Somatic variants are variations in an individual's genome acquired after the zygotic stadium and result from mitotic errors or not (fully) repaired DNA damage.
To investigate whether somatic ...mosaicism in T lymphocyte subsets is enriched early in multiple sclerosis (MS).
We identified somatic variants with variant allele fractions ≥1% across the whole exome in CD4
and CD8
T lymphocytes of 21 treatment-naive MS patients with <5 years of disease duration and 16 partially age-matched healthy controls. We investigated the known somatic
variant p.Y640F in peripheral blood in a larger cohort of 446 MS patients and 259 controls.
All subjects carried 1-142 variants in CD4
or CD8
T lymphocytes. Variants were more common, more abundant, and increased with age in CD8
T lymphocytes. Somatic variants were common in the genes
and especially
. Overall, the presence or abundance of somatic variants, including the
p.Y640F variant, did not differ between MS patients and controls.
Somatic variation in T lymphocyte subsets is widespread in both control individuals and MS patients. Somatic mosaicism in T lymphocyte subsets is not enriched in early MS and thus unlikely to contribute to MS risk, but future research needs to address whether a subset of variants influences disease susceptibility.
We explored whether genetically predicted increased body mass index (BMI) modulates multiple sclerosis (MS) risk through interleukin-6 (IL-6) signaling.
We performed a two-sample Mendelian ...randomization (MR) study using multiple genome-wide association studies (GWAS) datasets for BMI, IL-6 signaling, IL-6 levels and c-reactive protein (CRP) levels as exposures and estimated their effects on risk of MS from GWAS data from the International Multiple Sclerosis Genetics Consortium (IMSGC) in 14,802 MS cases and 26,703 controls.
In univariable MR analyses, genetically predicted increased BMI and IL-6 signaling were associated with higher risk of MS (BMI: odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.15-1.47,
= 3.76 × 10
; IL-6 signaling: OR = 1.51, 95% CI = 1.11-2.04,
= 0.01). Furthermore, higher BMI was associated with increased IL-6 signaling (β = 0.37, 95% CI = 0.32,0.41,
= 1.58 × 10
). In multivariable MR analyses, the effect of IL-6 signaling on MS risk remained after adjusting for BMI (OR = 1.36, 95% CI = 1.11-1.68,
= 0.003) and higher BMI remained associated with an increased risk for MS after adjustment for IL-6 signaling (OR = 1.16, 95% CI =1.00-1.34,
= 0.046). The proportion of the effect of BMI on MS mediated by IL-6 signaling corresponded to 43% (95% CI = 25%-54%). In contrast to IL-6 signaling, there was little evidence for an effect of serum IL-6 levels or CRP levels on risk of MS.
In this study, we identified IL-6 signaling as a major mediator of the association between BMI and risk of MS. Further explorations of pathways underlying the association between BMI and MS are required and will, together with our findings, improve the understanding of MS biology and potentially lead to improved opportunities for targeted prevention strategies.
Magnetization transfer ratio (MTR) and brain volumetric imaging are (semi-)quantitative MRI markers capturing demyelination, axonal degeneration and/or inflammation. However, factors shaping ...variation in these traits are largely unknown. In this study, we collected a longitudinal cohort of 33 multiple sclerosis (MS) patients and extended it cross-sectionally to 213. We measured MTR in lesions, normal-appearing white matter (NAWM), normal-appearing grey matter (NAGM) and total brain, grey matter, white matter and lesion volume. We also calculated the polygenic MS risk score. Longitudinally, inter-patient differences at inclusion and intra-patient changes during follow-up together explained > 70% of variance in MRI, with inter-patient differences at inclusion being the predominant source of variance. Cross-sectionally, we observed a moderate correlation of MTR between NAGM and NAWM and, less pronounced, with lesions. Age and gender explained about 30% of variance in total brain and grey matter volume. However, they contributed less than 10% to variance in MTR measures. There were no significant associations between MRI traits and the genetic risk score. In conclusion, (semi-)quantitative MRI traits change with ongoing disease activity but this change is modest in comparison to pre-existing inter-patient differences. These traits reflect individual variation in biological processes, which appear different from those involved in genetic MS susceptibility.
Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple ...strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.
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•Almost 20% of MS risk heritability can be attributed to common genetic variants•We show that nearly 5% of heritability is explained by coding low-frequency variants•We identify four novel genes driving risk independently of common-variant signals•These genes would not have been found by common-variant studies
In a large multi-cohort study, unexplained heritability for multiple sclerosis is detected in low-frequency coding variants that are missed by GWAS analyses, further underscoring the role of immune genes in MS pathology.
Background:
In contrast to successes for multiple sclerosis (MS) susceptibility, the genetic basis for clinical heterogeneity remains largely unresolved.
Objectives:
We investigate the first reported ...genetic association with relapse rate.
Methods:
We genotyped variant rs12988804 in LRP2 in a homogeneous study population of 527 Belgian MS patients with 970 documented relapses.
