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Biomedical subjects

C Wijmenga

Publications and source records attributed to C Wijmenga.

At least 19 recordsLinked to original sources
PubMed2006

Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort.

AIM/HYPOTHESIS: A strong association between susceptibility to type 2 diabetes and common variants of transcription factor 7-like 2 (TCF7L2), encoding an enteroendocrine transcription factor involved in glucose homeostasis, has been reported in three different populations (Iceland, Denmark and USA) by Grant et al. We aimed to replicate these findings in a Dutch cohort. METHODS: We analysed the genotypes of two intronic single nucleotide polymorphisms (SNPs) in TCF7L2 gene in 502 unrelated type 2 diabetes patients and in a set of healthy controls (n = 920). The two SNPs showed almost complete linkage disequilibrium (D' = 0.91). RESULTS: We were able to replicate the previously reported association in our Breda cohort. The minor alleles of both variants were significantly over-represented in cases (odds ratio [OR] 1.29, 95% CI 1.09-1.52, [Formula: see text] for rs12255372; OR 1.41, 95% CI 1.19-1.66, [Formula: see text] for rs7903146). In addition, TCF7L2 haplotypes were analysed for association with the disease. The analysis of haplotypes did not reveal any strong association beyond that expected from analysing individual SNPs. The TT haplotype carrying the minor alleles was more frequent among cases (OR 1.38, [Formula: see text]). CONCLUSIONS/INTERPRETATION: Our data strongly confirm that variants of the TCF7L2 gene contribute to the risk of type 2 diabetes. The population-attributable risk from this factor in the Dutch type 2 diabetes population is 10%.

Aged↗
PubMed2006

Genetic variants of RANTES are associated with serum RANTES level and protection for type 1 diabetes.

RANTES (regulated on activation, normal T-cell expressed and secreted) is a T-helper type 1 (Th1) chemokine that promotes T-cell activation and proliferation. RANTES is genetically associated with asthma, sarcoidosis and multiple sclerosis. The concentration of RANTES is increased at inflammation sites in different autoimmune diseases. Type 1 diabetes (T1D) is a Th1-mediated disease with complex genetic predisposition. We tested RANTES as a candidate gene for association with T1D using three single-nucleotide polymorphism (SNP) variants (rs4251719, rs2306630 and rs2107538) to capture haplotype information. The minor alleles of all SNPs were transmitted less frequently to T1D offspring (transmission rates 37.3% (P=0.002), 38.7% (P=0.007) and 41.0% (P=0.01)) and were less frequently present in patients compared to controls (P=0.009, 0.03 and 0.04, respectively). A similar protective effect was observed for the haplotype carrying three minor alleles (transmission disequilibrium test (TDT): P=0.003; odds ratio (OR)=0.55; confidence interval (CI): 0.37-0.83; case/control: P=0.03; OR=0.74; CI: 0.55-0.98). Both patients and controls carrying the protective haplotype express significantly lower serum levels of RANTES compared to non-carriers. Subsequently, we tested a cohort of 310 celiac disease patients, but failed to detect association. RANTES SNPs are significantly associated with RANTES serum concentration and development of T1D. The rs4251719*A-rs2306630*A-rs2107538*A haplotype associated with low RANTES production confers protection from T1D. Our data imply that RANTES is associated with T1D both genetically and functionally, and contributes to diabetes-prone Th1 cytokine profile.

Adolescent↗
PubMed2006

Lack of association of MYO9B genetic variants with coeliac disease in a British cohort.

BACKGROUND AND AIMS: Development of coeliac disease involves an interaction between environmental factors (especially dietary wheat, rye, and barley antigens) and genetic factors (there is strong inherited disease susceptibility). The known human leucocyte antigen (HLA)-DQ2 and -DQ8 association explains only a minority of disease heritability. A recent study in the Dutch population suggested that genetic variation in the 3' region of myosin IXB (MYO9B) predisposes to coeliac disease. MYO9B is a Rho family GTPase activating protein involved in epithelial cell cytoskeletal organisation. MYO9B is hypothesised to influence intestinal permeability and hence intestinal antigen presentation. METHODS: Four single nucleotide polymorphisms were chosen to tag all common haplotypes of the MYO9B 3' haplotype block (exons 15-27). We genotyped 375 coeliac disease cases and 1366 controls (371 healthy and 995 population based). All individuals were of White UK Caucasian ethnicity. RESULTS: UK healthy control and population control allele frequencies were similar for all MYO9B variants. Case control analysis showed no significant association of any variant or haplotype with coeliac disease. CONCLUSIONS: Genetic variation in MYO9B does not have a major effect on coeliac disease susceptibility in the UK population. Differences between populations, a weaker effect size than originally described, or possibly a type I error in the Dutch study might explain these findings.

