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Lind-Halldén, Christina
Publications (10 of 14) Show all publications
Manderstedt, E., Lind-Halldén, C., Lethagen, S. & Halldén, C. (2018). Genetic variation in the von Willebrand factor gene in Swedish von Willebrand disease patients. TH Open, 2(1), 39-48
Open this publication in new window or tab >>Genetic variation in the von Willebrand factor gene in Swedish von Willebrand disease patients
2018 (English)In: TH Open, ISSN 2512-9465, Vol. 2, no 1, p. 39-48Article in journal (Refereed) Published
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.

Keywords
DNA - molecular - diagnosis - Sweden - von Willebrand disease - von Willebrand factor
National Category
Natural Sciences
Identifiers
urn:nbn:se:hkr:diva-17851 (URN)10.1055/s-0037-1618571 (DOI)
Available from: 2018-02-05 Created: 2018-02-05 Last updated: 2019-07-03
Henmyr, V., Carlberg, D., Manderstedt, E., Lind-Halldén, C., Säll, T., Cardell, L. O. & Halldén, C. (2017). Genetic variation of the toll-like receptors in a Swedish allergic rhinitis case population. BMC Medical Genetics, 18(1), Article ID 18.
Open this publication in new window or tab >>Genetic variation of the toll-like receptors in a Swedish allergic rhinitis case population
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2017 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 18, no 1, article id 18Article in journal (Refereed) Published
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.

Keywords
Allergic rhinitis, Mutation spectrum, Next-generation sequencing, Rare variants, Toll-like receptor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:hkr:diva-16592 (URN)10.1186/s12881-017-0379-6 (DOI)000397484800001 ()28228119 (PubMedID)
Funder
Swedish Research Council
Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2019-07-03Bibliographically approved
Henmyr, V., Lind-Halldén, C., Halldén, C., Säll, T., Carlberg, D., Bachert, C. & Cardell, L.-O. (2016). Chronic rhinosinusitis patients show accumulation of genetic variants in PARS2. PLoS ONE, 11(6), Article ID e0158202.
Open this publication in new window or tab >>Chronic rhinosinusitis patients show accumulation of genetic variants in PARS2
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, article id e0158202Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:hkr:diva-16091 (URN)10.1371/journal.pone.0158202 (DOI)000378801200050 ()27348859 (PubMedID)
Available from: 2016-09-28 Created: 2016-09-28 Last updated: 2017-11-21Bibliographically approved
Henmyr, V., Lind-Halldén, C., Carlberg, D., Halldén, C., Melén, E., Wickman, M., . . . Cardell, L. O. (2015). Characterization of genetic variation in TLR8 in relation to allergic rhinitis. Allergy. European Journal of Allergy and Clinical Immunology
Open this publication in new window or tab >>Characterization of genetic variation in TLR8 in relation to allergic rhinitis
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2015 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995Article in journal (Refereed) Published
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.

Keywords
Adolescents, depression, school-based program, prevention, cognitive behavior program
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:hkr:diva-15026 (URN)10.1111/all.12805 (DOI)26556310 (PubMedID)
Available from: 2015-11-18 Created: 2015-11-18 Last updated: 2019-07-03Bibliographically approved
Halldén, C., Mårtensson, A., Nilsson, D., Säll, T., Lind-Halldén, C., Lidén, A. C. & Ljung, R. (2013). Origin of Swedish hemophilia B mutations. Journal of Thrombosis and Haemostasis, 11(11), 2001-2008
Open this publication in new window or tab >>Origin of Swedish hemophilia B mutations
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2013 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no 11, p. 2001-2008Article in journal (Refereed) Published
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.

Keywords
factor IX, founder effect, haplotypes, hemophilia B, mutation
National Category
Hematology
Identifiers
urn:nbn:se:hkr:diva-11227 (URN)10.1111/jth.12410 (DOI)000326764800008 ()24219067 (PubMedID)
Available from: 2013-11-15 Created: 2013-11-15 Last updated: 2019-07-03Bibliographically approved
Halldén, C., Nilsson, D., Säll, T., Lind-Halldén, C., Lidén, A. C. & Ljung, R. (2012). Origin of Swedish hemophilia A mutations. Journal of Thrombosis and Haemostasis, 10(12), 2503-2511
Open this publication in new window or tab >>Origin of Swedish hemophilia A mutations
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2012 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 10, no 12, p. 2503-2511Article in journal (Refereed) Published
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.

