The genetic basis of multiple sclerosis: a model for MS susceptibility

<p>Abstact</p> <p>Background</p> <p>MS-pathogenesis is known to involve both multiple environmental events, and several independent genetic risk-factors.</p> <p>Methods</p> <p>A model of susceptibility is developed and a mathematical analysis undertaken to elucidate the nature of genetic susceptibility to MS and to understand the constraints that are placed on the genetic basis of MS, both by the known epidemiological facts of this disease and by the known frequency of the HLA DRB1*1501 allele in the general populations of northern Europe and North America.</p> <p>Results</p> <p>For the large majority of cases (possibly all), MS develops, in part, because an individual is genetically susceptible. Nevertheless, 2.2% or less of the general population is genetically susceptible. Moreover, from the model, the number of susceptibility-loci that need to be in a "susceptible allelic state" to produce MS-susceptibility is small (11-18), whereas the total number of such susceptibility-loci is large (50-200), and their "frequency of susceptibility" is low (i.e., ≤ 0.12). The optimal solution to the model equations (which occurs when 80% of the loci are recessive) predicts the epidemiological data quite closely.</p> <p>Conclusions</p> <p>The model suggests that combinations of only a small number of genetic loci in a "susceptible allelic state" produce MS-susceptibility. Nevertheless, genome-wide associations studies with hundreds of thousands of SNPs, are plagued by both false-positive and false-negative identifications and, consequently, emphasis has been rightly placed on the replicability of findings. Nevertheless, because genome-wide screens don't distinguish between true susceptibility-loci and disease-modifying-loci, and because only true susceptibility-loci are constrained by the model, unraveling the two will not be possible using this approach.</p> <p>The model also suggests that HLA DRB1 may not be as uniquely important for MS-susceptibility as currently believed. Thus, this allele is only one among a hundred or more loci involved in MS susceptibility. Even though the "frequency of susceptibility" at the HLA DRB1 locus is four-fold that of other loci, the penetrance of those susceptible genotypes that include this allele is no different from those that don't. Also, almost 50% of genetically-susceptible individuals, lack this allele. Moreover, of those who have it, only a small fraction (≤ 5.2%) are even susceptible to getting MS.</p

Environmental factors in early childhood are associated with multiple sclerosis: a case-control study

<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with increasing incidence mainly in high-income countries. One explanation of this phenomenon may be a higher prevalence of allergic and autoimmune diseases in industrialized countries as a consequence of otherwise beneficial advances in sanitation (hygiene hypothesis). We investigated environmental factors in early childhood associated with MS.</p> <p>Methods</p> <p>A case-control study was performed of 245 MS patients and 296 population-based controls in Berlin. The study participants completed a standardized questionnaire on environmental factors in childhood and youth, including aspects of personal and community hygiene. Multivariable logistic regression analysis was performed to investigate factors in childhood and youth associated with the occurrence of MS.</p> <p>Results</p> <p>Mean age was 46 years (range, 20-80) in the MS group and 42 years (range 18-80) in the control group, of which 73.9% in the MS and 61.5% in the control group were female. The multivariable analysis showed that having at least two older siblings (OR 0.54; p = 0.05, for individuals with two older siblings compared to individuals without older siblings), attending a day-care center (OR 0.5; p = 0.004) and growing up in an urban center with more than 100, 000 inhabitants (OR 0.43; p = 0.009) were factors independently associated with a lower chance for MS.</p> <p>Conclusions</p> <p>The hygiene hypothesis may play a role in the occurrence of MS and could explain disease distribution and increasing incidence.</p

An extension to a statistical approach for family based association studies provides insights into genetic risk factors for multiple sclerosis in the HLA-DRB1 gene

