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  • 1.
    Halldén, Christer
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Mårtensson, A.
    Department of Paediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Lund University, Malmö.
    Nilsson, Daniel
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Säll, T.
    Department of Biology, Lund University.
    Lind-Halldén, Christina
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Lidén, Annika C.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Ljung, R.
    Department of Paediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Lund University, Malmö.
    Origin of Swedish hemophilia B mutations2013In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no 11, p. 2001-2008Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: More than 1100 mutations that cause hemophilia B (HB) have been identified. At the same time, specific F9 mutations are present at high frequencies in certain populations, which raise questions about the origin of HB mutations.

    OBJECTIVES: To describe the mutation spectrum of all HB families in Sweden and investigate if mutations appearing in several families are due to independent recurrent mutations (RMs) or to a common mutation event (i.e. are identical by descent (IBD)).

    PATIENTS/METHODS: The registered Swedish HB population consists of patients from 86 families. Mutations were identified by resequencing and identical haplotypes were defined using 74 markers and a control population of 285 individuals. The ages of IBD mutations were estimated using ESTIAGE.

    RESULTS: Out of 77 presumably unrelated patients with substitution mutations, 47 patients (61%) had mutations in common with other patients. Haplotyping of the 47 patients showed that 24 patients had IBD mutations (51%) with estimated ages of between two and 23 generations. A majority of these patients had mild disease. Eight of the 15 mutations observed in more than one family were C>T transitions in CpG sites and all eight were RMs.

    CONCLUSIONS: The association of IBD mutations with a mild phenotype is similar to what has been previously observed in hemophilia A. Noteworthy features of the mutations that are common to more than one family are the equal proportions of patients with RM and IBD mutations and the correlation between the occurrence of RMs and C>T transitions at CpG sites.

  • 2.
    Halldén, Christer
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Nilsson, Daniel
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Säll, Torbjorn
    Department of Biology, Lund University.
    Lind-Halldén, Christina
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Lidén, Annika C.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Ljung, R.
    Department of Pediatrics and Malmö Center for Thrombosis and Hemostasis, Lund University.
    Origin of Swedish hemophilia A mutations2012In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 10, no 12, p. 2503-2511Article in journal (Refereed)
    Abstract [en]

     Background: Hemophilia A (HA) has a high level of variation within the disease class, with more than 1000 mutations being listed in the HAMSTeRS database. At the same time a number of F8 mutations are present in specific populations at high frequencies. Objectives: The simultaneous presence of large numbers of rare mutations and a small number of high-frequency mutations raises questions about the origins of HA mutations. The present study was aimed at describing the origins of HA mutations in the complete Swedish population. The primary issue was to determine what proportion of identical mutations are identical by descent (IBD) and what proportion are attributable to recurrent mutation events. The age of IBD mutations was also determined. Patients/Methods: In Sweden, the care of HA is centralized, and the Swedish HA population consists of ∼ 750 patients from > 300 families (35% severe, 15% moderate, and 50% mild). Identical haplotypes were defined by single-nucleotide polymorphism and microsatellite haplotyping, and the ages of the mutations were estimated with estiage. Results: Among 212 presumably unrelated patients with substitution mutations, 97 (46%) had mutations in common with other patients. Haplotyping of the 97 patients showed that 47 had IBD mutations (22%) with estimated ages of between two and 35 generations. The frequency of mild disease increased with an increasing number of patients sharing the mutations. Conclusions: A majority of the IBD mutations are mild and have age estimates of a few hundred years, but some could date back to the Middle Ages.

  • 3.
    Henmyr, Viktor
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin. Lund University.
    Carlberg, Daniel
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Manderstedt, Eric
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Plattformen för molekylär analys. Lund University.
    Lind-Halldén, Christina
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Säll, T.
    Lund University.
    Cardell, L. O.
    Karolinska Institutet.
    Halldén, Christer
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Genetic variation of the toll-like receptors in a Swedish allergic rhinitis case population2017In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 18, no 1, article id 18Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Variation in the 10 toll-like receptor (TLR) genes has been significantly associated with allergic rhinitis (AR) in several candidate gene studies and three large genome-wide association studies. These have all investigated common variants, but no investigations for rare variants (MAF ≤ 1%) have been made in AR. The present study aims to describe the genetic variation of the promoter and coding sequences of the 10 TLR genes in 288 AR patients.

