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4 mai 2011 3 04 /05 /mai /2011 09:16

Sclérose en plaques et virus Epstein-Barr (EBV)

 

L'infection à virus Epstein-Barr (EBV), responsable de mononucléose infectieuse, semble interagir avec le niveau d'exposition aux UVB dans le risque de survenue d'une sclérose en plaques, suggère une étude anglaise publiée dans Neurology.

La sclérose en plaques (SEP) semble se développer chez des sujets présentant des facteurs de susceptibilité génétique, en interaction avec des facteurs de l'environnement.

Cette hypothèse du rôle de facteurs environnementaux est appuyée par la distribution géographique de la maladie, avec un gradient Nord-Sud assez prononcé.

Un autre facteur environnemental potentiel dans la SEP est l'infection à virus Epstein-Barr (EBV), qui peut provoquer une mononucléose infectieuse : le risque de SEP semble accru chez les sujets infectés.

Une équipe du Wellcome Trust Centre for Human Genetics, à l'université d'Oxford (Royaume-Uni), a examiné la distribution de la SEP et celle de la mononucléose infectieuse, en regard de l'exposition aux UVB à travers le Royaume-Uni. Pour cela, les auteurs ont analysé, dans les bases de données des hôpitaux du National Health Service (NHS), les dossiers de 56 681 cas de SEP et de 14 621 cas de mononucléose infectieuse sur sept ans. Ils ont aussi étudié les données de la NASA sur l’intensité des UVB sur l'Angleterre.

Résultats, publiés dans Neurology : la SEP est fortement corrélée à la fois à la latitude et à la mononucléose infectieuse. Et le lien entre SEP et UVB, quelle que soit la saison, est plus fort que le lien entre SEP et mononucléose infectieuse.

La régression linéaire multivariée suggère que l'exposition aux UVB seule pourrait expliquer 61% de la variation de la prévalence de la SEP à travers l'Angleterre. Lorsque l'exposition aux UVB et la mononucléose infectieuse sont associées, elles pourraient expliquer 72% de cette variation.

Les chercheurs émettent l’hypothèse qu’une exposition plus faible aux UVB réduirait la synthèse cutanée de vitamine D, ce qui perturberait la réponse du système immunitaire à l'EBV et favoriserait la survenue d'une mononucléose infectieuse. Des études supplémentaires sont nécessaires pour examiner le lien entre vitamine D, mononucléose infectieuse et SEP.

L'infection à virus Epstein-Barr (EBV), responsable de mononucléose infectieuse, semble interagir avec le niveau d'exposition aux UVB dans le risque de survenue d'une sclérose en plaques, suggère une étude anglaise publiée dans Neurology.

 

La sclérose en plaques (SEP) semble se développer chez des sujets présentant des facteurs de susceptibilité génétique, en interaction avec des facteurs de l'environnement. Cette hypothèse du rôle de facteurs environnementaux est appuyée par la distribution géographique de la maladie, avec un gradient Nord-Sud assez prononcé. Un autre facteur environnemental potentiel dans la SEP est l'infection à virus Epstein-Barr (EBV), qui peut provoquer une mononucléose infectieuse : le risque de SEP semble accru chez les sujets infectés.

Une équipe du Wellcome Trust Centre for Human Genetics, à l'université d'Oxford (Royaume-Uni), a examiné la distribution de la SEP et celle de la mononucléose infectieuse, en regard de l'exposition aux UVB à travers le Royaume-Uni. Pour cela, les auteurs ont analysé, dans les bases de données des hôpitaux du National Health Service (NHS), les dossiers de 56 681 cas de SEP et de 14 621 cas de mononucléose infectieuse sur sept ans. Ils ont aussi étudié les données de la NASA sur l’intensité des UVB sur l'Angleterre.

Résultats, publiés dans Neurology : la SEP est fortement corrélée à la fois à la latitude et à la mononucléose infectieuse. Et le lien entre SEP et UVB, quelle que soit la saison, est plus fort que le lien entre SEP et mononucléose infectieuse.