Adolescent↗
PubMed2006

Association analysis of MYO9B gene polymorphisms and inflammatory bowel disease in a Norwegian cohort.

Association between single nucleotide polymorphisms (SNPs) within the MYO9B gene and celiac disease was recently reported. The role of MYO9B in celiac disease was suggested to relate to an epithelial barrier defect. The region to which MYO9B localize is also linked with inflammatory bowel disease (IBD). For these reasons, we hypothesize that MYO9B could also be a susceptibility gene in IBD. To address this, we performed an association study of a Norwegian IBD cohort (149 patients with Crohn's disease, 308 patients with ulcerative colitis and 562 healthy controls) using SNPs, which tagged the celiac disease associated MYO9B haplotype. No association between these SNPs and IBD was observed. Our results failed to support the notion that MYO9B is a susceptibility gene in IBD.

Colitis, Ulcerative↗
PubMed2006

Linkage analysis localises a Kartagener syndrome gene to a 3.5 cM region on chromosome 15q24-25.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a genetic disorder caused by ciliary immotility/dysmotility due to ultrastructural defects of the cilia. Kartagener syndrome (KS), a subtype of PCD, is characterised by situs inversus accompanying the typical PCD symptoms of bronchiectasis and chronic sinusitis. In most cases, PCD is transmitted as an autosomal recessive trait, but its genetic basis is unclear due to extensive genetic heterogeneity. METHODS: In a genome-wide search for PCD loci performed in 52 KS families and in 18 PCD families with no situs inversus present (CDO, ciliary dysfunction-only), the maximal pairwise LOD score of 3.36 with D15S205 in the KS families indicated linkage of a KS locus to the long arm of chromosome 15. In the follow-up study, 65 additional microsatellite markers encompassing D15S205 were analysed. RESULTS: A maximal pairwise LOD score of 4.34 was observed with D15S154, further supporting linkage of the KS, but not the CDO, families to 15q24-25. Analysis of heterogeneity and haplotypes suggested linkage to this region in 60% of KS families. CONCLUSIONS: Reinforced by the results of multipoint linkage, our analyses indicate that a major KS locus is localised within a 3.5 cM region on 15q, between D15S973 and D15S1037.

Chromosome Mapping↗
PubMed2005

Lack of association between VEGF polymorphisms and ALS in a Dutch population.

Sequence alterations in the promoter region of the vascular endothelial growth factor (VEGF) gene have been implicated in increasing the risk of developing ALS. VEGF promoter haplotypes were determined in 373 patients with sporadic ALS and 615 matched healthy controls in The Netherlands. No significant association between the previously reported at-risk haplotypes and ALS was found. Pooling our results with the previously studied population still showed a significant association with the AAG haplotype.

Adult↗
PubMed2005

The many faces of the copper metabolism protein MURR1/COMMD1.

Copper is an essential transition metal but is toxic in excess; therefore, its metabolism needs to be tightly regulated. Defects in the regulation of copper can lead to various disorders characterized by copper deficiency or copper excess. Recently, we characterized the COMMD1 (previously MURR1) gene as the defective gene in canine copper toxicosis. The molecular functions of COMMD1 remain unknown, but significant progress has been made in identifying the cellular processes in which COMMD1 participates, through the identification of proteins interacting with COMMD1. This review discusses how COMMD1 functions as a regulator of not only copper homeostasis but also sodium transport and the NF-kappaB signaling pathway. We outline the possible mechanisms through which COMMD1 exerts these newly identified functions.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Genes and outcome after aneurysmal subarachnoid haemorrhage.

