Sex and gender issues in multiple sclerosis Harbo, Hanne F.; Gold, Ralf; Tintoré, Mar
Therapeutic advances in neurological disorders,
07/2013, Letnik:
6, Številka:
4
Journal Article
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Multiple sclerosis (MS) is universally found to be more prevalent in women than men. This has led to extensive studies of differences in the immune system or nervous system between women and men, ...which might be caused by the effects of gonadal hormones, genetic differences, and different environmental exposures and modern lifestyle in men and women. We review the effects of sex and gender from a genetic, immunological and clinical point of view. We discuss the effects of sex on the clinical expression of MS and responses to therapy, as well as issues concerning pregnancy.
Multiple sclerosis (MS) is a prevalent inflammatory disease of the central nervous system that often leads to disability in young adults. Treatment options are limited and often only partly ...effective. The disease is likely caused by a complex interaction between multiple genes and environmental factors, leading to inflammatory‐mediated central nervous system deterioration. A series of genomic studies have confirmed a central role for the immune system in the development of MS, including genetic association studies that have now dramatically expanded the roster of MS susceptibility genes beyond the longstanding human leukocyte antigen (HLA) association in MS first identified nearly 40 years ago. Advances in technology together with novel models for collaboration across research groups have enabled the discovery of more than 50 non‐HLA genetic risk factors associated with MS. However, with a large proportion of the disease heritability still unaccounted for, current studies are now geared towards identification of causal alleles, associated pathways, epigenetic mechanisms, and gene–environment interactions. This article reviews recent efforts in addressing the genetics of MS and the challenges posed by an ever increasing amount of analyzable data, which is spearheading development of novel statistical methods necessary to cope with such complexity.
•Brain age CNNs achieve state-of-the-art performance in a large, multisite dataset.•A regression-based architecture outperform others in generalizing to new scanners.•Deviations in brain age ...associate with plausible biological and lifestyle variables.•Encoded representations are better predictors for disorder than the brain age delta.
The discrepancy between chronological age and the apparent age of the brain based on neuroimaging data — the brain age delta — has emerged as a reliable marker of brain health. With an increasing wealth of data, approaches to tackle heterogeneity in data acquisition are vital. To this end, we compiled raw structural magnetic resonance images into one of the largest and most diverse datasets assembled (n=53542), and trained convolutional neural networks (CNNs) to predict age. We achieved state-of-the-art performance on unseen data from unknown scanners (n=2553), and showed that higher brain age delta is associated with diabetes, alcohol intake and smoking. Using transfer learning, the intermediate representations learned by our model complemented and partly outperformed brain age delta in predicting common brain disorders. Our work shows we can achieve generalizable and biologically plausible brain age predictions using CNNs trained on heterogeneous datasets, and transfer them to clinical use cases.
DNA methylation is an epigenetic mark that is influenced by environmental factors and is associated with changes to gene expression and phenotypes. It may link environmental exposures to disease ...etiology or indicate important gene pathways involved in disease pathogenesis. We identified genomic regions that are differentially methylated in T cells of patients with relapsing remitting multiple sclerosis (MS) compared to healthy controls. DNA methylation was assessed at 450,000 genomic sites in CD4+ and CD8+ T cells purified from peripheral blood of 94 women with MS and 94 healthy women, and differentially methylated regions were identified using bumphunter. Differential DNA methylation was observed near four loci: MOG/ZFP57, HLA-DRB1, NINJ2/LOC100049716, and SLFN12. Increased methylation of the first exon of the SLFN12 gene was observed in both T cell subtypes and remained present after restricting analyses to samples from patients who had never been on treatment or had been off treatment for more than 2.5 years. Genes near the regions of differential methylation in T cells were assessed for differential expression in whole blood samples from a separate population of 1,329 women with MS and 97 healthy women. Gene expression of HLA-DRB1, NINJ2, and SLFN12 was observed to be decreased in whole blood in MS patients compared to controls. We conclude that T cells from MS patients display regions of differential DNA methylation compared to controls, and corresponding gene expression differences are observed in whole blood. Two of the genes that showed both methylation and expression differences, NINJ2 and SLFN12, have not previously been implicated in MS. SLFN12 is a particularly compelling target of further research, as this gene is known to be down-regulated during T cell activation and up-regulated by type I interferons (IFNs), which are used to treat MS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Determine whether MS-specific DNA methylation profiles can be identified in whole blood or purified immune cells from untreated MS patients.
Whole blood, CD4+ and CD8+ T cell DNA from 16 female, ...treatment naïve MS patients and 14 matched controls was profiled using the HumanMethylation450K BeadChip. Genotype data were used to assess genetic homogeneity of our sample and to exclude potential SNP-induced DNA methylation measurement errors.
As expected, significant differences between CD4+ T cells, CD8+ T cells and whole blood DNA methylation profiles were observed, regardless of disease status. Strong evidence for hypermethylation of CD8+ T cell, but not CD4+ T cell or whole blood DNA in MS patients compared to controls was observed. Genome-wide significant individual CpG-site DNA methylation differences were not identified. Furthermore, significant differences in gene DNA methylation of 148 established MS-associated risk genes were not observed.
