61 research outputs found
Integrated Genomics of Crohn's Disease Risk Variant Identifies a Role for CLEC12A in Antibacterial Autophagy
No full textCopyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Acknowledgments We thank Mathieu Platteel (UMCG) for microarray experiments and Natalia Nedelsky for editorial assistance. R.J.X. was supported by the Leona M. and Harry B. Helmsley Charitable Trust, the Crohn’s and Colitis Foundation of America, and grants AI109725 and DK097485 from the NIH. C.W. is supported by funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Advanced grant agreement 2012-322698). M.G.N was supported by an ERC Consolidator Grant (no. 310372). G.D.B. was supported by the Wellcome Trust. H.B.J. was supported by a clinical fellowship from Alberta Innovates-Health Solutions (AIHS), Alberta, Canada.Peer reviewe
Teachers of mother-tongue education in action: Teachers designing concept-context-enriched education in an action-research setting.
No full textIn this paper we report on the first year of a two year action-research project in the Netherlands. Fourteen teachers of mother-tongue education worked together to design concept-contextenriched education. Three teachers of higher vocational education with knowledge of action research facilitated the project and an academic researcher from the university (first author of this paper) researched the implementation of this action-research project as the teachers were experiencing it. This paper reports on the knowledge the teachers developed, the materials they produced, and the mothertongue (or L1 concepts and contexts) they applied during the first ten months of the project. With this paper we wish to contribute to the knowledge on how in-service action-research projects develop and elaborate on what lessons may be learned from the first year of an action-research project in which teachers design concept-context enriched education
Teachers of mother-tongue education in action
No full textIn this paper we report on the first year of a two year action-research project in the Netherlands. Fourteen teachers of mother-tongue education worked together to design concept-contextenriched education. Three teachers of higher vocational education with knowledge of action research facilitated the project and an academic researcher from the university (first author of this paper) researched the implementation of this action-research project as the teachers were experiencing it. This paper reports on the knowledge the teachers developed, the materials they produced, and the mothertongue (or L1 concepts and contexts) they applied during the first ten months of the project. With this paper we wish to contribute to the knowledge on how in-service action-research projects develop and elaborate on what lessons may be learned from the first year of an action-research project in which teachers design concept-context enriched education. Teaching and Teacher Learning (ICLON
Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex Phenotype Converge on Intermediate Genes, with a Major Role for the HLA
No full textThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Identification of a novel PROS1 c.1113T -> GG frameshift mutation in a family with mixed type I/type III protein S deficiency
No full textWe report a family with type I and type III protein S (PS) deficiency, which showed to be phenotypic variants of the same genetic disease. Direct sequencing analysis of the PROS1 gene was performed to establish the genotype. The ratio of protein C antigen and total PS antigen levels (protein C/S ratio) was used to classify subjects at risk of venous thromboembolism. All PS deficient subjects had increased protein C/S ratios as well as a novel PROS4 c.1113T -> GG frameshift mutation.</p
Identification of a novel PROS1 c.1113T -> GG frameshift mutation in a family with mixed type I/type III protein S deficiency
No full textWe report a family with type I and type III protein S (PS) deficiency, which showed to be phenotypic variants of the same genetic disease. Direct sequencing analysis of the PROS1 gene was performed to establish the genotype. The ratio of protein C antigen and total PS antigen levels (protein C/S ratio) was used to classify subjects at risk of venous thromboembolism. All PS deficient subjects had increased protein C/S ratios as well as a novel PROS4 c.1113T -> GG frameshift mutation
PROS1 analysis in 87 pedigrees with hereditary protein S deficiency demonstrates striking genotype-phenotype associations
No full textHereditary protein S (PS) deficiency predisposes to venous thrombosis. Previously, we demonstrated a difference in risk of venous thrombosis between PS deficiency type I and type III. We used direct sequencing, multiplex ligation-dependent probe amplification (MLPA), and linkage analysis to study whether this difference could be explained by molecular heterogeneity. The study contained two sets of families with PS deficiency type I (cohort 1; 35 probands, 155 relatives) or type III (cohort 2; 52 probands, 241 relatives). In cohort 1, a mixed type I/type III PS-deficient phenotype was observed in 66% of the pedigrees. A total of 34 probands carried a mutant PROS1 allele, compared to one proband in cohort 2 (P <10(-10)). The proband's mutation was identified in all type I, but only in 57% of type III PS deficient relatives. MLPA-analysis in the mutation negative families did not reveal PROS1 deletions or insertions. Linkage analysis in 16 families showed cosegregation of PROS1 markers in the family with type I deficiency, but not in the 15 families with type III deficiency. The genotype-phenotype associations point to differences in genetic architecture. Whereas PS deficiency type I is a monogenic disease due to PROS1 allelic heterozygosity, PS deficiency type III is most likely a more complex or heterogeneous disorder
Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant
No full textUsing the Immunochip for genotyping, we identified 39 non-human leukocyte antigen (non-HLA) loci associated to celiac disease (CeD), an immune-mediated disease with a worldwide frequency of 1. The most significant non-HLA signal mapped to the intronic region of 70 kb in the LPP gene. Our aim was to fine map and identify possible functional variants in the LPP locus. We performed a meta-analysis in a cohort of 25 169 individuals from six different populations previously genotyped using Immunochip. Imputation using data from the Genome of the Netherlands and 1000 Genomes projects, followed by meta-analysis, confirmed the strong association signal on the LPP locus (rs2030519, P 1.79 10(49)), without any novel associations. The conditional analysis on this top SNP-indicated association to a single common haplotype. By performing haplotype analyses in each population separately, as well as in a combined group of the four populations that reach the significant threshold after correction (P 0.008), we narrowed down the CeD-associated region from 70 to 2.8 kb (P 1.35 10(44)). By intersecting regulatory data from the ENCODE project, we found a functional SNP, rs4686484 (P 3.12 10(49)), that maps to several B-cell enhancer elements and a highly conserved region. This SNP was also predicted to change the binding motif of the transcription factors IRF4, IRF11, Nkx2.7 and Nkx2.9, suggesting its role in transcriptional regulation. We later found significantly low levels of LPP mRNA in CeD biopsies compared with controls, thus our results suggest that rs4686484 is the functional variant in this locus, while LPP expression is decreased in CeD
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