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Biomedical subjects

Johannes Oldenburg

Publications and source records attributed to Johannes Oldenburg.

At least 19 recordsLinked to original sources
PubMed2006

Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A.

The HLA class I/II alleles and the tumor necrosis factor alpha (TNFA) locus are closely linked in the MHC complex. We have characterized the causative factor VIII mutation, HLA alleles as well as 4 polymorphisms (-827C>T, -308G>A, -238A>G, and 670A>G) in the TNFA gene in 164 patients (124 severe, 26 moderate, and 14 mild) in 78 families with hemophilia A enrolled in the Malmö International Brother Study (MIBS). Inhibitors were identified in 77.8% of patients with a single haplotype (Hap 2) and 72.7% of the patients with the TNFA -308 A/A genotype within this haplotype compared with 39.7% for TNFA -308 G/G patients and 46.9% for TNFA -308 G/A heterozygotes (OR 4.0; 95% CI, 1.4-11.5; P = .008). The association between the -308 A/A genotype and inhibitors was enhanced in subgroups of patients with severe hemophilia (OR 19.2; 95% CI 2.4-156.5; P < .001) and with inversions (n = 75; OR, 11.8; 95% CI, 1.3-105.1; P = .013). Associations were found for the HLA A26 and B44 alleles, but these were not consistent in the subgroup analysis. Our data imply that the TNFA -308G>A polymorphism within Hap 2 is a useful marker and potential modulator of the immune response to replacement therapy in patients with hemophilia.

Blood Coagulation Factor Inhibitors↗
PubMed2006

Familial molar tissues due to mutations in the inflammatory gene, NALP7, have normal postzygotic DNA methylation.

An imprinting disorder has been believed to underlie the etiology of familial biparental hydatidiform moles (HMs) based on the abnormal methylation or expression of imprinted genes in molar tissues. However, the extent of the epigenetic defect in these tissues and the developmental stage at which the disorder begins have been poorly defined. In this study, we assessed the extent of abnormal DNA methylation in two HMs caused by mutations in the recently identified 19q13.4 gene, NALP7. We demonstrate normal postzygotic DNA methylation patterns at major repetitive and long interspersed nuclear elements (LINEs), genes on the inactive X-chromosome, three-cancer related genes, and CpG rich regions surrounding the PEG3 differentially methylated region (DMR). Our data provide a comprehensive assessment of DNA methylation in familial molar tissues and indicate that abnormal DNA methylation in these tissues is restricted to imprinted DMRs. The known role of NALP7 in apoptosis and inflammation pinpoints previously unrecognized pathways that could directly or indirectly underlie the abnormal methylation of imprinted genes in molar tissues.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Recurrent intracardiac thrombosis as an unusual manifestation of inherited thrombophilia.

Patients with inherited thrombophilia are at high risk for the development of venous thrombosis that manifests mainly as deep venous thrombosis of the legs and/or pulmonary embolism. We report spontaneous right-sided intracardiac thrombosis in a young man as an unusual manifestation of inherited thrombophilia. The diagnosis of thrombophilia was confirmed by demonstration of the prothrombin-G20210A-mutation in the homozygous state. A second spontaneous intracardiac thrombosis occurred 3 years after discontinuation of oral anticoagulant treatment. This indicates the high risk for recurrence in patients developing intracardiac thrombosis in the absence of an underlying cardiac disease and warrants long-term oral anticoagulant treatment.

Adult↗
PubMed2006

Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population.

BACKGROUND: Chinese and Malay subjects have been reported to require less maintenance warfarin than Indians that could not be accounted for by cytochrome P450 (CYP) 2C9 variants. Vitamin K epoxide reductase complex 1 (VKORC1) is the target enzyme of warfarin, and VKORC1 intronic variants and haplotypes have recently been shown to influence VKORC1 activity and warfarin requirements. METHODS: We sequenced the coding regions of CYP2C9 and VKORC1 and inferred VKORC1 haplotype from 10 intronic variants in 147 Chinese, 85 Malay, and 43 Indian patients receiving maintenance warfarin. RESULTS: The mean weight-normalized warfarin dose was lower for Chinese and Malays than for Indians (0.058 +/- 0.025 mg/kg, 0.059 +/- 0.023 mg/kg, and 0.089 +/- 0.036 mg/kg, respectively; P < .001 for comparisons between Chinese and Malays with Indians). CYP2C9*2 and VKORC1 coding region variants were rare (<2%), whereas CYP2C9*3 associated with lower warfarin requirements was less common in Chinese and Malays (7% and 9%, respectively) than in Indians (18%) and could not account for their lower warfarin requirements. VKORC1 H1 and H7/H8/H9 haplotypes were associated with lower and higher warfarin requirements, respectively (0.050 +/- 0.019 mg/kg and 0.092 +/- 0.057 mg/kg, respectively; P < .001). VKORC1 H1 haplotype (requiring low warfarin doses) was common in Chinese (87%) and Malays (65%) but uncommon in Indians (12%), whereas H7, H8, and H9 haplotypes (requiring high warfarin doses) were rare in Chinese (9%), intermediate in Malays (30%), and common in Indians (82%). The interethnic difference in warfarin requirements became nonsignificant when adjusted for VKORC1 haplotype. CONCLUSIONS: Interethnic difference in VKORC1 haplotypes accounts for the difference in warfarin requirements between Chinese, Malays, and Indians, providing interesting insights into genetic variation between ethnogeographically distinct Asian groups.