While genome-wide significant DNA methylation differences were not detected for individual CpG-sites, strong evidence for DNA hypermethylation of CD8+ T cells for MS patients was observed, indicating a role for DNA methylation in MS. Further, our results suggest that large DNA methylation differences for CpG-sites tested here do not contribute to MS susceptibility. In particular, large DNA methylation differences for CpG-sites within 148 established MS candidate genes tested in our study cannot explain missing heritability. Larger studies of homogenous MS patients and matched controls are warranted to further elucidate the impact of CD8+ T cell and more subtle DNA methylation changes in MS development and pathogenesis.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, ...including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG.
This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥ 60 years) (OR 2.38, p(c)7.4 × 10(-5)). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, p(c) 4.71 × 10(-4)), a finding not previously described. No significant association was found to the DRB1*07:01 allele (p(nc) = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies.
The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multiple sclerosis (MS) is a complex disease of the central nervous system of unknown etiology. The human leukocyte antigen (HLA) locus on chromosome 6 confers a considerable part of the ...susceptibility to MS, and the most important factor is the class II allele HLA-DRB1*15:01. In addition, we and others have previously established a protective effect of HLA-A*02. Here, we genotyped 1,784 patients and 1,660 healthy controls from Scandinavia for the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes and investigated their effects on MS risk by logistic regression. Several allele groups were found to exert effects independently of DRB1*15 and A*02, in particular DRB1*01 (OR = 0.82, p = 0.034) and B*12 (including B*44/45, OR = 0.76, p = 0.0028), confirming previous reports. Furthermore, we observed interaction between allele groups: DRB1*15 and DRB1*01 (multiplicative: OR = 0.54, p = 0.0041; additive: AP = 0.47, p = 4 × 10(-06)), DRB1*15 and C*12 (multiplicative: OR = 0.37, p = 0.00035; additive: AP = 0.58, p = 2.6 × 10(-05)), indicating that the effect size of these allele groups varies when taking DRB1*15 into account. Analysis of inferred haplotypes showed that almost all DRB1*15 bearing haplotypes were risk haplotypes, and that all A*02 bearing haplotypes were protective as long as they did not carry DRB1*15. In contrast, we found one class I haplotype, carrying A*02-C*05-B*12, which abolished the risk of DRB1*15. In conclusion, these results confirms a complex role of HLA class I and II genes that goes beyond DRB1*15 and A*02, in particular by including all three classical HLA class I genes as well as functional interactions between DRB1*15 and several alleles of DRB1 and class I genes.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Changes is lymphocyte subpopulations in peripheral blood have been proposed as biomarkers for evaluation of disease activity in multiple sclerosis (MS). Serum neurofilament light chain (sNfL) is a ...biomarker reflecting neuro-axonal injury in MS that could be used to monitor disease activity, response to drugs and to prognosticate disease course. Here we show a moderate correlation between sNfL and lymphocyte cell subpopulations, and our data furthermore suggest that sNfL and specific immune cell subpopulations together could predict future disease worsening in MS.
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•Serum NfL concentration and frequencies of immune cell subpopulations such as CD4+ T cells and Th1 cells, are positively correlated in MS patients.•Serum NfL concentration and frequencies of immune-regulatory cells, such as regulatory NK cells and B-regulatory cells, are negatively correlated in MS patients.•The concentration of sNfL is associated with increased risk of MS disease worsening.•Combining sNfL with circulating immune cell subset frequencies could be a better predictor for disease worsening than one parameter alone.
New treatment options may make "no evidence of disease activity" (NEDA: no relapses or disability progression and no new/enlarging MRI lesions, as opposed to "evidence of disease activity" (EDA) with ...at least one of the former), an achievable goal in relapsing-remitting multiple sclerosis (RRMS). The objective of the present study was to determine whether early RRMS patients with EDA at one-year follow-up had different disability, cognition, treatment and gray matter (GM) atrophy rates from NEDA patients and healthy controls (HC). RRMS patients (mean age 34 years, mean disease duration 2.2 years) were examined at baseline and one-year follow-up with neurological (n = 72), neuropsychological (n = 56) and structural MRI (n = 57) examinations. Matched HC (n = 61) were retested after three years. EDA was found in 46% of RRMS patients at follow-up. EDA patients used more first line and less second line disease modifying treatment than NEDA (p = 0.004). While the patients groups had similar disability levels at baseline, they differed in disability at follow-up (p = 0.010); EDA patients progressed (EDSS: 1.8-2.2, p = 0.010), while NEDA patients improved (EDSS: 2.0-1.7, p<0.001). Cognitive function was stable in both patient groups. Subcortical GM atrophy rates were higher in EDA patients than HC (p<0.001). These results support the relevance of NEDA as outcome in RRMS and indicate that pathological neurodegeneration in RRMS mainly occur in patients with evidence of disease activity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective:
The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG).
Methods:
We have carried out a 2‐stage genome‐wide association study on ...a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region.
Results:
We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 × 10−92; odds ratio OR, 6.25). By imputation and conditional analyses, HLA‐B*08 proves to be the major associated allele (p = 2.87 × 10−113; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 × 10−10), an imputed coding variant (rs2233290) at position 151 (Pro→Ala) in the TNFAIP3‐interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 × 10−10).
Interpretation:
The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin‐dependent dysregulation of NF‐κB signaling. The localization of the major HLA signal to the HLA‐B*08 allele suggests that CD8+ T cells may play a key role in disease initiation or pathogenesis. ANN NEUROL 2012;
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