    METHODS: Sanger sequencing and Ion Torrent next-generation sequencing was used to identify polymorphisms in a Swedish AR population and these were subsequently compared and evaluated using 1000Genomes and Exome Aggregation Consortium (ExAC) data.

    RESULTS: The overall level of genetic variation was clearly different among the 10 TLR genes. The TLR10-TLR1-TLR6 locus was the most variable, while the TLR7-TLR8 locus was consistently showing a much lower level of variation. The AR patients had a total of 37 promoter polymorphisms with 14 rare (MAF ≤ 1%) and 14 AR-specific polymorphisms. These numbers were highly similar when comparing the AR and the European part of the 1000Genomes populations, with the exception of TLR10 where a significant (P = 0.00009) accumulation of polymorphisms were identified. The coding sequences had a total of 119 polymorphisms, 68 were rare and 43 were not present in the European part of the 1000Genomes population. Comparing the numbers of rare and AR-specific SNPs in the patients with the European part of the 1000Genomes population it was seen that the numbers were quite similar both for individual genes and for the sum of all 10 genes. However, TLR1, TLR5, TLR7 and TLR9 showed a significant excess of rare variants in the AR population when compared to the non-Finnish European part of ExAC. In particular the TLR1 S324* nonsense mutation was clearly overrepresented in the AR population.

    CONCLUSIONS: Most TLR genes showed a similar level of variation between AR patients and public databases, but a significant excess of rare variants in AR patients were detected in TLR1, TLR5, TLR7, TLR9 and TLR10. This further emphasizes the frequently reproduced TLR10-TLR1-TLR6 locus as being involved in the pathogenesis of allergic rhinitis.

  • 4. Henmyr, Viktor
    et al.
    Lind-Halldén, Christina
    Carlberg, Daniel
    Halldén, Christer
    Melén, E
    Karolinska institutet.
    Wickman, M
    Karolinska institutet.
    Bergström, A
    Karolinska institutet.
    Säll, T
    Lund University.
    Cardell, L O
    Karolinska institutet.
    Characterization of genetic variation in TLR8 in relation to allergic rhinitis2015In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A previous investigation of all 10 TLR-genes for associations with allergic rhinitis (AR) detected a number of significant SNPs in the TLR8 locus. The associations indicated that an accumulation of rare variants could explain the signal. The present study therefore searches for rare variants in the TLR8 region and also investigates the reproducibility of previous SNP associations.

    METHODS: The TLR8 gene was re-sequenced in 288 AR patients from Malmö and the data was compared with publically available data. Seven previously AR-associated SNPs from TLR8 were analyzed for AR-associations in 422 AR patients and 859 controls from the BAMSE cohort. The associations detected in present and previous studies were compared.

    RESULTS: Sequencing detected 13 polymorphisms (3 promotor, 10 coding) among 288 AR patients. Four of the coding polymorphisms were rare (MAF <1%) and three of those were novel. Two coding polymorphisms were benign missense mutations and the rest were synonymous. Comparison with 1000Genomes and Exome Aggregation Consortium data revealed no accumulation of rare variants in the AR cases. The AR-association tests made using the BAMSE cohort yielded 5 P-values < 0.05. Tests of IgE-levels yielded 4 significant SNP associations to birch pollen. Comparing results between different populations revealed opposing risk alleles, different gender effects and response to different allergens in the different populations.

    CONCLUSIONS: Rare variants in TLR8 are not associated with AR. Comparison of present and previous association studies reveal contradictory results for common variants. Thus, no associations exist between genetic variation in TLR8 and AR. This article is protected by copyright. All rights reserved.