Anticoagulants↗
PubMed2006

Founder mutation Arg485Pro led to recurrent compound heterozygous GGCX genotypes in two German patients with VKCFD type 1.

Congenital combined deficiency of the vitamin-K-dependent coagulation factors (VKCFD) represents a rare autosomal recessive inherited bleeding disorder caused by mutations in either the gamma-glutamyl carboxylase gene (VKCFD type 1) or the vitamin K epoxide reductase gene (VKCFD type 2). Four different mutations of the gamma-glutamyl carboxylase gene (GGCX) have so far been reported in three unrelated patients with VKCFD type 1. Here we report on a fourth patient who presented with two compound heterozygous missense mutations of the GGCX gene, His404Pro and Arg485Pro. The His404Pro mutation has not been described previously, while the Arg485Pro mutation has been reported in another compound heterozygous VKCFD type 1 patient from Germany. Most interestingly, haplotype analysis revealed that Arg485Pro is due to a founder mutation, suggesting that this mutation is present in the German population at some low frequency. The founder mutation explains that the only two compound heterozygous VKCFD type 1 patients known today originated from Germany.

Adult↗
PubMed2006

Protection from type 1 diabetes by vitamin D receptor haplotypes.

Vitamin D has been involved in the modulation of calcium and bone metabolism as well as in the immune system, where it suppresses the proliferation of activated T cells. These effects are exerted via the vitamin D receptor (VDR). Polymorphisms within this gene have been exhaustively studied in diverse autoimmune diseases but with inconsistent results. We previously reported a positive association of polymorphisms within the VDR gene (Apa I, Taq I, Bsm I, and Fok I). In the present article we extended our previous reports to seven additional polymorphisms (rs757343, rs9729, rs2853559, rs1989969, rs3847987, rs2238135, and rs4516035) in a larger set of German simplex type 1 diabetes families. Additionally we correlated serum levels of 25(OH)D(3) and 1,25(OH)(2)D(3) with VDR genotypes and haplotypes. The haplotypes "CG" (Taq I-Apa I), "CGG" (Taq I-Apa I-Tru I), "CGC" (Taq I-Apa I-Fok I), "GCTG" (rs9729-Taq I-Apa I-Tru I), and "CGGC"(Taq I-Apa I, Tru I, Fok I) were less often transmitted, thus negatively associated with type 1 diabetes. Patients who carried the genotype "CC" of the rs3847987 polymorphism had higher median serum levels of 25(OH)D(3). Furthermore, the majority of patients with this genotype possessed normal serum levels of 25(OH)D(3). We conclude that variants of the VDR may confer a genetic protection from type 1 diabetes. Furthermore, normal serum levels of 25(OH)D(3) appear to correlate with a VDR genotype. This supports a role of vitamin D in the immune pathogenesis of type 1 diabetes.

Calcifediol↗
PubMed2006

New insight into the molecular basis of hemophilia A.

Since publication of the sequence of the factor VIII gene (F8) in 1984, a large number of mutations that cause hemophilia A (HA) have been identified. With the technical advances associated with mutation screenings, it is now possible to identify a putative F8 sequence alteration in the great majority of HA patients. The mutation spectrum includes 2 inversion hot spots (intron 1 and intron 22 inversions) mediated by intrachromosomal recombination between 2 copies of long inverted repeats, one of which lies within the F8 gene whereas the other is extragenic. Point mutations are distributed over all of the exons, and deletions or insertions of different sizes and mutations affecting splice sites account for the rest of the known mutations. In a small number of cases, however, we are unable to find any disease-determining DNA changes in the coding regions of the F8 gene. This fact points to possibilities of unknown gene rearrangements that disrupt the F8 gene or mutations in other genes that play a role in the processing/secretion of the factor VIII protein. Moreover, the proof of an absence of F8 messenger RNA (mRNA) in one patient points to either a defect in the expression of F8 mRNA or its rapid degradation, which may represent a novel mechanism leading to HA.

