HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRV

[Background] Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Multiple Sclerosis Associated Retrovirus (MSRV) is a member of HERV-W, a multicopy human endogenous retroviral family repeatedly implicated in MS pathogenesis. MSRV envelope protein is elevated in the serum of MS patients and induces inflammation and demyelination but, in spite of this pathogenic potential, its exact genomic origin and mechanism of generation are unknown. A possible link between the HERV-W copy on chromosome Xq22.3, that contains an almost complete open reading frame, and the gender differential prevalence in MS has been suggested.[Results] MSRV transcription levels were higher in MS patients than in controls (U-Mann–Whitney; p = 0.004). Also, they were associated with the clinical forms (Spearman; p = 0.0003) and with the Multiple Sclerosis Severity Score (MSSS) (Spearman; p = 0.016). By mapping a 3 kb region in Xq22.3, including the HERV-W locus, we identified three polymorphisms: rs6622139 (T/C), rs6622140 (G/A) and rs1290413 (G/A). After genotyping 3127 individuals (1669 patients and 1458 controls) from two different Spanish cohorts, we found that in women rs6622139 T/C was associated with MS susceptibility: [χ2; p = 0.004; OR (95% CI) = 0.50 (0.31-0.81)] and severity, since CC women presented lower MSSS scores than CT (U-Mann–Whitney; p = 0.039) or TT patients (U-Mann–Whitney; p = 0.031). Concordantly with the susceptibility conferred in women, rs6622139*T was associated with higher MSRV expression (U-Mann–Whitney; p = 0.003).[Conclusions] Our present work supports the hypothesis of a direct involvement of HERV-W/MSRV in MS pathogenesis, identifying a genetic marker on chromosome X that could be one of the causes underlying the gender differences in MS.This work was supported by grants from: Instituto de Salud Carlos III-Fondo Investigaciones Sanitarias FIS (10/01985 and 09/02074), Fundación Genzyme, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, and Fundación LAIR.Peer Reviewe

Multiple sclerosis retrovirus-like envelope gene: Role of the chromosome 20 insertion

Background: The genetic basis involved in multiple sclerosis (MS) susceptibility was not completely revealed by genome-wide association studies. Part of it could lie in repetitive sequences, as those corresponding to human Endogenous Retroviruses (HERVs). Retrovirus-like particles were isolated from MS patients and the genome of the MS-associated retrovirus (MSRV) was the founder of the HERV-W family. We aimed to ascertain which chromosomal origin encodes the pathogenic ENV protein by genomic analysis of the HERV-W insertions. Methods/results: In silico analyses allowed to uncover putative open reading frames containing the specific sequence previously reported for MSRV-like envelope (env) detection. Out of the 261 genomic insertions of HERV-W env, only 9 copies harbor the specific primers and probe featuring MSRV-like env. The copy from chromosome 20 was further studied considering its size, a truncated homologue of the functional HERV-W env sequence encoding syncytin. High Resolution Melting analysis of this sequence identified two single nucleotide polymorphisms, subsequently genotyped by Taqman chemistry in 668 MS patients and 678 healthy controls. No significant association of these polymorphisms with MS risk was evidenced. Transcriptional activity of this MSRV-like env copy was detected in peripheral blood mononuclear cells from patients and controls. RNA expression levels of chromosome 20-specific MSRV-like env did not show significant differences between MS patients and controls, neither were related to genotypes of the two mentioned polymorphisms. Conclusions: The lack of association with MS risk of the identified polymorphisms together with the transcription results discard chromosome 20 as genomic origin of MSRV-like env

HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRV.