  • 5.
    Henmyr, Viktor
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Lind-Halldén, Christina
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Halldén, Christer
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Säll, Torbjörn
    Lund University.
    Carlberg, Daniel
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Bachert, Claus
    Belgien.
    Cardell, Lars-Olaf
    Karolinska institutet.
    Chronic rhinosinusitis patients show accumulation of genetic variants in PARS22016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, article id e0158202Article in journal (Refereed)
    Abstract [en]

    Genetic studies of chronic rhinosinusitis (CRS) have identified a total of 53 CRS-associated SNPs that were subsequently evaluated for their reproducibility in a recent study. The rs2873551 SNP in linkage disequilibrium with PARS2 showed the strongest association signal. The present study aims to comprehensively screen for rare variants in PARS2 and evaluate for accumulation of such variants in CRS-patients. Sanger sequencing and long-range PCR were used to screen for rare variants in the putative promoter region and coding sequence of 310 CRS-patients and a total of 21 variants were detected. The mutation spectrum was then compared with data from European populations of the 1000Genomes project (EUR) and the Exome Aggregation Consortium (ExAC). The CRS population showed a significant surplus of low-frequency variants compared with ExAC data. Haplotype analysis of the region showed a significant excess of rare haplotypes in the CRS population compared to the EUR population. Two missense mutations were also genotyped in the 310 CRS patients and 372 CRS-negative controls, but no associations with the disease were found. This is the first re-sequencing study in CRS research and also the first study to show an association of rare variants with the disease.

  • 6.
    Jakobsson, M.
    et al.
    Department of Cell and Organism Biology, Genetics, Lund University.
    Säll, T.
    Department of Cell and Organism Biology, Genetics, Lund University.
    Lind-Halldén, Christina
    Kristianstad University, Department of Mathematics and Science.
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital.
    The evolutionary history of the common chloroplast genome of Arabidopsis thaliana and A. suecica2007In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 20, no 1, p. 104-121Article in journal (Refereed)
    Abstract [en]

    The evolutionary history of the common chloroplast (cp) genome of the allotetraploid Arabidopsis suecica and its maternal parent A. thaliana was investigated by sequencing 50 fragments of cpDNA, resulting in 98 polymorphic sites. The variation in the A. suecica sample was small, in contrast to that of the A. thaliana sample. The time to the most recent common ancestor (T(MRCA)) of the A. suecica cp genome alone was estimated to be about one 37th of the T(MRCA) of both the A. thaliana and A. suecica cp genomes. This corresponds to A. suecica having a MRCA between 10 000 and 50 000 years ago, suggesting that the entire species originated during, or before, this period of time, although the estimates are sensitive to assumptions made about population size and mutation rate. The data was also consistent with the hypothesis of A. suecica being of single origin. Isolation-by-distance and population structure in A. thaliana depended upon the geographical scale analysed; isolation-by-distance was found to be weak on the global scale but locally pronounced. Within the genealogical cp tree of A. thaliana, there were indications that the root of the A. suecica species is located among accessions of A. thaliana that come primarily from central Europe. Selective neutrality of the cp genome could not be rejected, despite the fact that it contains several completely linked protein-coding genes.

  • 7.
    Jakobsson, Mattias
    et al.
    Bioinformatics Program, Department of Human Genetics, University of Michigan.
    Hagenblad, Jenny
    Department of Biology, Linköping University.
    Tavaré, Simon
    Molecular and Computational Biology, University of Southern California.
    Säll, Torbjörn
    Department of Cell and Organism Biology, Genetics, Lund University.
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital.
    Lind-Halldén, Christina
    Kristianstad University, Department of Mathematics and Science.
    Nordborg, Magnus
    Molecular and Computational Biology, University of Southern California.
    A unique recent origin of the allotetraploid species Arabidopsis suecica: evidence from nuclear DNA markers2006In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 23, no 6, p. 1217-1231Article in journal (Refereed)
    Abstract [en]