OBJECTIVES: Initial and secondary ischaemia are important determinants of outcome after subarachnoid haemorrhage (SAH). Cerebral ischaemia is a potent stimulus for expression of genes that may influence recovery.We investigated whether functional polymorphisms in the apolipoprotein E (APOE), insulin-like growth factor-1 (IGF-1), tumor necrosis factor-A (TNF-A), interleukin-1A (IL-1A), interleukin-1B (IL-1B), and interleukin-6 (IL-6) genes are related with outcome after aneurysmal SAH. METHODS: Genotyping of the polymorphisms was performed in a consecutive series of 167 patients with aneurysmal SAH. The risk of a poor outcome was analysed with logistic regression with adjustment for prognostic factors for outcome after SAH, using the homozygotes for the wild type alleles as a reference. RESULTS: Patients carrying any IGF-1 non-wild type allele had a lower risk of a poor outcome (OR 0.4, 95% CI 0.2-1.0), while carriers of the TNF-A non-wild type allele had a higher risk (OR 2.3, 95% CI 1.0-5.4). We could not demonstrate an association with outcome for APOE (APOE epsilon4 OR 0.4, 95% CI 0.1-1.2; APOE epsilon2 OR 0.7, 95% CI 0.2-2.4), IL-1A (OR 1.8, 95% CI 0.8-4.0), IL-1B (OR 0.7, 95% CI 0.3-1.5) and IL-6 (OR 0.7, 95% CI 0.3-1.8) polymorphisms. CONCLUSIONS: Variation in some genes that are expressed after cerebral ischaemia may partly explain the large differences in outcome between patients with aneurysmal SAH. SAH patients homozygote for the IGF-1 wild type allele or carriers of the TNF-A non-wild type allele have a higher risk of poor outcome. Additional studies in other populations are needed to assess the generalisability of our results.

Aged↗
PubMed2005

Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population.

Protein tyrosine phosphatase PTPN22 is involved in the negative regulation of T-cell responsiveness. Recently, the association of a coding variant of the PTPN22 gene-R620W(1858C>T) with a number of autoimmune diseases has been described. Therefore, we tested the association of PTPN22 1858*T allele in Dutch early onset type 1 diabetes (T1D) and rheumatoid arthritis (RA) patients, as well as celiac disease (CD) patients, for which no previous study of PTPN22 has been reported. The PTPN22 variant was strongly associated with T1D in cases vs controls (P=2 x 10(-7), OR=2.3, 95% CI=1.7-3.1) as well as in a transmission disequilibrium test in nuclear trio's (P=9 x 10(-9), OR=3.3, CI=2.1-5.0), RA (case/control: P=0.003, OR=1.8 CI =1.2-2.6), but not CD, in spite of a trend of increased homozygosity (P=0.05) and early age at onset (P=0.01). PTPN22 is not generally associated with T-cell mediated autoimmune diseases, although it might play a role in the CD patients with early clinical manifestation.

Adolescent↗
PubMed2005

Characterization of the COMMD1 (MURR1) mutation causing copper toxicosis in Bedlington terriers.

Copper toxicosis is an autosomal recessive disorder affecting Bedlington terriers, characterized by elevated liver copper levels and early death of affected dogs. Genetic linkage mapping studies initially identified linkage between the disease and the microsatellite marker C04107. Subsequently, the deletion of exon 2 of the copper metabolism domain containing 1 (COMMD1) gene (formerly MURR1) was shown to be the major cause of copper toxicosis, although the deletion breakpoints were not defined. In this investigation, polymerase chain reaction (PCR)-based techniques and sequencing were used to isolate the deletion breakpoints, utilizing the newly available dog genome sequence. The breakpoints were positioned at 65.3091 and 65.3489 Mb of dog chromosome 10, in intron 1 and intron 2 of COMMD1 respectively, a deletion of 39.7 kb. The two breakpoints share sequence homology suggesting that homologous recombination may have been responsible for the deletion. Using this information, a genomic diagnostic test for the COMMD1 deletion was developed and compared with microsatellite C04107 genotypes of 40 Bedlington terriers. Results from the 40 samples showed allele 2 of C04107 to be in linkage disequilibrium with the COMMD1 deletion.