La régression linéaire multivariée suggère que l'exposition aux UVB seule pourrait expliquer 61% de la variation de la prévalence de la SEP à travers l'Angleterre. Lorsque l'exposition aux UVB et la mononucléose infectieuse sont associées, elles pourraient expliquer 72% de cette variation.

Les chercheurs émettent l’hypothèse qu’une exposition plus faible aux UVB réduirait la synthèse cutanée de vitamine D, ce qui perturberait la réponse du système immunitaire à l'EBV et favoriserait la survenue d'une mononucléose infectieuse. Des études supplémentaires sont nécessaires pour examiner le lien entre vitamine D, mononucléose infectieuse et SEP.

 

J Neurol Neurosurg Psychiatry. 2011 Jan 6. [Epub ahead of print]

Geography of hospital admissions for multiple sclerosis in England and comparison with the geography of hospital admissions for infectious mononucleosis: a descriptive study.

Ramagopalan SV, Hoang U, Seagroatt V, Handel A, Ebers GC, Giovannoni G, Goldacre MJ.

Source

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

 

Objective It is well recognised that variation in the geographical distribution of multiple sclerosis (MS) exists.

Early studies in England have shown the disease to have been more common in the North than the South.

However, this could be an artefact of inaccurate diagnosis and ascertainment, and recent data on MS prevalence are lacking.

In the present study, data were analysed to provide a more contemporary map of the distribution of MS in England and, as infectious mononucleosis (IM) has been shown to be associated with the risk of MS, the geographical distribution of IM with that of MS was compared.

Methods Analysis of linked statistical abstracts of hospital data for England between 1999 and 2005. Results There were 56 681 MS patients. The admission rate for MS was higher in females (22/10(5); 95% CI 21.8 to 22.3) than males (10.4/10(5); 95% CI 10.2 to 10.5). The highest admission rate for MS was seen for residents of Cumbria and Lancashire (North of England) (20.1/10(5); 95% CI 19.3 to 20.8) and the lowest admission rate was for North West London residents (South of England) (12.4/10(5); 95% CI 11.8 to 13.1). The geographical distributions of IM and MS were significantly correlated (weighted regression coefficient (r (w))=0.70, p<0.0001). Admission rates for MS were lowest in the area quintile with the highest level of deprivation and they were also lowest in the area quintile with the highest percentage of population born outside the UK. A significant association between northernliness and MS remained after adjustment for deprivation and UK birthplace.

 

Conclusions

The results show the continued existence of a latitude gradient for MS in England and show a correlation with the distribution of IM.

The data have implications for healthcare provision, because lifetime costs of MS exceed £1 million per case in the UK, as well as for studies of disease causality and prevention.

 

PMID: 21212107 [PubMed - as supplied by publisher]

 

 

 

PLoS One. 2011 Jan 27;6(1):e14606.

The epidemiology of multiple sclerosis in Scotland: inferences from hospital admissions.

Handel AE, Jarvis L, McLaughlin R, Fries A, Ebers GC, Ramagopalan SV.

Source

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

 

BACKGROUND:

Multiple sclerosis (MS) is a neurological disorder with a highly characteristic disease distribution. Prevalence and incidence in general increase with increasing distance from the equator. Similarly the female to male sex ratio increases with increasing latitude. Multiple possible risk factors have been hypothesised for this epidemiological trend, including human leukocyte antigen allele frequencies, ultraviolet exposure and subsequent vitamin D levels, smoking and Epstein-Barr virus. In this study we undertook a study of medical records across Scotland on an NHS health board level of resolution to examine the epidemiology of MS in this region.

METHODS AND RESULTS:

We calculated the number and rate of patient-linked hospital admissions throughout Scotland between 1997 and 2009 from the Scottish Morbidity Records. We used weighted-regression to examine correlations between these measures of MS, and latitude and smoking prevalence. We found a highly significant relationship between MS patient-linked admissions and latitude (r weighted by standard error (r(sw)) = 0.75, p = 0.002). There was no significant relationship between smoking prevalence and MS patient-linked admissions.