Results:
The rs12988804*T allele is associated with a 1.16-fold increased hazard rate for a relapse occurring (P = 0.0078) and a higher baseline relapse rate prior to immunomodulatory treatment (P = 0.044).
Conclusion:
Variant rs12988804 in LRP2, the first example of a genome-wide significant association with relapse rate in MS, is replicated in an independent study.
Although fingolimod and interferon-β are two mechanistically different multiple sclerosis (MS) treatments, they both induce B cell activating factor (BAFF) and shift the B cell pool towards a ...regulatory phenotype. However, whether there is a shared mechanism between both treatments in how they influence the B cell compartment remains elusive. In this study, we collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-β, 29 fingolimod) and determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an
in vitro
B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-β treated patients including measurement of intracellular IL-10 levels. Our flow experiments showed that interferon-β and fingolimod induced BAFF protein and mRNA expression (P ≤ 3.15 x 10
-4
) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P = 5.70 x 10
-6
), decrease in switched B cells (P = 3.29 x 10
-4
), and reduction in B cell-surface BAFF-R expression (P = 2.70 x 10
-10
), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and
in vitro
experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels. In conclusion, treatment-induced BAFF correlates with a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.
role of the CD58 locus in multiple sclerosis De Jager, Philip L; Baecher-Allan, Clare; Maier, Lisa M ...
Proceedings of the National Academy of Sciences - PNAS,
03/2009, Letnik:
106, Številka:
13
Journal Article
Recenzirano
Odprti dostop
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system associated with demyelination and axonal loss. A whole genome association scan suggested that allelic variants in the ...CD58 gene region, encoding the costimulatory molecule LFA-3, are associated with risk of developing MS. We now report additional genetic evidence, as well as resequencing and fine mapping of the CD58 locus in patients with MS and control subjects. These efforts identify a CD58 variant that provides further evidence of association with MS (P = 1.1 x 10⁻⁶, OR 0.82) and the single protective effect within the CD58 locus is captured by the rs2300747G allele. This protective rs2300747G allele is associated with a dose-dependent increase in CD58 mRNA expression in lymphoblastic cell lines (P = 1.1 x 10⁻¹⁰) and in peripheral blood mononuclear cells from MS subjects (P = 0.0037). This protective effect of enhanced CD58 expression on circulating mononuclear cells in patients with MS is supported by finding that CD58 mRNA expression is higher in MS subjects during clinical remission. Functional investigations suggest a potential mechanism whereby increases in CD58 expression, mediated by the protective allele, up-regulate the expression of transcription factor FoxP3 through engagement of the CD58 receptor, CD2, leading to the enhanced function of CD4⁺CD25high regulatory T cells that are defective in subjects with MS.
We report a 29-year-old woman with acute supratentorial hydrocephalus due to intraventricular neurocysticercosis (NC). Aqueductal stenosis due to web formation and a free floating intraventricular ...cyst with scolex were pathognomonic and led to the diagnosis of NC. Worldwide, NC is the most important parasitic infection of the central nervous system but is very uncommon in non-endemic regions. Intraventricular abnormalities occur in approximately 30% of the patients. Magnetic resonance imaging (MRI) plays a crucial role in the diagnostic work-up and in guiding intervention.
Brain magnetic resonance imaging in intraventricular neurocysticercosis is pathognomonic and essential in guiding treatment.
Multiple sclerosis (MS) is a complex disease with both genetic variants and environmental factors involved in disease susceptibility. The main environmental risk factors associated with MS in ...observational studies include obesity, vitamin D deficiency, Epstein-Barr virus infection and smoking. As modifying these environmental and lifestyle factors may enable prevention, it is important to pinpoint causal links between these factors and MS. Leveraging genetics through the Mendelian randomization (MR) paradigm is an elegant way to inform prevention strategies in MS. In this review, we summarize MR studies regarding the impact of environmental factors on MS susceptibility, thereby paying attention to quality criteria which will aid readers in interpreting any MR studies. We draw parallels and differences with observational studies and randomized controlled trials and look forward to the challenges that such work presents going forward.
The matrix metalloproteinases (MMPs) form an enzyme family of which gelatinase B (MMP-9) represents the largest and most complex member. We focus here on the biochemical properties, regulation, and ...functions of gelatinase B. The tight regulation of gelatinase B activity is highly complex and is established at five different levels. The transcription of the gelatinase B-gene depends on various cis-elements in its gene promotor and is induced or repressed by a large variety of soluble factors, including cytokines, growth factors, and hormones and by cellular contacts acting through specific signaling pathways. The specific regulation of its secretion occurs in cells storing gelatinase B in granules. After secretion, progelatinase B must be activated through an activation network. The enzyme activity is further regulated by inhibition and by other mechanisms, such as fine-tuning and stabilization by glycosylation. The ability of gelatinase B to degrade components of the extracellular matrix and to regulate the activity of a number of soluble proteins confers an important role in various physiological and pathological processes. These include reproduction, growth, development, inflammation, and vascular and proliferative diseases.
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