Animals↗
PubMed2004

Association of polymorphisms and haplotypes in the elastin gene in Dutch patients with sporadic aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: A locus containing the elastin gene has been linked to familial intracranial aneurysms in 2 distinct populations. We investigated the association of single-nucleotide polymorphisms (SNPs) and haplotypes of SNPs in the elastin gene with the occurrence of subarachnoid hemorrhage (SAH) from sporadic aneurysms in the Netherlands. METHODS: We genotyped 167 SAH patients and 167 matching controls for 18 exonic and intronic SNPs in the elastin gene. A Bonferroni correction was applied for multiple comparisons with all novel associations, with a correction factor derived from the number of SNPs tested (P value after Bonferroni correction [P(corr)]). RESULTS: SAH was statistically significant associated with an SNP in exon 22 of the elastin gene (minor allele frequency was 0.000 in patients and 0.028 in controls; odds ratio [OR], 0.0; 95% CI, 0.0 to 0.7; P=0.004; P(corr)=0.05) and possibly with an SNP in intron 5 (minor allele frequency was 0.062 in patients and 0.128 in controls; OR, 0.5; 95% CI, 0.2 to 0.8; P=0.007; P(corr)=0.08). Haplotypes of intron 5/exon 22 (P(corr)=0.002), intron 4/exon 22 (P(corr)=0.02), and intron 4/intron 5/exon 22 (P=9.0x10(-9)) were also associated with aneurysmal SAH. CONCLUSIONS: Variants and haplotypes within the elastin gene are associated with the risk of sporadic SAH in Dutch patients. Gradual increase of statistical power with the inclusion of 2 or 3 SNPs in the studied haplotypes supports the validity of our conclusion that the elastin gene is a susceptibility locus for SAH.

Alleles↗
PubMed2004

Defining the contribution of the HLA region to cis DQ2-positive coeliac disease patients.

The major genetic susceptibility to coeliac disease is contributed by the human leukocyte antigen (HLA) region. The primary association is with the HLA-DQ2 molecule, encoded by the DQA1*05 and DQB1*02 alleles, which is expressed by over 90% of patients. The aim of our study was to perform an extensive scan of the entire HLA region to determine whether there is evidence for the presence of additional HLA susceptibility genes for coeliac disease in the Dutch population, acting independently of DQ2. In all, 16 microsatellite markers and the DQA1 and DQB1 genes were genotyped in simplex cis DQ2-positive coeliac disease families and cis DQ2-positive control families. Allele frequencies of markers on phase-known DQ2-positive haplotypes transmitted to patients were compared to a combined group of DQ2-positive nontransmitted and control haplotypes, thereby controlling for the DQ2 contribution. No significant differences at any of the marker loci were detected, suggesting that DQ2 is the major HLA risk factor for coeliac disease. Individuals homozygous for DQ2 or heterozygous for DQA1*05-DQB1*02/DQA1*0201-DQB1*02 were found to be at five-fold increased risk for development of coeliac disease (P<10(-8)). This risk seems to be conferred by the presence of a second DQB1*02 allele next to one DQA1*05-DQB1*02 haplotype, independently of the second DQA1 allele.

Adolescent↗
PubMed2004

A microarray screen for novel candidate genes in coeliac disease pathogenesis.

BACKGROUND AND AIMS: The causative molecular pathways underlying the pathogenesis of coeliac disease are poorly understood. To unravel novel aspects of disease pathogenesis, we used microarrays to determine changes in gene expression of duodenal biopsies. METHODS: cDNA microarrays representing 19 200 genes were used to compare gene expression profiles of duodenal biopsies from 15 coeliac disease patients with villous atrophy (Marsh III) and seven control individuals with normal biopsies (Marsh 0). In addition, the specific effect of gluten was studied by comparing the expression profiles of Marsh III lesions of seven patients exposed to gluten with four patients on a gluten free diet. RESULTS: Comparing Marsh III with Marsh 0 lesions identified 109 genes that differed significantly (p<0.001) in expression levels between patients and controls. A large number of these genes have functions in proliferation and differentiation pathways and might be important for correct development of crypt-villous units. Alterations in these pathways may lead to the characteristic hyperplasia and villous atrophy seen in coeliac disease. The analyses also revealed 120 differentially expressed genes (p<0.005) when comparing patients on a gluten free diet with those exposed to gluten. These genes further strengthen our observation of increased cell proliferation in the presence of gluten. CONCLUSIONS: Our study provides new candidate genes in the pathogenesis of coeliac disease. Based on our results, we hypothesise that villous atrophy in coeliac disease patients is due to failure in cell differentiation. These genes are involved in pathways not previously implicated in coeliac disease pathogenesis and they may provide new targets for therapy.

