显高于对照组（分别为33．7％和10．9％，P〈0．01），携带T等位基因可增加MS患病危险性（OR=3．482，P〈0．01）；ICOS-2119位点携带C-等位基因MS组明显低于对照组（分别为4．8％和15．5％，P〈0．05）。CD28-372位点基因型等位基因频率分布MS组与对照组差异无统计学意义。CD24 E2＋226位点T等位基因频率MS组较对照组增多（分别为44．6％和33．2％，P〈0．05）。单倍体型关联分析显示CD24 E2＋226T等位基因分别与ICOS-2394T及ICOS-2119C联合可明显增加MS患病危险性，CD28基因多态与ICOS基因多态构成的单体型在MS和对照组中差异无统计学意义。结论中国汉族人群ICOS-2394C／T、ICOS-2119C／T及CD24E2＋226C／T多态性与Ms发病相关，两基因可能均是MS的易患基因或与易患基因相连锁。CD28-372位点多态性与MS患病无直接相关。     

髓鞘碱性蛋白基因与多发性硬化相关性的研究

目的探讨中国人群中多发性硬化（ＭＳ）的遗传易患性与髓鞘碱性蛋白基因５′端四核苷酸重复序列多态性的相关性。方法以２８例确诊ＭＳ患者及４７名正常对照为研究对象,从外周血白细胞中提取ＤＮＡ,利用聚合酶链反应技术特异性扩增ＭＢＰ基因５′端四核苷酸重复序列,并通过琼脂糖凝胶电泳分析扩增产物的多态性。结果发现四种等位基因,片段大小为１．０６ｋｂ,０．９８ｋｂ,０．６１ｋｂ和０．５４ｋｂ,以前两种多见。１．０６ｋｂ基因片段在女性中出现频率很高,达７３％,ＭＳ组与对照组无差别。男性中１．０６ｋｂ基因片段出现频率ＭＳ组（６９％）明显高于对照组（３９％）。ＭＳ组中等位基因的分布无性别差异。结论中国人群中ＭＢＰ基因第一个外显子５′端四核苷酸重复序列多态位点等位基因的分布有性别差异,１．０６ｋｂ的等位基因片段可能与ＭＳ易患性相关。     

An examination of the association between beta2 adrenergic receptor polymorphisms and multiple sclerosis

In multiple sclerosis (MS), beta-adrenergic receptor densities on peripheral blood mononuclear cells are enhanced, while the astrocytes present in plaques lack beta2 adrenergic receptor (beta2AR) expression. This differentially altered expression suggests that beta2ARs may influence the pathogenesis of MS. In the present study, we investigated the association of polymorphisms of the beta2AR gene with the occurrence of MS. Our results showed no significant differences in the distribution of the polymorphisms between MS patients overall and control subjects. Furthermore, no association was observed between the presence of beta2AR gene polymorphisms and clinical characteristics, such as age at disease onset and disease severity. While a trend towards an increase of the Gly allele frequency in codon 16 was observed in the secondary-progressive MS, this result was not significantly different from that observed in relapsing-remitting MS patients or control subjects. Together, our findings suggest that the presence of beta2AR gene polymorphisms may be inconclusive in the susceptibility to MS or in the clinical characteristics of Japanese patients with MS and, therefore, need further studies.     

HLA complement gene polymorphisms in multiple sclerosis

We studied C4A, C4B, and Bf complement gene polymorphisms in 80 Italian patients with multiple sclerosis (MS). We observed a significantly higher frequency of C4AQ0 allele in patients with the relapsing-remitting form of MS than in ethnically homogeneous controls. Restriction fragment length polymorphism analysis by Southern blotting of the C4/CYP21 gene complex showed that a structural gene deletion was present in 45% of patients with the C4AQ0 allele. Our data support the hypothesis that relapsing-remitting MS and primarily chronic progressive MS are immunogenetically distinct diseases; further, complement factor abnormalities typical of autoimmune diseases could influence the pathogenesis of MS.     

PAI and TPA gene polymorphisms in multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system. It manifests as acute focal inflammatory demyelination and axonal loss with limited remyelination and results in the chronic multifocal sclerotic plaques. Previously published data showed impaired fibrinolysis in MS. Tissue plasminogen activator t-PA is a serine protease that catalyses the activation of plasmin, which mediates the effects of fibrinolytic system. Alu insertion/deletion (I/D) genetic polymorphism in TPA gene in MS patients has not been analysed previously. The major inhibitor of t-PA is plasminogen activator inhibitor-1 (PAI-1). Its gene expression is modulated by functional genetic polymorphism in the promoter (4G/5G). In the present study, an association of two genetic polymorphisms with MS, its progression and subtype were analysed. TPA DD/PAI-1 4G4G genotype combination has reached a borderline significance for reduced risk for MS (OR = 0.543, 95% CI 0.301-0.978, P = 0.04), suggesting a gene-gene interaction. The explanation for this interaction may be a complex interplay between these two pleiotropic proteins within the brain tissue and in plasma.