DISCUSSION:

There is a definite latitudinal effect on MS risk across Scotland, arising primarily from an excess of female MS patients at more Northerly latitudes. Whether this is a true gradient or whether a threshold effect may apply at particular latitude will be revealed only by further research. A number of genetic and environmental factors may underlie this effect.

 

Neurology. 2011 Feb 1;76(5):425-31.

Association of UV radiation with multiple sclerosis prevalence and sex ratio in France.

Orton SM, Wald L, Confavreux C, Vukusic S, Krohn JP, Ramagopalan SV, Herrera BM, Sadovnick AD, Ebers GC.

Source

Wellcome Trust Centre for Human Genetics and Department of Clinical Neurology, University of Oxford, Oxford, UK.


BACKGROUND:

French farmers and their families constitute an informative population to study multiple sclerosis (MS) prevalence and related epidemiology. We carried out an ecological study to evaluate the association of MS prevalence and ultraviolet (UV) radiation, a candidate climatologic risk factor.

METHODS:

Mean annual and winter (December-March) UVB irradiation values were systematically compared to MS prevalence rates in corresponding regions of France. UVB data were obtained from the solar radiation database (SoDa) service and prevalence rates from previously published data on 2,667 MS cases registered with the national farmer health insurance system, Mutualité Sociale Agricole (MSA). Pearson correlation was used to examine the relationship of annual and winter UVB values with MS prevalence. Male and female prevalence were also analyzed separately. Linear regression was used to test for interaction of annual and winter UVB with sex in predicting MS prevalence.

RESULTS:

There was a strong association between MS prevalence and annual mean UVB irradiation (r = -0.80, p < 0.001) and average winter UVB (r = -0.87, p < 0.001). Both female (r = -0.76, p < 0.001) and male (r = -0.46, p = 0.032) prevalence rates were correlated with annual UVB. Regression modeling showed that the effect of UVB on prevalence rates differed by sex; the interaction effect was significant for both annual UVB (p = 0.003) and winter UVB (p = 0.002).

CONCLUSIONS:

The findings suggest that regional UVB radiation is predictive of corresponding MS prevalence rates and supports the hypothesis that sunlight exposure influences MS risk.

The evidence also supports a potential role for gender-specific effects of UVB exposure.

PMID: 21282589 [PubMed - indexed for MEDLINE] PMCID: PMC3034408 [Available on 2011/7/26]

 

Neuroepidemiology. 2009;32(4):257-62. Epub 2009 Feb 11.

Association of infectious mononucleosis with multiple sclerosis. A population-based study.

Source

Wellcome Trust Centre for Human Genetics, Oxford, UK.

BACKGROUND:

 

Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Several studies have attempted to correlate exposure to viral illness with the subsequent development of MS. Here in a population-based Canadian cohort, we investigate the relationship between prior clinical infection or vaccination and the risk of MS.

METHODS:

 

Using the longitudinal Canadian database, 14,362 MS index cases and 7,671 spouse controls were asked about history of measles, mumps, rubella, varicella and infectious mononucleosis as well as details about vaccination with measles, mumps, rubella, hepatitis B and influenza vaccines. Comparisons were made between cases and spouse controls.

RESULTS:

 

Spouse controls and stratification by sex appear to correct for ascertainment bias because with a single exception we found no significant differences between cases and controls for all viral exposures and vaccinations. However, 699 cases and 165 controls reported a history of infectious mononucleosis (p < 0.001, corrected odds ratio 2.06, 95% confidence interval 1.71-2.48). Females were more aware of disease history than males (p < 0.001).

CONCLUSIONS:

The data further confirms a reporting distortion between males and females. Historically reported measles, mumps, rubella, varicella and vaccination for hepatitis B, influenza, measles, mumps and rubella are not associated with increased risk of MS later in life.

A clinical history of infectious mononucleosis is conspicuously associated with increased MS susceptibility.