Keywords
founder, haplotype, hemophilia A, identical by descent, recurrent mutation
National Category
Hematology
Identifiers
urn:nbn:se:hkr:diva-9964 (URN)10.1111/jth.12010 (DOI)000312539600011 ()23020595 (PubMedID)
Available from: 2012-12-23 Created: 2012-12-23 Last updated: 2019-07-03Bibliographically approved
Lind-Halldén, C., Dahlen, A., Hillarp, A., Zöller, B., Dahlbäck, B. & Halldén, C. (2012). Small and large PROS1 deletions but no other types of rearrangements detected in patients with protein S deficiency. Thrombosis and Haemostasis, 108(1), 94-100
Open this publication in new window or tab >>Small and large PROS1 deletions but no other types of rearrangements detected in patients with protein S deficiency
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2012 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 108, no 1, p. 94-100Article in journal (Refereed) Published
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.

Keywords
thrombophilia, Venous thrombosis, Familial thrombosis, protein C/S pathway, molecular biology methods
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:hkr:diva-9427 (URN)10.1160/TH12-01-0040 (DOI)000306538400014 ()22627709 (PubMedID)
Available from: 2012-06-19 Created: 2012-06-19 Last updated: 2019-07-03Bibliographically approved
Jakobsson, M., Säll, T., Lind-Halldén, C. & Halldén, C. (2007). Evolution of chloroplast mononucleotide microsatellites in Arabidopsis thaliana. Theoretical and Applied Genetics, 114(2), 223-235
Open this publication in new window or tab >>Evolution of chloroplast mononucleotide microsatellites in Arabidopsis thaliana
2007 (English)In: Theoretical and Applied Genetics, ISSN 0040-5752, E-ISSN 1432-2242, Vol. 114, no 2, p. 223-235Article in journal (Refereed) Published
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.

Keywords
SIMPLE-SEQUENCE REPEATS, DNA, MUTATION, LOCI, POPULATION, CONSTRAINTS, DIVERGENCE, DIVERSITY, EXPANSION, DYNAMICS
National Category
Natural Sciences
Identifiers
urn:nbn:se:hkr:diva-191 (URN)10.1007/s00122-006-0425-9 (DOI)000245855700003 ()0040-5752 (ISBN)
Available from: 2009-02-16 Created: 2009-02-11 Last updated: 2019-07-03Bibliographically approved
Jakobsson, M., Säll, T., Lind-Halldén, C. & Halldén, C. (2007). The evolutionary history of the common chloroplast genome of Arabidopsis thaliana and A. suecica. Journal of Evolutionary Biology, 20(1), 104-121
Open this publication in new window or tab >>The evolutionary history of the common chloroplast genome of Arabidopsis thaliana and A. suecica
2007 (English)In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 20, no 1, p. 104-121Article in journal (Refereed) Published
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.

Keywords
Arabidopsis suecica, Arabidopsis thaliana, chloroplast, DNA sequence polymorphism, evolutionary history, polyploidy, population structure, speciation
National Category
Biological Sciences
Identifiers
urn:nbn:se:hkr:diva-8173 (URN)10.1111/j.1420-9101.2006.01217.x (DOI)000242904600019 ()17210004 (PubMedID)
Available from: 2011-06-17 Created: 2011-06-17 Last updated: 2019-07-03Bibliographically approved
Jakobsson, M., Hagenblad, J., Tavaré, S., Säll, T., Halldén, C., Lind-Halldén, C. & Nordborg, M. (2006). A unique recent origin of the allotetraploid species Arabidopsis suecica: evidence from nuclear DNA markers. Molecular biology and evolution, 23(6), 1217-1231
Open this publication in new window or tab >>A unique recent origin of the allotetraploid species Arabidopsis suecica: evidence from nuclear DNA markers
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2006 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 23, no 6, p. 1217-1231Article in journal (Refereed) Published
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.

Keywords
Arabidopsis suecica, Arabidopsis thaliana, polyploidy, polymorphism, speciation, founders
National Category
Biological Sciences
Identifiers
urn:nbn:se:hkr:diva-8177 (URN)10.1093/molbev/msk006 (DOI)000237696800015 ()16549398 (PubMedID)
Available from: 2011-06-17 Created: 2011-06-17 Last updated: 2019-07-03Bibliographically approved
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