Adult↗
PubMed2004

Anticipation and phenotype in familial intracranial aneurysms.

BACKGROUND: In familial intracranial aneurysms there is evidence for genetic heterogeneity, probably from mutations at separate loci. OBJECTIVES: To compare demographic and clinical features in patients of families with familial intracranial aneurysm and different patterns of inheritance; and to compare the ages of patients with subarachnoid haemorrhage (SAH) in affected parent-child pairs to determine whether there is anticipation. METHODS: Pedigrees for 53 families with familial intracranial aneurysms were constructed, divided into patterns of inheritance suggestive or not suggestive of autosomal dominant transmission. Demographic and clinical features were compared. The age at time of SAH in affected parent-child pairs was compared using the Wilcoxon test. RESULTS: No differences in demographic or clinical features were found between families compatible with an autosomal dominant pattern of inheritance and those with a non-dominant pattern. In families with affected members in two successive generations the age at time of SAH in parents was 55.2 years and in children 35.4 years (mean difference, 19.8 years, p<0.001). CONCLUSIONS: Phenotypes are similar in families with and without a probable autosomal dominant pattern of inheritance. Thus in future genetic studies on familial intracranial aneurysms, stratification according to phenotype is not likely to be useful. Anticipation probably occurs, as affected parents are significantly older at the time of SAH than their affected children.

Adult↗
PubMed2003

Anticipation in familial intracranial aneurysms in consecutive generations.

Intracranial aneurysms (IA) are the major cause of subarachnoid haemorrhages (SAH). A positive family history for SAH is reported in 5-10% of the patients. The mode of inheritance is not unambiguously established; both autosomal dominant and recessive modes have been reported. In sporadic as well as in familial SAH, approximately 60% of the SAH patients are female. Recently, anticipation has been described in familial SAH. Since up to 15% of the SAHs are not caused by an IA, we have analysed anticipation, sex ratio and mode of inheritance only in families with patients with a proven IA in two consecutive generations. A total of 10 families were studied in which at least two persons in consecutive generations were affected by SAH, a symptomatic IA (SIA) or a presymptomatic IA (PIA). We also analysed published data from families with a proven IA in two consecutive generations on age of SIA onset and sex ratios among affected family members (both SIA and PIA). The age of SIA onset in the parental generation (mean 55.5 years) differed significantly from the age of onset in their children (mean 32.4 years). In the parental generation 11 men and 37 women were affected (both SIA and PIA), in the consecutive generation these numbers were 28 men and 32 women. There is a significant difference in sex ratio of affected family members when the generations are compared (P<0.02). No family could be found in which three consecutive generations were affected by an IA (SIA or PIA).

Adult↗
PubMed2003

Genome-wide screen in obese pedigrees with type 2 diabetes mellitus from a defined Dutch population.

A genome scan was performed in obese type 2 diabetes mellitus pedigrees to identify susceptibility loci involved in obesity-driven type 2 diabetes mellitus. We studied the 20% most obese diabetes pedigrees from a confined Dutch population from around the town of Breda. Previously we, and others, have already shown that a susceptibility locus influencing obesity in diabetes may reside on chromosome 18p11. We now report evidence to also suggest linkage for type 2 diabetes in these obese pedigrees on chromosome regions 11p (genome-wide P-value </= 0.061) and 12q (genome-wide P-value </= 0.029), thereby confirming previous findings from corresponding regions. The linkage found in the Breda Cohort of type 2 diabetes patients is influenced by obesity. This supports the notion that a genetic predisposition to obesity is probably intertwined with a genetic predisposition to type 2 diabetes. Further efforts should address the question of how, on a genetic level, these two factors interact.

Adult↗