These findings support studies implicating Epstein-Barr virus in MS disease susceptibility, but a co-association between MS susceptibility and clinically apparent infectious mononucleosis cannot be excluded.

PMID:
 
19209005
 
[PubMed - indexed for MEDLINE]

 

Neurol Clin. 2011 May;29(2):207-17.

Epidemiology of multiple sclerosis.

Ramagopalan SV, Sadovnick AD.

Source

The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Department of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Level 3 West Wing, Oxford OX3 9DU, UK.

Multiple sclerosis (MS) is the most common disease of the central nervous system that causes permanent disability in young adults. Based on strong circumstantial evidence, MS is considered to be putative autoimmune disorder, but much remains to be understood about the etiology and clinical onset of the disease. It seems unlikely that MS results from a single causative event, but rather is the result of genetic and environmental factors and the interactions thereof. This articlediscusses the epidemiology of MS.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID: 21439437 [PubMed - in process]

 

J Neurol Sci. 2011 Mar 25. [Epub ahead of print]

Vitamin D metabolic pathway genes and risk of multiple sclerosis in Canadians.

Orton SM, Ramagopalan SV, Para AE, Lincoln MR, Handunnetthi L, Chao MJ, Morahan J, Morrison KM, Sadovnick AD, Ebers GC.

Source

Wellcome Trust Centre for Human Genetics and Department of Clinical Neurology, University of Oxford, Oxford, UK.

 

BACKGROUND:

Multiple sclerosis (MS) is determined by interactions between genes and environment and the influence of vitamin D adequacy has been proposed. Previous studies have shown that serum 25-hydroxyvitaminD (25(OH)D) levels are genetically influenced. Polymorphisms in vitamin D pathway genes are candidates for association with MS susceptibility.

METHODS:

MS patients (n=1364) and their unaffected first-degree relatives (n=1661) were ascertained through the Canadian Collaborative study. Seventy-one SNPs, across four genes [vitamin D receptor (VDR), 1-alpha-hydroxylase (CYP27B1) enzyme, vitamin D binding protein (DBP), 24-hydroxylase (CYP24)], were genotyped and tested for association with MS susceptibility using TDT in PLINK. Secondary analyses included stratification for HLA-DRB1*15 and parent of origin transmission effects.

RESULTS:

We found no significant association of vitamin D pathway genes with MS susceptibility after correction for multiple comparisons. However, the VDR Fok1 variant (rs2228570), selected for previously positive associations with MS susceptibility and 25(OH)D levels in MS patients showed marginally distorted transmission in DRB15-negative patients (p=0.03). There was no evidence for differential maternal versus paternal allele transmission.

CONCLUSIONS:

The findings fail to directly connect vitamin D metabolism genes to MS susceptibility, despite a large sample size and comprehensive gene coverage.

 

Copyright © 2011 Elsevier B.V. All rights reserved.

PMID: 21440908 [PubMed - as supplied by publisher]

 

J Neurol. 2011 Mar;258(3):353-8. Epub 2010 Nov 2.

The emerging role of vitamin D binding protein in multiple sclerosis.

Source

Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7BN, UK.

 

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). A growing body of evidence supports a role for vitamin D in MS aetiology.

Vitamin D binding protein (DBP) is the major plasma carrier of vitamin D metabolites and genetic differences in DBP gene have been found to influence vitamin D levels.

We review here evidence supporting a role of DBP in MS.

Several recent studies show that DBP levels in the cerebrospinal fluid correlate with MS course, being lower during relapses and higher in the secondary progressive phase.

Further studies are needed to elucidate the potential use of DBP as a biological marker of MS course, but may be of use given the current lack of diagnostic tools for the prediction of MS development and progression.

PMID:
 
21042807
 
[PubMed - in process]



Neurology. 2010 Jun 8;74(23):1905-10.

Multiple sclerosis, vitamin D, and HLA-DRB1*15.

Source

Wellcome Trust Centre for Human Genetics and the Department of Clinical Neurology, University of Oxford, Oxford, UK.