    A coalescent-based method was used to investigate the origins of the allotetraploid Arabidopsis suecica, using 52 nuclear microsatellite loci typed in eight individuals of A. suecica and 14 individuals of its maternal parent Arabidopsis thaliana, and four short fragments of genomic DNA sequenced in a sample of four individuals of A. suecica and in both its parental species A. thaliana and Arabidopsis arenosa. All loci were variable in A. thaliana but only 24 of the 52 microsatellite loci and none of the four sequence fragments were variable in A. suecica. We explore a number of possible evolutionary scenarios for A. suecica and conclude that it is likely that A. suecica has a recent, unique origin between 12,000 and 300,000 years ago. The time estimates depend strongly on what is assumed about population growth and rates of mutation. When combined with what is known about the history of glaciations, our results suggest that A. suecica originated south of its present distribution in Sweden and Finland and then migrated north, perhaps in the wake of the retreating ice.

  • 8.
    Jakobsson, Mattias
    et al.
    Department of Cell and Organism Biology, Genetics, Lund University.
    Säll, Torbjörn
    Department of Cell and Organism Biology, Genetics, Lund University.
    Lind-Halldén, Christina
    Kristianstad University, Department of Mathematics and Science.
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital.
    Evolution of chloroplast mononucleotide microsatellites in Arabidopsis thaliana2007In: Theoretical and Applied Genetics, ISSN 0040-5752, E-ISSN 1432-2242, Vol. 114, no 2, p. 223-235Article in journal (Refereed)
    Abstract [en]

    The level of variation and the mutation rate were investigated in an empirical study of 244 chloroplast microsatellites in 15 accessions of Arabidopsis thaliana. In contrast to SNP variation, microsatellite variation in the chloroplast was found to be common, although less common than microsatellite variation in the nucleus. No microsatellite variation was found in coding regions of the chloroplast. To evaluate different models of microsatellite evolution as possible explanations for the observed pattern of variation, the length distribution of microsatellites in the published DNA sequence of the A. thaliana chloroplast was subsequently used. By combining information from these two analyses we found that the mode of evolution of the chloroplast mononucleotide microsatellites was best described by a linear relation between repeat length and mutation rate, when the repeat lengths exceeded about 7 bp. This model can readily predict the variation observed in non-coding chloroplast DNA. It was found that the number of uninterrupted repeat units had a large impact on the level of chloroplast microsatellite variation. No other factors investigated-such as the position of a locus within the chromosome, or imperfect repeats-appeared to affect the variability of chloroplast microsatellites. By fitting the slippage models to the Genbank sequence of chromosome 1, we show that the difference between microsatellite variation in the nucleus and the chloroplast is largely due to differences in slippage rate.

  • 9.
    Lind-Halldén, Christina
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Dahlen, Anna
    Section of Clinical Genetics, Lund University Hospital.
    Hillarp, Andreas
    Department of Laboratory Medicine, Clinical Chemistry, Lund University.
    Zöller, Bengt
    Center for Primary Health Care Research, Malmö University Hospital.
    Dahlbäck, Björn
    Department of Laboratory Medicine, Clinical Chemistry, Lund University.
    Halldén, Christer
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Small and large PROS1 deletions but no other types of rearrangements detected in patients with protein S deficiency2012In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 108, no 1, p. 94-100Article in journal (Refereed)
    Abstract [en]

    Protein S deficiency is a dominantly inherited disorder that results from mutations in the PROS1 gene. Previous sequencing of the gene failed to detect mutations in eight out of 18 investigated Swedish families, whereas segregation analyses detected large deletions in three out of the eight families. The present study investigates more thoroughly for the presence of deletions but also for other types of rearrangements. FISH analysis confirmed the existence of the three previously identified large deletions, but failed to identify any other type of rearrangement among the eight analysed families. MLPA analysis of the PROS1 gene revealed two smaller deletions covering two and four exons, respectively. Thus, deletions could be found in five out of eight families where no point mutations could be found despite sequencing of the gene. Twelve additional, not previously analysed, families were subsequently analysed using MLPA. The analysis identified two smaller deletions (3 and 4 exons). Including all PS-deficient families, i.e. also the 10 families where sequencing found a causative point mutation, deletions were identified in seven out of 30 PS-deficient families. A strategy of sequencing followed by MLPA analysis in mutation-negative families identified the causative mutation in 15 out of 18 of Swedish PS-deficient families. Most deletions were different as determined by their sizes, locations and flanking haplotypes. FISH (8 families) and MLPA analysis (20 families) failed to identify other types of rearrangements.