Journal Article; Research Support, Non-U.S. Gov't;BACKGROUND Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Multiple Sclerosis Associated Retrovirus (MSRV) is a member of HERV-W, a multicopy human endogenous retroviral family repeatedly implicated in MS pathogenesis. MSRV envelope protein is elevated in the serum of MS patients and induces inflammation and demyelination but, in spite of this pathogenic potential, its exact genomic origin and mechanism of generation are unknown. A possible link between the HERV-W copy on chromosome Xq22.3, that contains an almost complete open reading frame, and the gender differential prevalence in MS has been suggested. RESULTS MSRV transcription levels were higher in MS patients than in controls (U-Mann-Whitney; p = 0.004). Also, they were associated with the clinical forms (Spearman; p = 0.0003) and with the Multiple Sclerosis Severity Score (MSSS) (Spearman; p = 0.016). By mapping a 3 kb region in Xq22.3, including the HERV-W locus, we identified three polymorphisms: rs6622139 (T/C), rs6622140 (G/A) and rs1290413 (G/A). After genotyping 3127 individuals (1669 patients and 1458 controls) from two different Spanish cohorts, we found that in women rs6622139 T/C was associated with MS susceptibility: [χ2; p = 0.004; OR (95% CI) = 0.50 (0.31-0.81)] and severity, since CC women presented lower MSSS scores than CT (U-Mann-Whitney; p = 0.039) or TT patients (U-Mann-Whitney; p = 0.031). Concordantly with the susceptibility conferred in women, rs6622139*T was associated with higher MSRV expression (U-Mann-Whitney; p = 0.003). CONCLUSIONS Our present work supports the hypothesis of a direct involvement of HERV-W/MSRV in MS pathogenesis, identifying a genetic marker on chromosome X that could be one of the causes underlying the gender differences in MS.Instituto de Salud Carlos III-Fondo Investigaciones Sanitarias FIS (10/01985 and 09/02074), Fundación Genzyme, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, and Fundación LAIR.Ye

Role of the Human Endogenous Retrovirus HERV-K18 in Autoimmune Disease Susceptibility: Study in the Spanish Population and Meta-Analysis

<div><p>Background</p><p>Human endogenous retroviruses (HERVs) are genomic sequences that resulted from ancestral germ-line infections by exogenous retroviruses and therefore are transmitted in a Mendelian fashion. Increased HERV expression and antibodies to HERV antigens have been found in various autoimmune diseases. HERV-K18 in chromosome 1 was previously associated with type one diabetes and multiple sclerosis (MS). The etiology of these complex conditions has not been completely elucidated even after the powerful genome wide association studies (GWAS) performed. Nonetheless, this approach does not scrutinize the repetitive sequences within the genome, and part of the missing heritability could lie behind these sequences. We aimed at evaluating the role of HERV-K18 in chromosome 1 on autoimmune disease susceptibility.</p><p>Methods</p><p>Two HERV-K18 SNPs (97Y/C and 154W/Stop substitutions) conforming three haplotypes were genotyped in Spanish cohorts of multiple sclerosis (n = 942), rheumatoid arthritis (n = 462) and ethnically matched controls (n = 601). Our findings were pooled in a meta-analysis including 5312 autoimmune patients and 4032 controls.</p><p>Results</p><p>Significant associations of both HERV-K18 polymorphisms in chromosome 1 with MS patients stratified by HLA-<i>DRB1*15∶01</i> were observed [97Y/C p = 0.02; OR (95% CI) = 1.5 (1.04–2.17) and 154W/Stop: p = 0.001; OR (95% CI) = 1.6 (1.19–2.16)]. Combined meta-analysis of the previously published association studies of HERV-K18 with different autoimmune diseases, together with data derived from Spanish cohorts, yielded a significant association of the HERV-K18.3 haplotype [97Y–154W: p_M-H = 0.0008; OR_M-H (95% CI) = 1.22 (1.09–1.38)].</p><p>Conclusion</p><p>Association of the HERV-K18.3 haplotype in chromosome 1 with autoimmune-disease susceptibility was confirmed through meta-analysis.</p></div