Factor VIII↗
PubMed2006

Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system.

OBJECT: Important central nervous system (CNS) manifestations in patients with hereditary hemorrhagic telangiectasia (HHT) include arteriovenous malformations (AVMs) and dural arteriovenous fistulas (DAVFs). Hereditary hemorrhagic telangiectasia is caused by germline mutations of two genes: ENG (HHT Type 1) and ACVRL1 (HHT Type 2). The ENG gene variations have been associated with the formation of intracranial aneurysms. The authors studied whether sequence variations in ACVRL1 or ENG are associated with the development of clinically sporadic arteriovenous dysplasias and aneurysms of the CNS. METHODS: The coding sequence (in 44 patients with AVMs and 27 with aneurysms) and the 5' end and the polyA site (in 53 patients with AVMs) of the ACVRL1 gene were analyzed for sequence variations using direct sequencing and single-strand conformational polymorphism analysis. One ENG and three ACVRL1 gene polymorphisms were genotyped using restriction enzyme-based analysis in 101 patients with sporadic AVMs and DAVFs of the CNS, 79 patients treated for intracranial aneurysms, and 202 control volunteers. The authors identified a statistically significant association between the IVS3 -35A/T polymorphism in intron 3 of the ACVRL1 gene and the development of AVMs and DAVFs (p = 0.004; odds ratio [OR] 1.73; 95% confidence interval [CI] 1.19-2.51; after adjustments for age and sex), but not aneurysms (crude OR 0.82; 95% CI 0.55-1.18). CONCLUSIONS: The results of this study link ACVRL1 (HHT Type 2 gene) to the formation of the clinically sporadic variants of vascular malformations of the CNS most commonly seen in patients with HHT, that is, AVMs and DAVFs.

Activin Receptors, Type II↗
PubMed2006

Detection of heterozygous large deletions in the antithrombin gene using multiplex polymerase chain reaction and denatured high performance liquid chromatography.

The present study reports a method for the easy, rapid and cost effective detection of heterozygous large deletions. As a model gene all exons of the antithrombin gene were amplified in a one tube multiplex polymerase chain reaction (PCR) and the products separated according to their size by reverse-phase ion-pair high performance liquid chromatography. A significant reduction in the height of a peak in the probandOs sample compared to in the control indicates the presence of a large deletion of the corresponding allele. Using this approach we identified heterozygous deletions in four patients: the deletions affected exons 1 and 2, exon 7 and the whole antithrombin gene.

Antithrombin III↗
PubMed2005

Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A.

The aim of the Malmö International Brother Study (MIBS) is to evaluate host genetic factors associated with the development of inhibitory antibodies in patients with hemophilia. Factor VIII gene mutations and genetic polymorphisms of the IL1beta, IL4, and IL10 genes, known to influence antibody production in autoimmune diseases, were analyzed in 164 patients (124 with severe, 26 with moderate, and 14 with mild disease) in 78 unrelated families with hemophilia A. Seventy-seven (47%) patients in 54 families had a history of inhibitors (57 high responding, 20 low responding). Inversions were found in 36 families (75 patients). There was no association between the development of inhibitor and the IL1beta Taq I RFLP alleles in exon 5 or the -590 C/T single nucleotide polymorphism (SNP) in the promoter region of IL4. There was, however, a strong association between an allele with 134 bp in one of the CA repeat microsatellites, IL10G, located in the promoter region of the IL10 gene, and the development of inhibitor (odds ratio [OR], 4.4; 95% confidence interval [95% CI], 2.1-9.5; P < .001). The association was consistent in the subgroup of families with severe hemophilia and inversions. IL10 is the first gene located outside the causative factor VIII gene mutation to be associated with inhibitor development.

Antibody Formation↗
PubMed2005

Lack of F8 mRNA: a novel mechanism leading to hemophilia A.

Hemophilia A (HA) is caused by partial or total deficiency of F8 protein activity. In a small group, about 1.8% of patients with HA, no mutation is found in the F8 gene. Among this group, we report here on one patient with severe HA in whom no mRNA of the F8 gene was detected. Using 2 common polymorphisms in F8 exon 14, we were able to show that the same allele shared by the patient, his mother, and his sister was not detected by reverse transcription-polymerase chain reaction (RT-PCR) from total blood mRNA. Skewed X-chromosome inactivation in both the mother and the sister was excluded by studying the methylation profile of the androgen receptor gene (HUMARA locus). These findings strongly suggest that the cause of HA in this patient is either absence or rapid degradation of the F8 mRNA, which points to a novel mechanism leading to HA.