  • 10.
    Lind-Halldén, Christina
    et al.
    Kristianstad University, Department of Mathematics and Science.
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital.
    Säll, T.
    Department of Genetics, Lund University.
    Genetic variation in Arabidopsis suecica and its parental species A. arenosa and A. thaliana2002In: Hereditas, ISSN 0018-0661, E-ISSN 1601-5223, Vol. 136, no 1, p. 45-50Article in journal (Refereed)
    Abstract [en]

    Random amplified polymorphic DNA (RAPD) markers were used to estimate the level of genetic variation in Swedish accessions of the allopolyploid Arabidopsis suecica and its parental species A. thaliana and A. arenosa. The results showed clear differences among the three species with respect to the level of variation. A. arenosa was highly variable, A. thaliana showed a moderate level of variation whereas A. suecica was much less variable than the two other species. An extended analysis covering 19 Swedish populations of A. suecica corroborated the low level of variation in this species, yet 16 unique phenotypes were observed. No isolation by distance was observed. When the genetic variation was partitioned among and within populations of A. suecica, the results showed that the majority of the variation (81%) occurred among populations. This result is interpreted as a strong indication that A. suecica is autogamous in nature.

  • 11.
    Lind-Halldén, Christina
    et al.
    Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Manderstedt, Eric
    Kristianstad University, Plattformen för molekylär analys. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Carlberg, Daniel
    Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Lethagen, Stefan
    Skåne University Hospital in Malmö.
    Halldén, Christer
    Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Genetic variation in the syntaxin-binding protein STXBP5 in type 1 von Willebrand disease patients2018In: Thrombosis and haemostasis, ISSN 2567-689X, Vol. 118, no 8, p. 1382-1389Article in journal (Refereed)
    Abstract [en]

    von Willebrand factor (VWF) levels in healthy individuals and in patients with type 1 von Willebrand disease (VWD) are influenced by genetic variation in several genes, for example, VWF, ABO and STXBP5. Here, we comprehensively screen for STXBP5 variants and investigate their association with type 1 VWD in Swedish patients and controls. The coding region of the STXBP5 gene was re-sequenced in 107 type 1 VWD patients and the detected variants were genotyped in the type 1 VWD population and a Swedish control population (464 individuals). The functional effects of missense alleles were predicted in silico and the pattern of genetic variation in STXBP5 was analysed. Re-sequencing of 107 type 1 VWD patients identified three missense and three synonymous variants in the coding sequence of STXBP5. The low-frequency missense variants rs144099092 (0.005) and rs148830578 (0.029) were predicted to be damaging, but were not accumulated in patients. No other rare candidate mutations were detected. STXBP5 showed a high level of linkage disequilibrium and a low overall nucleotide diversity of π = 3.2 × 10-4 indicating intolerance to variants affecting protein function. Three previously type 1 VWD-associated single nucleotide polymorphisms were located on one haplotype that showed an increased frequency in patients versus controls. No differences in messenger ribonucleic acid abundance among haplotypes could be found using Genotype-Tissue Expression project data. In conclusion, a haplotype containing the STXBP5 Asn436Ser (rs1039084) mutation is associated with type 1 VWD and no rare STXBP5 mutations contribute to type 1 VWD in the Swedish population.