Evaluation Of The Cases With Intracranial Hypertension

Amaç: Düzce Üniversitesi Araştırma ve Uygulama Hastanesi, Nöroloji kliniğinde İHH tanısı konulmuş hastaların klinik bulgu ve tedavilerinin prognoz ile ilişkilerinin incelenmesi amaçlanmıştır. Gereç ve Yöntem: İİH tanısı ile tedavi ve takip edilen 23 hasta incelendi. Çalışmada Modifiye Dandy Kriterleri esas alındı. Kranial görüntüleme yapılarak, lomber ponksiyonları gerçekleştirildi. Bulgular: İİH tanılı hastaların %78,3'si kadın, %21,7 si erkekti. En sık başvuru nedeni olan baş ağrısına, bulanık görme, bakış kısıtlılığı, geçici görme kaybı, göz ağrısı, çift görme, bulantı, ışıktan rahatsız olma, baş dönmesi ve kulak çınlaması eşlik ediyordu. Hastaların %60.9'u obezdi. Beş hastada papil ödem gözlenmeksizin İİH tanısı saptandı.Empty sella dışında kranial görüntüleme normal sınırlardaydı. Tedavide, asetozolamid, metilprednisolon ve/veya topiramat verildi. Takip süresi 3-6 ay olarak düzenlendi. Bu süreç içinde görme kaybı yaşayan hastamız olmadı. Sonuç: Devamlılık gösteren atipik baş ağrı vakalarında, obezite varsa İİH tanısı düşünülerek ileri tetkik yapılmalıdır. Erken tedavi, olası görme kayıplarını önlemede önem taşımaktadır.Objective: In this study clinical findings of patients, who diagnosed with IIH in Duzce Univesity Research and Teaching Hospital Neurology Clinic were investigated. Materials and Methods: Treatment and follow-up of 23 patients were examined with diagnosis of IIH from the records. The study was based on modified Dandy criteria. The patients who were performed lumbar puncture and were done cranial imaging included in the study. Results: The patients diagnosed with IIH were 78.3% female and 21.7% male. The most common reason for admission was headache and it was accompanied by blurred vision, visual of limitation, temporary loss of vision, eye pain, double vision, nausea, dislike of light, dizziness and tinnitus. 60.9% of the patients were obese. Five patients without papilledema were diagnosed with IIH. The cranial imagings were in normal limits except for empty cella. In treatment, the patients were given acetozolamide, methylprednisolone and/or topiramate. The follow-up period was arranged in 3-6 months. In the process, there were not any patients who had loss of vision. Conclusion: Continuity in atypical cases of headache, if they have obesity, there should be further examination in mind of an IIH diagnosis. Early diagnosis and treatment are import to prevent the possible loss of vision

Role of HERV-K18 haplotypes A) Meta-analysis of case-control studies in different autoimmune disease cohorts; B) Spanish data stratified by HLA susceptibility alleles (<i>DRB1*15∶01</i> in MS and shared epitope in RA).

<p>Role of HERV-K18 haplotypes A) Meta-analysis of case-control studies in different autoimmune disease cohorts; B) Spanish data stratified by HLA susceptibility alleles (<i>DRB1*15∶01</i> in MS and shared epitope in RA).</p

Strategy used for the selection of studies finally included in the meta-analysis.

<p>Strategy used for the selection of studies finally included in the meta-analysis.</p

Genotypic frequencies of polymorphisms within the HERV-K18 sequence in autoimmune disease Spanish patients and controls.

1<p>GG vs AG+AA: MS 1501⁺ vs 1501⁻: p = 0.01; MS 1501⁺ vs. Controls: p = 0.02, OR (95%CI) = 1.50 (1.04–2.17).</p>2<p>GG vs AG+AA: MS 1501⁺ vs 1501⁻: p = 0.0009; MS 1501⁺ vs. Controls: p = 0.001, OR (95%CI) = 1.60 (1.19–2.16).</p

Demographic characteristics of the MS patients included in the study.

<p>Demographic characteristics of the MS patients included in the study.</p