Background: Multiple sclerosis (MS) is a complex trait in which genes in the MHC class II region exert the single strongest effect on genetic susceptibility. The principal MHC class II haplotype that increases MS risk in individuals of Northern European descent are those that bear HLA-DRB1*15. However, several other HLA-DRB1 alleles have been positively and negatively associated with MS and each of the main allelotypes is composed of many sub-allelotypes with slightly different sequence composition. Given the role of this locus in antigen presentation it has been suggested that variations in the peptide binding site of the allele may underlie allelic variation in disease risk. Methods: In an investigation of 7,333 individuals from 1,352 MS families, we assessed the nucleotide sequence of HLA-DRB1 for any effects on disease susceptibility extending a recently published method of statistical analysis for family-based association studies to the particular challenges of hyper-variable genetic regions. Results: We found that amino acid 60 of the HLA-DRB1 peptide sequence, which had previously been postulated based on structural features, is unlikely to play a major role. Instead, empirical evidence based on sequence information suggests that MS susceptibility arises primarily from amino acid 13. Conclusion: Identifying a single amino acid as a major risk factor provides major practical implications for risk and for the exploration of mechanisms, although the mechanism of amino acid 13 in the HLA-DRB1 sequence's involvement in MS as well as the identity of additional variants on MHC haplotypes that influence risk need to be uncovered

Methylation of class II transactivator gene promoter IV is not associated with susceptibility to Multiple Sclerosis

<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci <it>HLA-DRB1 </it>and <it>HLA-DQB1 </it>contribute significantly to genetic risk. The MHC class II transactivator (<it>MHC2TA</it>) is the master controller of expression of class II genes, and methylation of the promoter of this gene has been previously been shown to alter its function. In this study we sought to assess whether or not methylation of the <it>MHC2TA </it>promoter pIV could contribute to MS disease aetiology.</p> <p>Methods</p> <p>In DNA from peripheral blood mononuclear cells from a sample of 50 monozygotic disease discordant MS twins the <it>MHC2TA </it>promoter IV was sequenced and analysed by methylation specific PCR.</p> <p>Results</p> <p>No methylation or sequence variation of the <it>MHC2TA </it>promoter pIV was found.</p> <p>Conclusion</p> <p>The results of this study cannot support the notion that methylation of the pIV promoter of <it>MHC2TA </it>contributes to MS disease risk, although tissue and timing specific epigenetic modifications cannot be ruled out.</p

Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D

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

The Causal Cascade to Multiple Sclerosis: A Model for MS Pathogenesis

BACKGROUND: MS pathogenesis seems to involve both genetic susceptibility and environmental risk factors. Three sequential factors are implicated in the environmental risk. The first acts near birth, the second acts during childhood, and the third acts long thereafter. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem well suited to the first two environmental events. METHODOLOGY/PRINCIPAL FINDINGS: A mathematical Model for MS pathogenesis is developed, incorporating these environmental and genetic factors into a causal scheme that can explain some of the recent changes in MS-epidemiology (e.g., increasing disease prevalence, a changing sex-ratio, and regional variations in monozygotic twin concordance rates). CONCLUSIONS/SIGNIFICANCE: This Model suggests that genetic susceptibility is overwhelmingly the most important determinant of MS pathogenesis. Indeed, over 99% of individuals seem genetically incapable of developing MS, regardless of what environmental exposures they experience. Nevertheless, the contribution of specific genes to MS-susceptibility seems only modest. Thus, despite HLA DRB1*1501 being the most consistently identified genetic marker of MS-susceptibility (being present in over 50% of northern MS patient populations), only about 1% of individuals with this allele are even genetically susceptible to getting MS. Moreover, because genetic susceptibility seems so similar throughout North America and Europe, environmental differences principally determine the regional variations in disease characteristics. Additionally, despite 75% of MS-patients being women, men are 60% more likely to be genetically-susceptible than women. Also, men develop MS at lower levels of environmental exposure than women. Nevertheless, women are more responsive to the recent changes in environmental-exposure (whatever these have been). This explains both the changing sex-ratio and the increasing disease prevalence (which has increased by a minimum of 32% in Canada over the past 35 years). As noted, environmental risk seems to result from three sequential components of environmental exposure. The potential importance of this Model for MS pathogenesis is that, if correct, a therapeutic strategy, designed to interrupt one or more of these sequential factors, has the potential to markedly reduce or eliminate disease prevalence in the future

Genotypes at the APOE and SCA2 loci do not predict the course of multiple sclerosis in patients of Portuguese origin

