M. Knop

Evidence for VAV2 and ZNF433 as susceptibility genes for multiple sclerosis

In a genome wide association study consisting of 592 German multiple sclerosis (MS) patients and 825 controls we were able to replicate the association of the HLA region with MS independently of previous case control studies. No SNPs outside the HLA region reached a genome wide level of significance. Nevertheless, we found suggestive evidence for an association of MS with variants in two new genes, the VAV2 gene and the gene for ZNF433.

Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine

Chaperone switching at the kinase CDK5 mediates epigenetic effects of antidepressants. Antidepressants chaperone DNA methylation Epigenetic changes are associated with depression. Some depressed patients have increased DNA methylation and decreased expression of the gene encoding BDNF, a secreted factor important for synaptic plasticity. Rein et al. found that some antidepressants inhibit epigenetic changes by causing a switch in chaperone binding to the DNA methyltransferase DNMT1. The chaperones FKBP51 and FKBP52 competed for binding to CDK5, a kinase that activates DNMT1. The authors found that cells from depressed patients or cultured mouse astrocytes exposed to the antidepressant paroxetine favored the FKBP51-CDK5 interaction, resulting in reduced activity of DNMT1 and DNA methylation, and increased the expression of BDNF. These effects of paroxetine on patient blood cells isolated before therapy correlated with a positive clinical response to antidepressants, suggesting that a simple blood test may aid in personalizing treatment for depression. Epigenetic processes, such as DNA methylation, and molecular chaperones, including FK506-binding protein 51 (FKBP51), are independently implicated in stress-related mental disorders and antidepressant drug action. FKBP51 associates with cyclin-dependent kinase 5 (CDK5), which is one of several kinases that phosphorylates and activates DNA methyltransferase 1 (DNMT1). We searched for a functional link between FKBP51 (encoded by FKBP5) and DNMT1 in cells from mice and humans, including those from depressed patients, and found that FKBP51 competed with its close homolog FKBP52 for association with CDK5. In human embryonic kidney (HEK) 293 cells, expression of FKBP51 displaced FKBP52 from CDK5, decreased the interaction of CDK5 with DNMT1, reduced the phosphorylation and enzymatic activity of DNMT1, and diminished global DNA methylation. In mouse embryonic fibroblasts and primary mouse astrocytes, FKBP51 mediated several effects of paroxetine, namely, decreased the protein-protein interactions of DNMT1 with CDK5 and FKBP52, reduced phosphorylation of DNMT1, and decreased the methylation and increased the expression of the gene encoding brain-derived neurotrophic factor (Bdnf). In human peripheral blood cells, FKBP5 expression inversely correlated with both global and BDNF methylation. Peripheral blood cells isolated from depressed patients that were then treated ex vivo with paroxetine revealed that the abundance of BDNF positively correlated and phosphorylated DNMT1 inversely correlated with that of FKBP51 in cells and with clinical treatment success in patients, supporting the relevance of this FKBP51-directed pathway that prevents epigenetic suppression of gene expression.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms already known gene loci. We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

More CLEC16A gene variants associated with multiple sclerosis

Nischwitz S, Cepok S, Kroner A, Wolf C, Knop M, Müller‐Sarnowski F, Pfister H, Rieckmann P, Hemmer B, Ising M, Uhr M, Bettecken T, Holsboer F, Müller‐Myhsok B, Weber F. More CLEC16A gene variants associated with multiple sclerosis.
Acta Neurol Scand: 2011: 123: 400–406.
© 2010 John Wiley & Sons A/S.

Brain Volume and Diffusion Markers as Predictors of Disability and Short-Term Disease Evolution in Multiple Sclerosis

BACKGROUND AND PURPOSE: MRI markers of neuroaxonal damage in MS have emerged as critical long-term predictors of MS-related disability. Here we investigated the potential of whole-brain diffusivity and brain volume for the prediction of cross-sectional disability and short- to medium-term clinical evolution. MATERIALS AND METHODS: In this multimodal prospective longitudinal MRI study of 54 patients with MS (87% under immunomodulatory therapy, baseline and follow-up at a median of 12 months), ADC histogram analysis, WM lesion load, BPF, whole-brain atrophy rate, MSFC score, and EDSS score were obtained. A total of 44 patients with no relapse at both time points were included. RESULTS: At both time points, ADC histogram analysis provided robust predictors of the MSFC scores (maximal R2 = 0.576, P < .001), incorporated cognition and fine-motor skill subscores, and EDSS scores. Significant changes beyond physiologic age-related changes at follow-up were noted for ADC histogram markers and BPF. Stronger diffusivity alterations and brain volume at baseline predicted MSFC decline, as demonstrated by multiple linear regression analysis (mean ADC, R2 = 0.203; P = .003) and lower baseline BPF in patients with declined compared with stable MSFC scores (P = .001). Results were independent of intercurrent relapses. CONCLUSIONS: Diffusion histogram analysis provided stable surrogates of disability in MS and proved sensitive for monitoring disease progression during a median of 12 months. Advanced neuroaxonal pathology at baseline was indicative of an increased risk for sustained progression during a median of 12 months, independent of intercurrent relapses.

Interferon β‐1a reduces increased interleukin‐16 levels in multiple sclerosis patients

There is convergent evidence for an important role of interleukin‐16 (IL‐16) in the pathogenesis of multiple sclerosis (MS). IL‐16 serves as a chemoattractant for different immune cells that are involved in developing lesions. Here, we compared IL‐16 levels of MS patients and controls and addressed the long‐term effect of IFN‐β, the most common immunomodulatory MS therapy, on IL‐16 serum levels in MS patients over 2 years. Beyond this, we analysed the expression of IL‐16 in two CD4+ T‐cell subsets, Th1 and Th17 cells, which are important autoimmune mediators and affected by IFN‐β treatment, derived from myelin‐specific T‐cell transgenic mice.

Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array.

Genome‐wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1‐Chip. Genotype calling was performed with the Illumina Genome StudioTM Genotyping Module, followed by zCall. Single‐nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome‐wide significant associations with MS (P values < 5 × 10−8). These associations have been reported previously. In addition, SNPs in three previously reported regions outside the HLA region yielded P values < 10−5. The effect of nine SNPs in the HLA region remained (P < 10−5) after adjustment for other significant SNPs in the HLA region. All of these findings have been reported before or are driven by known risk loci. In summary, findings from previous GWAS for MS could be successfully replicated. We conclude that the regions identified in previous GWAS are also associated in the German population. This reassures the need for detailed investigations of the functional mechanisms underlying the replicated associations.

USPIO-gestützte Charakterisierung der weißen Substanz bei MS

Die MRT kann durch neuere Sequenztechniken, Kontrastmittel und Analysetechniken zur Aufklärung der pathogenetischen Vorgänge der MS beitragen, die bezüglich Läsionshistopathologie und klinischem Verlauf heterogen sind. Ein wichtiger MRT-Index für den Krankheitsprogress sind wiederholt nachweisbare BlutHirn-Schranken-Störungen, die durch Gd dargestellt werden. Chronische Entzündungsund/oder Reparaturvorgänge können bisher jedoch nur eingeschränkt erfasst werden. USPIO sind eine viel versprechende Technik, um Makrophagen zu kontrastieren. In dieser Studie werden verschiedene Aspekte des USPIO-Aufnahmeverhaltens bei Gd-floriden und -nichtfloriden Patienten untersucht.