  • 12.
    Manderstedt, Eric
    et al.
    Kristianstad University, Plattformen för molekylär analys. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Lind-Halldén, Christina
    Kristianstad University, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Lethagen, Stefan
    Danmark & Lund University.
    Halldén, Christer
    Kristianstad University, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Genetic variation in the C-type lectin receptor CLEC4M in type 1 von Willebrand Disease patients2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 2Article in journal (Refereed)
    Abstract [en]

    von Willebrand factor (VWF) levels in healthy individuals and in patients with type 1 von Willebrand disease (VWD) are influenced by genetic variation in several genes, e.g. VWF, ABO, STXBP5 and CLEC4M. This study aims to screen comprehensively for CLEC4M variants and investigate their association with type 1 VWD in the Swedish population. In order to screen for CLEC4M variants, the CLEC4M gene region was re-sequenced and the polymorphic neck region was genotyped in 106 type 1 VWD patients from unrelated type 1 VWD families. Single nucleotide variants (SNV) and variable number tandem repeat (VNTR) allele and genotype frequencies were then compared with 294 individuals from the 1000Genomes project and 436 Swedish control individuals. Re-sequencing identified a total of 42 SNVs. Rare variants showed no accumulation in type 1 VWD patients and are not thought to contribute substantially to type 1 VWD. The only missense mutation (rs2277998, NP_001138379.1:p.Asp224Asn) had a higher frequency in type 1 VWD patients than in controls (4.9%). The VNTR genotypes 57 and 67 were observed at higher frequencies than expected in type 1 VWD patients (6.4% and 6.2%) and showed an increase in patients compared with controls (7.4% and 3.1%). Strong linkage disequilibrium in the CLEC4M region makes it difficult to distinguish between the effect of the missense mutation and the VNTR genotypes. In conclusion, heterozygous VNTR genotypes 57 and 67 of CLEC4M were highly enriched and are the most likely mechanism through which CLEC4M contributes to disease in the Swedish type 1 VWD population.

  • 13.
    Manderstedt, Eric
    et al.
    Kristianstad University, Plattformen för molekylär analys. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Lind-Halldén, Christina
    Kristianstad University, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Lethagen, Stefan
    Danmark.
    Halldén, Christer
    Kristianstad University, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Genetic variation in the von Willebrand factor gene in Swedish von Willebrand disease patients2018In: TH Open, ISSN 2512-9465, Vol. 2, no 1, p. 39-48Article in journal (Refereed)
    Abstract [en]

    von Willebrand factor (VWF) level and function are influenced by genetic variation in VWF and several other genes in von Willebrand disease type 1 (VWD1) patients. This study comprehensively screened for VWF variants and investigated the presence of ABO genotypes and common and rare VWF variants in Swedish VWD1 patients. The VWF gene was resequenced using Ion Torrent and Sanger sequencing in 126 index cases historically diagnosed with VWD. Exon 7 of the ABO gene was resequenced using Sanger sequencing. Multiplex ligation-dependent probe amplification analysis was used to investigate for copy number variants. Genotyping of 98 single nucleotide variants allowed allele frequency comparisons with public databases. Seven VWD2 mutations and 36 candidate VWD1 mutations (5 deletions, 4 nonsense, 21 missense, 1 splice, and 5 synonymous mutations) were identified. Nine mutations were found in more than one family and nine VWD1 index cases carried more than one candidate mutation. The T-allele of rs1063857 (c.2385T > C, p.Y795 = ) and blood group O were both frequent findings and contributed to disease in the Swedish VWD1 population. VWD2 mutations were found in 20 and candidate VWD1 mutations in 51 index cases out of 106 (48%). VWF mutations, a VWF haplotype, and blood group O all contributed to explain disease in Swedish VWD1 patients.

  • 14.
    Manderstedt, Eric
    et al.
    Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap. Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin.
    Lind-Halldén, Christina
    Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Svensson, Peter
    Lund University.
    Zöller, Bengt
    Lund University.
    Halldén, C
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin.
    Next-generation sequencing of 17 genes associated with venous thromboembolism reveals a deficit of non-synonymous variants in procoagulant genes2019In: Thrombosis and haemostasis, ISSN 2567-689X, Vol. 119, no 9, p. 1441-1450Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:  The heritability of venous thromboembolism (VTE) is only partially explained by variants in 17 previously VTE-associated genes.

