Martine J van Belzen

Publications (8)67.83 Total impact

• Article: Parent-of-origin differences of mutant HTT CAG repeat instability in Huntington's disease.

  N Ahmad Aziz, Martine J van Belzen, Ilona D Coops, René D M Belfroid, Raymund A C Roos
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  ABSTRACT: Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). The CAG domain of mutant HTT is unstable upon intergenerational transmission, however, little is known about the underlying mechanisms. From the HD archives of the Leiden University Medical Centre DNA samples from all parent-offspring pairs involving 36 CAG repeats or more were selected. To minimize procedural variability, CAG repeat lengths in both mutant and normal HTT were reassessed using the same standardized protocol, which resulted in the identification of 337 parent-offspring transmissions. The effects of both parental (mutant and normal CAG repeat size, age and gender) and offspring (gender and season of conception) characteristics on CAG repeat instability were assessed. Paternal transmissions were often associated with CAG repeat expansion, whereas maternal transmissions mainly resulted in CAG repeat contraction (mean change: +1.76 vs. -0.07, p<0.001). Only in paternal transmissions larger mutant CAG repeat size was associated with a greater degree of CAG repeat expansion (β=0.73; p<0.001). Conversely, only in maternal transmissions larger CAG repeat size of the normal allele was associated with a greater degree of CAG repeat contraction (β=-0.07; p=0.029). Parental age, offspring gender and season of conception were not related to CAG repeat instability. Our findings suggest a slight maternal contraction bias as opposed to a paternal expansion bias of the mutant HTT CAG repeat during intergenerational transmission, which only in the maternal line is associated with normal HTT CAG repeat size.
  European journal of medical genetics 04/2011; 54(4):e413-8. · 1.57 Impact Factor
• Source

  Available from: Erica van Oort

  Article: Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect.

  Alienke J Monsuur, Paul I W de Bakker, Behrooz Z Alizadeh, Alexandra Zhernakova, Marianna R Bevova, Eric Strengman, Lude Franke, Ruben van't Slot, Martine J van Belzen, Ineke C M Lavrijsen, Begoña Diosdado, Mark J Daly, Chris J J Mulder, M Luisa Mearin, Jos W R Meijer, Gerrit A Meijer, Erica van Oort, Martin C Wapenaar, Bobby P C Koeleman, Cisca Wijmenga
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  ABSTRACT: Celiac disease is probably the best-understood immune-related disorder. The disease presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor. Although HLA class II genes explain 40% of the heritable risk, non-HLA genes accounting for most of the familial clustering have not yet been identified. Here we report significant and replicable association (P = 2.1 x 10(-6)) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 x 10(-5)). This result is suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier.
  Nature Genetics 01/2006; 37(12):1341-4. · 35.53 Impact Factor
• Article: Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect

  Alienke J Monsuur, Paul I W de Bakker, Behrooz Z Alizadeh, Alexandra Zhernakova, Marianna R Bevova, Eric Strengman, Lude Franke, Ruben van't Slot, Martine J van Belzen, Ineke C M Lavrijsen, Bego|[ntilde]|a Diosdado, Mark J Daly, Chris J J Mulder, M Luisa Mearin, Jos W R Meijer, Gerrit A Meijer, Erica van Oort, Martin C Wapenaar, Bobby P C Koeleman, Cisca Wijmenga
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  ABSTRACT: Celiac disease is probably the best-understood immune-related disorder. The disease presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor1. Although HLA class II genes explain 40% of the heritable risk, non-HLA genes accounting for most of the familial clustering have not yet been identified. Here we report significant and replicable association (P = 2.1 10-6) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes2, 3. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 10-5). This result is suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier.
  Nature Genetics. 11/2005; 37(12):1341-1344.
• Article: CTLA4 +49 A/G and CT60 polymorphisms in Dutch coeliac disease patients.