Adolescent↗
PubMed2005

The genetic basis of resistance to anticoagulants in rodents.

Anticoagulant compounds, i.e., derivatives of either 4-hydroxycoumarin (e.g., warfarin, bromadiolone) or indane-1,3-dione (e.g., diphacinone, chlorophacinone), have been in worldwide use as rodenticides for >50 years. These compounds inhibit blood coagulation by repression of the vitamin K reductase reaction (VKOR). Anticoagulant-resistant rodent populations have been reported from many countries and pose a considerable problem for pest control. Resistance is transmitted as an autosomal dominant trait although, until recently, the basic genetic mutation was unknown. Here, we report on the identification of eight different mutations in the VKORC1 gene in resistant laboratory strains of brown rats and house mice and in wild-caught brown rats from various locations in Europe with five of these mutations affecting only two amino acids (Tyr139Cys, Tyr139Ser, Tyr139Phe and Leu128Gln, Leu128Ser). By recombinant expression of VKORC1 constructs in HEK293 cells we demonstrate that mutations at Tyr139 confer resistance to warfarin at variable degrees while the other mutations, in addition, dramatically reduce VKOR activity. Our data strongly argue for at least seven independent mutation events in brown rats and two in mice. They suggest that mutations in VKORC1 are the genetic basis of anticoagulant resistance in wild populations of rodents, although the mutations alone do not explain all aspects of resistance that have been reported. We hypothesize that these mutations, apart from generating structural changes in the VKORC1 protein, may induce compensatory mechanisms to maintain blood clotting. Our findings provide the basis for a DNA-based field monitoring of anticoagulant resistance in rodents.

Amino Acid Motifs↗
PubMed2005

Haemophilia A: from mutation analysis to new therapies.

Haemophilia is caused by hundreds of different mutations and manifests itself in clinical conditions of varying severity. Despite being inherited in monogenic form, the clinical features of haemophilia can be influenced by other genetic factors, thereby confounding the boundary between monogenic and multifactorial disease. Unlike sufferers of other genetic diseases, haemophiliacs can be treated successfully by intravenous substitution of coagulation factors. Haemophilia is also the most attractive model for developing gene-therapy protocols, as the normal life expectancy of haemophiliacs allows the side effects of gene therapy, as well as its efficiency, to be monitored over long periods.

DNA Mutational Analysis↗
PubMed2005

Patients with familial biparental hydatidiform moles have normal methylation at imprinted genes.

In molar tissues from patients with recurrent biparental hydatidiform moles, we could previously demonstrate that differentially methylated regions (DMRs) of four imprinted genes are abnormally methylated on the maternal alleles. It remained unclear if this abnormal methylation originated de novo in the molar tissues or if it is even recognizable in the patient somatic tissues. To address this question, we investigated the DNA methylation of four imprinted genes in total blood from the two sister-patients. Here, we show that both patients retain normal methylation levels at the DMRs of the four genes in blood tissues. For two maternally expressed genes, we could use informative SNPs to follow the inheritance of the abnormally methylated maternal alleles in the molar tissues. We find that the transmitted abnormally methylated maternal alleles to the moles originated from the maternal grandmother and that the same alleles are not methylated in the patients. Our data suggest that the abnormal methylation in familial biparental molar tissues was acquired de novo in the patients'germline as a result of a false reprogramming or during the postzygotic development of the conceptuses that led to moles.

Alleles↗
PubMed2005

gammaAla82Gly represents a common fibrinogen gamma-chain variant in Caucasians.

Screening of 200 blood donors for the presence of polymorphisms in three fibrinogen genes (FGA, FGB, FGG), revealed two individuals with a heterozygous missense mutation (c.323C > G, gammaAla82Gly) in the FGG gene. This mutation has been reported previously to cause mild hypofibrinogenaemia. Analysis of an additional 416 blood donors showed two more heterozygous gammaAla82Gly mutations, resulting in an overall gammaAla82Gly allele frequency of 0.0032. Haplotype analysis demonstrated that the gammaAla82Gly mutation originated from a common founder. From these data we estimated that homozygous individuals for gammaAla82Gly should occur at a frequency of 1: 95 000, suggesting that hypofibrinogenaemia represents a more frequent condition in the population than so far believed.

Amino Acid Substitution↗