    OBJECTIVE:  This article screens for additional rare variants in the 17 genes and investigates the relative contributions of pro- and anticoagulant genes to VTE.

    PATIENTS AND METHODS:  Ninety-six VTE patients from the population-based Malmö Thrombophilia Study were analysed using an AmpliSeq strategy and Ion Torrent sequencing and the variant data were compared with data from public databases.

    RESULTS:  A total of 102 non-synonymous and 76 synonymous variants were identified. Forty-six non-synonymous variants were present in the human gene mutation database. Anticoagulant and procoagulant genes showed 14 and 22 rare non-synonymous variants, respectively. Individual patients showed varying numbers of risk factors; 13 patients had non-synonymous mutations in SERPINC1, PROC and PROS1 genes and 42 had factor V Leiden or prothrombin mutations generating a total of 47 patients with at least one of these risk factors. Ten common VTE-associated variants showed low level enrichments and no correlation to the other risk factors. The enrichment of previously identified risk factors was similar to previous studies. Determination of the nsyn/syn ratio (number of non-synonymous variants per non-synonymous site, nsyn, to the number of synonymous variants per synonymous site, syn) showed, as expected in patients, an increase of non-synonymous relative to synonymous anticoagulant variants compared with controls (nsyn/syn, 0.95 vs. 0.68). In contrast, non-synonymous procoagulant variants (nsyn/syn, 0.31 vs. 0.63) showed a decrease. We suggest that the deficit of non-synonymous variants in procoagulant genes is a novel mechanism contributing to VTE.

  • 15.
    Manderstedt, Eric
    et al.
    Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap. Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin.
    Nilsson, Rosanna
    Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap. rosanna.nilsson@hkr.se .
    Lind-Halldén, Christina
    Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Ljung, Rolf
    Skåne University Hospital.
    Astermark, Jan
    Skåne University Hospital.
    Halldén, Christer
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin.
    Targeted re-sequencing of F8, F9 and VWF: characterization of Ion Torrent data and clinical implications for mutation screening.2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 4Article in journal (Refereed)
    Abstract [en]

    Mutations are not identified in ~5% of hemophilia A and 10-35% of type 1 VWD patients. The bleeding tendency also varies among patients carrying the same causative mutation, potentially indicating variants in additional genes modifying the phenotype that cannot be identified by routine single-gene analysis. The F8, F9 and VWF genes were analyzed in parallel using an AmpliSeq strategy and Ion Torrent sequencing. Targeting all exonic positions showed an average read depth of >2000X and coverage close to 100% in 24 male patients with known disease-causing mutations. Discrimination between reference alleles and alternative/indel alleles was adequate at a 25% frequency threshold. In F8, F9 and VWF there was an absolute majority of all reference alleles at allele frequencies >95% and the average alternative allele and indel frequencies never reached above 10% and 15%, respectively. In VWF, 4-5 regions showed lower reference allele frequencies; in two regions covered by the pseudogene close to the 25% cut-off for reference alleles. All known mutations, including indels, gross deletions and substitutions, were identified. Additional VWF variants were identified in three hemophilia patients. The presence of additional mutations in 2 out of 16 (12%) randomly selected hemophilia patients indicates a potential mutational contribution that may affect the disease phenotype and counseling in these patients. Parallel identification of disease-causing mutations in all three genes not only confirms the deficiency, but differentiates phenotypic overlaps and allows for correct genetic counseling.