  Martine J van Belzen, Chris J J Mulder, Alexandra Zhernakova, Peter L Pearson, Roderick H J Houwen, Cisca Wijmenga
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  ABSTRACT: Coeliac disease is an autoimmune disorder, characterised by villous atrophy of the small intestine, which results from a T-cell-mediated response to gluten-derived peptides. The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is involved in the regulation of T-cell activation and the CTLA4 +49 A/G polymorphism in exon 1 has been implicated in several autoimmune disorders, including coeliac disease. However, this polymorphism was recently excluded as being the causal variant in Graves' disease, autoimmune hypothyroidism and type I diabetes mellitus. This causal variant was mapped to the 3' region of CTLA4, with the CT60 polymorphism showing the strongest association. The aim of this study was to determine the role of the CTLA4 gene in coeliac disease in the Dutch population. The +49 A/G and CT60 polymorphisms were genotyped in a case-control cohort of 215 patients and controls. The frequency of the +49 G-allele was increased in cases, although not significantly. However, the frequency of the CT60 G-allele was increased with borderline significance in coeliac disease patients (P = 0.048), although the genotype distributions did not show a significant difference between cases and controls. These results indicate the involvement of the CTLA4 gene in coeliac disease development. The haplotype carrying the CT60 G-allele was shown to be associated with lower mRNA levels of the soluble CTLA-4 isoform, providing a possible mechanism for the T-cell-mediated destruction of the small intestine.
  European Journal of HumanGenetics 10/2004; 12(9):782-5. · 4.40 Impact Factor
• Source

  Available from: uu.nl

  Article: The interferon gamma gene in celiac disease: augmented expression correlates with tissue damage but no evidence for genetic susceptibility.

  Martin C Wapenaar, Martine J van Belzen, Justin H Fransen, Aranzazu Fariña Sarasqueta, Roderick H J Houwen, Jos W R Meijer, Chris J J Mulder, Cisca Wijmenga
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  ABSTRACT: Celiac disease (CD) is a complex genetic disorder characterized by gluten intolerance. The Th1 immune response, with a key position for interferon gamma (IFN-gamma), is an important determinant of intestinal remodeling in CD. We aimed at further ascertaining the role of IFN-gamma, either as a genetic factor in the etiology, or as a facilitator of disease initiation/progression. Duodenal biopsies were sampled across distinct histopathological stages of the disease, including refractory CD (RCD), and used to determine IFN-gamma gene (IFNG) expression by real-time RT-PCR. INFG expression correlated with the extent of tissue restructuring, reaching a 240-fold higher expression in total villous atrophy compared to healthy tissue. CD and RCD patients with similar lesions had comparable expression levels. Interestingly, patients in complete remission still had 7.6-fold residual over-expression. An INFG marker was tested in three cohorts of Dutch patients for both genetic linkage and association. Linkage analysis yielded no significant scores for IFNG or its flanking markers. In addition, IFNG allele frequencies were not differently distributed between cases and controls. Likewise, all alleles were randomly transmitted to affected children in parents-case trios. There is no evidence for IFNG as a predisposing gene in CD, despite its enhanced expression in patients in complete remission.
  Journal of Autoimmunity 10/2004; 23(2):183-90. · 7.37 Impact Factor
• Article: A genomewide screen in a four-generation Dutch family with celiac disease: evidence for linkage to chromosomes 6 and 9.

  Martine J van Belzen, Martine M Vrolijk, Jos W R Meijer, J Bart A Crusius, Peter L Pearson, Lodewijk A Sandkuijl, Roderick H J Houwen, Cisca Wijmenga
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  ABSTRACT: Celiac disease is caused by the interaction of multiple genes and environmental factors. Inheritance of the disease shows a complex pattern with a 10% sibling recurrence risk. The HLA-region is a major genetic risk locus in celiac disease, but genes outside this region are expected to contribute to the disease risk as well. The aim of this study was to identify the loci causing celiac disease in one large Dutch family with apparent dominant transmission of the disease. The family comprised 17 patients in four generations, with possible transmission of the disease by both grandparents. Microsatellite markers evenly spread over all chromosomes were genotyped and linkage analysis was performed using both dominant and recessive disease models and a model-free analysis. Disease susceptibility in the family was linked to the HLA-region (lod score of 2.33) and all patients were HLA-DQ2. A dominantly inherited non-HLA locus with a maximum lod score of 2.61 was detected at 9p21-13, which was shared by 16 patients. Model-free analysis identified another possible non-HLA locus, at 6q25.3, which was shared by 14 patients (p = 0.01). Neither of these regions was detected in a genomewide screen in Dutch affected sibpairs, but the 9p21 locus has been implicated in Scandinavian families. Two potential non-HLA loci for celiac disease were identified in this large Dutch family. Our results provide replication of the Scandinavian 9p21 locus, and suggest that this locus plays a role in celiac disease patients from different Caucasian populations.
  The American Journal of Gastroenterology 04/2004; 99(3):466-71. · 7.28 Impact Factor
• Article: A major non-HLA locus in celiac disease maps to chromosome 19.