Prova tipográfica (In Press)Multiple sclerosis (MS) is a demyelinating disease that affects about one in 500 young Europeans. In order to test the previously proposed influence of the APOE and SCA2 loci on susceptibility to MS, we studied these loci in 243 Portuguese patients and 192 healthy controls and both parents of 92 patients. We did not detect any significant difference when APOE and SCA2 allele frequencies of cases and controls were compared, or when we compared cases with different forms of the disease. Disequilibrium of transmission was tested for both loci in the 92 trios, and we did not observe segregation distortion. To test the influence of the APOE o4 and SCA2 22 CAGs alleles on severity of disease, we compared age at onset and progression rate between groups with and without those alleles. We did not observe an association of the o4 or the 22 CAGs alleles with rate of progression in our total patient population; allele o4 was associated with increased rate of progression of MS in a subset of patients with less than 10 years of the disease. However, globally in the Portuguese population, the APOE and SCA2 genes do not seem to be useful in the clinical context as prognostic markers of this disorder.Fundação para a Ciência e a Tecnologia (FCT) - grant SFRH/BD/9111/2002.Serono Portugal

The size of the treatment effect: do patients and proxies agree?

Background: This study examined whether MS patients and proxy respondents agreed on change in disease impact, which was induced by treatment. This may be of interest in situations when patients suffer from limitations that interfere with reliable self-assessment, such as cognitive impairment.Methods: MS patients and proxies completed the Multiple Sclerosis Impact Scale (MSIS-29) before and after intravenous steroid treatment. Analyses focused on patient-proxy agreement between MSIS-29 change scores. Transition ratings were used to measure the patient's judgement of change and whether this change was reflected in the MSIS-29 change of patients and proxies. Receiver operating characteristic (ROC) analyses were also performed to examine the diagnostic properties of the MSIS-29 when completed by patients and proxies.Results: 42 patients and proxy respondents completed the MSIS-29 at baseline and follow-up. Patient-proxy differences between change scores on the physical and psychological MSIS-29 subscale were quite small, although large variability was found. The direction of mean change was in concordance with the transition ratings of the patients. Results of the ROC analyses of the MSIS-29 were similar when completed by patients (physical scale: AUC = 0.79, 95% CI: 0.65 - 0.93 and 0.66, 95% CI: 0.48 - 0.84 for the psychological scale) and proxies (physical scale: 0.80, 95% CI: 0.72 - 0.96 and 0.71, 95% CI: 0.56 - 0.87 for the psychological scale)Conclusion: Although the results need to be further explored in larger samples, these results do point towards possible use of proxy respondents to assess patient perceived treatment change at the group level

Prevalence and psychopathological characteristics of depression in consecutive otorhinolaryngologic inpatients

<p>Abstract</p> <p>Background</p> <p>High prevalence of depression has been reported in otorhinolaryngologic patients (ORL). However, studies using a semi-structured interview to determine the prevalence of depression in ORL are lacking. Therefore the present study sought to determine the depression prevalence in ORL applying a semi-structured diagnostic interview and to further characterize the pathopsychological and demographic characteristics of depression in these patients.</p> <p>Methods</p> <p>One-hundred inpatients of the otorhinolaryngologic department of a German university hospital participated voluntarily (age M = 38.8 years, SD = 13.9; 38.0% female). Depression was assessed using a clinical interview in which the International Diagnostic Checklist for depression (IDCL) was applied. Patients completed the Brief Symptom Inventory (BSI) which constitutes three composite scores and nine symptom scales and the Beck Depression Inventory (BDI). Multivariate analyses of variance, correlations and effect sizes were conducted.</p> <p>Results</p> <p>A prevalence of depression of 21.0% was determined, 38.0% of the depressed patients were female. Depressed patients showed higher scores on the BSI-scales "interpersonal sensitivity", "depression", "anxiety", "phobic anxiety" and "psychoticism" with medium effect sizes.</p> <p>Conclusions</p> <p>High prevalence of depression was found which is in accordance with results of prior studies. Depressed patients showed higher psychological distress as compared to non-depressed patients. The results call for carrying on in engaging in depression research and routine depression screening in ORL.</p