  • 16.
    Säll, T.
    et al.
    Department of Cell and Organism Biology, Genetics, Lund University.
    Jakobsson, M.
    Department of Cell and Organism Biology, Genetics, Lund University.
    Lind-Halldén, Christina
    Kristianstad University, Department of Mathematics and Science.
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital.
    Chloroplast DNA indicates a single origin of the allotetraploid Arabidopsis suecica2003In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 16, no 5, p. 1019-1029Article in journal (Refereed)
    Abstract [en]

    DNA sequencing was performed on up to 12 chloroplast DNA regions [giving a total of 4288 base pairs (bp) in length] from the allopolyploid Arabidopsis suecica (48 accessions) and its two parental species, A. thaliana (25 accessions) and A. arenosa (seven accessions). Arabidopsis suecica was identical to A. thaliana at all 93 sites where A. thaliana and A. arenosa differed, thus showing that A. thaliana is the maternal parent of A. suecica. Under the assumption that A. thaliana and A. arenosa separated 5 million years ago, we estimated a substitution rate of 2.9 x 10(-9) per site per year in noncoding single copy sequence. Within A. thaliana we found 12 substitution (single bp) and eight insertion/deletion (indel) polymorphisms, separating the 25 accessions into 15 haplotypes. Eight of the A. thaliana accessions from central Sweden formed one cluster, which was separated from a cluster consisting of central European and extreme southern Swedish accessions. This latter cluster also included the A. suecica accessions, which were all identical except for one 5 bp indel. We interpret this low level of variation as a strong indication that A. suecica effectively has a single origin, which we dated at 20 000 years ago or more.

  • 17.
    Säll, T.
    et al.
    Department of Genetics, Lund University.
    Lind-Halldén, Christina
    Kristianstad University, Department of Mathematics and Science.
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital,.
    Primer mixtures in RAPD analysis2000In: Hereditas, ISSN 0018-0661, E-ISSN 1601-5223, Vol. 132, no 3, p. 203-208Article in journal (Refereed)
    Abstract [en]

    RAPD (random amplified polymorphic DNA) is a multiplex marker system that conventionally uses single-primer PCR to amplify random DNA fragments. Because of its multiplex nature, it is frequently used in bulked segregant analysis (BSA). In view of the very large numbers of markers BSA often requires, we investigated the use of mixtures of primers as a method of increasing the number of markers available. Theoretically, if a single-primer reaction produces x bands on average, an unrestrained PCR process using a primers should produce xa2 bands. Initially, we investigated mixtures containing from one to five primers. The average number of products increased slightly from the single-primer to the multiple-primer case, whereas it was rather constant for the different multi-primer combinations. This deviation from the theoretical expectations, which we attribute to the effects of competition, shows mixtures of more than two primers to be inefficient. The properties of two-primer mixtures in which the proportions of the two primers were varied were also investigated. The intensities of most of the products were influenced by the proportions of the primers used to create the mixture. A good fit was obtained to a model in which the average competitive ability of a band is directly proportional to the probability of randomly obtaining the band-producing primer combination from the pool of primers. Using two-primer mixtures, a(a-1)/2 different two-primer mixtures can be produced. A comparison of different schemes for constructing the two-primer mixtures indicates that the degree of resampling is similar for all schemes. In conclusion, the use of two-primer mixtures is a simple but very powerful strategy in BSA as it can generate an extremely large number of markers.

  • 18.
    Säll, Torbjörn
    et al.
    Department of Cell and Organism Biology, Genetics, Lund University.
    Lind-Halldén, Christina
    Kristianstad University, Department of Mathematics and Science.
    Jakobsson, Mattias
    Department of Cell and Organism Biology, Genetics, Lund University.
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital.
    Mode of reproduction in Arabidopsis suecica2004In: Hereditas, ISSN 0018-0661, E-ISSN 1601-5223, Vol. 141, no 3, p. 313-317Article in journal (Refereed)
    Abstract [en]

    The breeding system of Arabidopsis suecica was investigated through genetic analysis of microsatellite segregation patterns in five controlled crosses as well as in 16 single-mother families collected in the wild. Analysis of single and two-locus segregations in the F2 generation following a cross clearly shows that A. suecica is reproduces sexually. The single-mother families show a high level of homozygosity corroborating earlier results indicating a high level of inbreeding. The high level of individual homozygosity is due both to a high level of selfing and to the underlying population structure.

1 - 18 of 18
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