 

BACKGROUND:

Multiple sclerosis (MS) has a remarkable geographic distribution inversely paralleling that of regional ultraviolet radiation, supporting the hypothesis that vitamin D plays a central role in the disease etiology.

The major histocompatibility complex exerts the largest genetic contribution to MS susceptibility, but much risk remains unexplained and direct gene-environment interaction is a strong candidate for this additional risk. Such interactions may hold the key for disease prevention.


RECENT DEVELOPMENTS:

 

Several recent studies strengthen the candidacy of vitamin D as a key player in the causal cascade to MS.

This includes a newly identified gene-environment interaction between vitamin D and the main MS-linked HLA-DRB1*1501 allele and evidence showing that vitamin D levels are significantly lower in patients with MS as compared to controls.

Also, a recent study in twins with MS supports the notion that vitamin D levels are under regulation by genetic variation in the 1alpha-hydroxylase and vitamin D receptor genes, perhaps pointing to their importance in the disease pathogenesis.

CONCLUSIONS:

These findings have important practical implications for studies of disease mechanisms and prevention.

Missing genetic risk may partly be explained by gene-environment interactions.

More practically important is that these observations highlight a pressing need to determine if vitamin D supplementation can reduce the risk of multiple sclerosis (MS).

However, the timing of action and the tissues in which this interaction takes place are not clear and future studies in prospective cohorts and animal models will be essential for deciphering the role of vitamin D in MS.


PMID:
 
20530326
 
[PubMed - indexed for MEDLINE] 
PMCID: PMC2882222
 [Available on 2011/6/8]


Eur J Neurol. 2010 Sep;17(9):1210-4. Epub 2010 Mar 22.

Genetic and environmental factors and the distribution of multiple sclerosis in Europe.

Source

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

BACKGROUND:

The observation that the incidence of multiple sclerosis (MS) increases further from the equator has prompted considerable interest in the factors that might underlie this latitude gradient. Potential candidates include population frequencies of disease-associated Human Leukocyte Antigen (HLA) alleles which are the major genetic component of MS susceptibility. Ultraviolet (UV) exposure and smoking have also been implicated as key environmental risk factors.

METHODS:

We used multiple sources of published data on MS prevalence, HLA allele frequencies, UV index and cigarette smoking to assess the contributions of both nature and nurture to the distribution of MS within Europe.

RESULTS:

We observed that HLA alleles unequivocally interact with a population-wide level to determine disease risk. The UV index and smoking behaviour was also shown to correlate with disease distribution in Europe. For countries with HLA, UV and smoking data, these three factors were shown to account for 75% of the variance in MS prevalence.

CONCLUSIONS:

 

Genetic (HLA) and environmental (UV and smoking) risk factors thus interact in a complex manner with each other to determine a large proportion of MS susceptibility within Europe.

PMID:
 
20345929
 
[PubMed - indexed for MEDLINE]
PLoS Genet. 2009 Feb;5(2):e1000369. Epub 2009 Feb 6.

Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D.

Source

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Multiple sclerosis (MS) is a complex trait in which allelic variation in the MHC class II region exerts the single strongest effect on genetic risk. Epidemiological data in MS provide strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of this disease.

Growing evidence implicates sunlight or vitamin D as a key environmental factor in aetiology. We hypothesised that this environmental candidate might interact with inherited factors and sought responsive regulatory elements in the MHC class II region.

Sequence analysis localised a single MHC vitamin D response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among non-MS-associated haplotypes.

Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15.

Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15 gene promoter showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 (P = 0.002) that was lost both on deletion of the VDRE or with the homologous "VDRE" sequence found in non-MS-associated HLA-DRB1 haplotypes.

Flow cytometric analysis showed a specific increase in the cell surface expression of HLA-DRB1 upon addition of vitamin D only in HLA-DRB1*15 bearing lymphoblastoid cells.

This study further implicates vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility.

These findings support a connection between the main epidemiological and genetic features of this disease with major practical implications for studies of disease mechanism and prevention.

 

 


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