  Martine J Van Belzen, Jos W R Meijer, Lodewijk A Sandkuijl, Alfons F J Bardoel, Chris J J Mulder, Peter L Pearson, Roderick H J Houwen, Cisca Wijmenga
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  ABSTRACT: The pathogenesis of celiac disease is still unknown despite its well-known association with human leukocyte antigen (HLA)-DQ2 and DQ8. It is clear that non-HLA genes contribute to celiac disease development as well, but none of the previous genome-wide screens in celiac disease have resulted in identification of these genes. We, therefore, performed a 2-stage, genome-wide screen in 101 affected sibpairs from 82 Dutch families who met strict diagnostic criteria. The small intestinal biopsy samples, on which the original celiac disease diagnoses had been based, showed a Marsh III lesion in all patients on reevaluation by 1 pathologist. For association analysis of markers in regions linked to celiac disease, 216 independent MIII patients and 216 age- and sex-matched controls were available. As expected, highly significant linkage to the HLA-region was detected (multipoint maximum lod score [MMLS] = 8.14). More importantly, significant linkage was also present at 19p13.1 (MMLS = 4.31), with the peak at marker D19S899. Moreover, this marker was also significantly associated with celiac disease in the case-control study (corrected P = 0.016). Furthermore, we identified suggestive linkage to 6q21-22, which is approximately 70 cM downstream from the HLA region (MMLS = 3.10). Significant linkage of celiac disease to chromosome region 19p13.1 was detected in our genome-wide screen. These results were confirmed by the association of D19S899 to celiac disease in an independent case-control cohort. Furthermore, we identified a possible second celiac disease locus on chromosome region 6q21-22.
  Gastroenterology 11/2003; 125(4):1032-41. · 11.68 Impact Factor
• Article: The interferon gamma gene in celiac disease: augmented expression correlates with tissue damage but no evidence for genetic susceptibility

  Martin C. Wapenaar, Martine J. van Belzen, Justin H. Fransen, Aranzazu Fariña Sarasqueta, Roderick H.J. Houwen, Jos W.R. Meijer, Chris J.J. Mulder, Cisca Wijmenga
  [show abstract] [hide abstract]
  ABSTRACT: Celiac disease (CD) is a complex genetic disorder characterized by gluten intolerance. The Th1 immune response, with a key position for interferon gamma (IFN-γ), is an important determinant of intestinal remodeling in CD. We aimed at further ascertaining the role of IFN-γ, either as a genetic factor in the etiology, or as a facilitator of disease initiation/progression. Duodenal biopsies were sampled across distinct histopathological stages of the disease, including refractory CD (RCD), and used to determine IFN-γ gene (IFNG) expression by real-time RT-PCR. INFG expression correlated with the extent of tissue restructuring, reaching a 240-fold higher expression in total villous atrophy compared to healthy tissue. CD and RCD patients with similar lesions had comparable expression levels. Interestingly, patients in complete remission still had 7.6-fold residual over-expression. An INFG marker was tested in three cohorts of Dutch patients for both genetic linkage and association. Linkage analysis yielded no significant scores for IFNG or its flanking markers. In addition, IFNG allele frequencies were not differently distributed between cases and controls. Likewise, all alleles were randomly transmitted to affected children in parents-case trios. There is no evidence for IFNG as a predisposing gene in CD, despite its enhanced expression in patients in complete remission.
  Journal of Autoimmunity.