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  • 1. Almany, Glenn R.
    et al.
    DE Arruda, Maurício P.
    Arthofer, Wolfgang
    Atallah, Z.K.
    Beissinger, Steven R.
    Berumen, Michael L.
    Bogdanowicz, S M
    Brown, S D
    Bruford, Michael W
    Burdine, C
    Busch, Jeremiah W
    Campbell, Nathan R
    Carey, D
    Carstens, Bryan C
    Chu, K H
    Cubeta, Marc A
    Cuda, J P
    Cui, Zhaoxia
    Datnoff, L E
    Dávila, J A
    Davis, Emily S
    Davis, R M
    Diekmann, Onno E
    Eizirik, Eduardo
    Fargallo, J A
    Fernandes, Fabiano
    Fukuda, Hideo
    Gale, L R
    Gallagher, Elizabeth
    Gao, Yongqiang
    Girard, Philippe
    Godhe, Anna
    Gonçalves, Evonnildo C
    Gouveia, Licinia
    Grajczyk, Amber M
    Grose, M J
    Gu, Zhifeng
    Halldén, Christer
    Dept Clinical Chemistry, Swegene Center for Profiling Polygenic Disease, Malmö University Hospital.
    Härnström, Karolina
    Hemmingsen, Amanda H
    Holmes, Gerald
    Huang, C H
    Huang, Chuan-Chin
    Hudman, S P
    Jones, Geoffrey P
    Kanetis, Loukas
    Karunasagar, Iddya
    Karunasagar, Indrani
    Keyghobadi, Nusha
    Klosterman, S J
    Klug, Page E
    Koch, J
    Koopman, Margaret M
    Köppler, Kirsten
    Koshimizu, Eriko
    Krumböck, Susanne
    Kubisiak, T
    Landis, J B
    Lasta, Mario L
    Lee, Chow-Yang
    Li, Qianqian
    Li, Shou-Hsien
    Lin, Rong-Chien
    Liu, M
    Liu, Na
    Liu, W C
    Liu, Yuan
    Loiseau, A
    Luan, Weisha
    Maruthachalam, K K
    McCormick, Helen M
    Mellick, Rohan
    Monnahan, P J
    Morielle-Versute, Eliana
    Murray, Tomás E
    Narum, Shawn R
    Neufeld, Katie
    De Nova, P J G
    Ojiambo, Peter S
    Okamoto, Nobuaki
    Othman, Ahmad Sofiman
    Overholt, W A
    Pardini, Renata
    Paterson, Ian G
    Patty, Olivia A
    Paxton, Robert J
    Planes, Serge
    Porter, Carolyn
    Pratchett, Morgan S
    Püttker, Thomas
    Rasic, Gordana
    Rasool, Bilal
    Rey, O
    Riegler, Markus
    Riehl, C
    Roberts, John M K
    Roberts, P D
    Rochel, Elisabeth
    Roe, Kevin J
    Rossetto, Maurizio
    Ruzzante, Daniel E
    Sakamoto, Takashi
    Saravanan, V
    Sarturi, Cladinara Roberts
    Schmidt, Anke
    Schneider, Maria Paula Cruz
    Schuler, Hannes
    Serb, Jeanne M
    Serrão, Ester T A
    Shi, Yaohua
    Silva, Artur
    Sin, Y W
    Sommer, Simone
    Stauffer, Christian
    Strüssmann, Carlos Augusto
    Subbarao, K V
    Syms, Craig
    Tan, Feng
    Tejedor, Eugenio Daniel
    Thorrold, Simon R
    Trigiano, Robert N
    Trucco, María I
    Tsuchiya-Jerep, Mirian Tieko Nunes
    Vergara, P
    Van De Vliet, Mirjam S
    Wadl, Phillip A
    Wang, Aimin
    Wang, Hongxia
    Wang, R X
    Wang, Xinwang
    Wang, Yan
    Weeks, Andrew R
    Wei, Fuwen
    Werner, William J
    Wiley, E O
    Williams, D A
    Wilkins, Richard J
    Wisely, Samantha M
    With, Kimberly A
    Wu, Danhua
    Yao, Cheng-Te
    Yau, Cynthia
    Yeap, Beng-Keok
    Zhai, Bao-Ping
    Zhan, Xiangjiang
    Zhang, Guo-Yan
    Zhang, S Y
    Zhao, Ru
    Zhu, Lifeng
    Permanent Genetic Resources added to Molecular Ecology Resources Database 1 May 2009-31 July 20092009In: Molecular ecology resources, ISSN 1755-0998, Vol. 9, no 6, p. 1460-1466Article in journal (Refereed)
    Abstract [en]

    This article documents the addition of 512 microsatellite marker loci and nine pairs of Single Nucleotide Polymorphism (SNP) sequencing primers to the Molecular Ecology Resources Database. Loci were developed for the following species: Alcippe morrisonia morrisonia, Bashania fangiana, Bashania fargesii, Chaetodon vagabundus, Colletes floralis, Coluber constrictor flaviventris, Coptotermes gestroi, Crotophaga major, Cyprinella lutrensis, Danaus plexippus, Fagus grandifolia, Falco tinnunculus, Fletcherimyia fletcheri, Hydrilla verticillata, Laterallus jamaicensis coturniculus, Leavenworthia alabamica, Marmosops incanus, Miichthys miiuy, Nasua nasua, Noturus exilis, Odontesthes bonariensis, Quadrula fragosa, Pinctada maxima, Pseudaletia separata, Pseudoperonospora cubensis, Podocarpus elatus, Portunus trituberculatus, Rhagoletis cerasi, Rhinella schneideri, Sarracenia alata, Skeletonema marinoi, Sminthurus viridis, Syngnathus abaster, Uroteuthis (Photololigo) chinensis, Verticillium dahliae, Wasmannia auropunctata, and Zygochlamys patagonica. These loci were cross-tested on the following species: Chaetodon baronessa, Falco columbarius, Falco eleonorae, Falco naumanni, Falco peregrinus, Falco subbuteo, Didelphis aurita, Gracilinanus microtarsus, Marmosops paulensis, Monodelphis Americana, Odontesthes hatcheri, Podocarpus grayi, Podocarpus lawrencei, Podocarpus smithii, Portunus pelagicus, Syngnathus acus, Syngnathus typhle,Uroteuthis (Photololigo) edulis, Uroteuthis (Photololigo) duvauceli and Verticillium albo-atrum. This article also documents the addition of nine sequencing primer pairs and sixteen allele specific primers or probes for Oncorhynchus mykiss and Oncorhynchus tshawytscha; these primers and assays were cross-tested in both species.

  • 2.
    Andiappan, Anand Kumar
    et al.
    Department of Biological Sciences, National University of Singapore.
    Nilsson, Daniel
    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.
    Yun, Wang De
    Department of Otolaryngology, National University of Singapore.
    Säll, Torbjörn
    Department of Cell and Organism Biology, Lund University.
    Cardell, Lars Olaf
    Division of ENT Diseases, CLINTEC, Karolinska Institutet.
    Tim, Chew Fook
    Department of Biological Sciences, National University of Singapore.
    Investigating highly replicated asthma genes as candidate genes for allergic rhinitis2013In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 14, p. 51-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Asthma genetics has been extensively studied and many genes have been associated with the development or severity of this disease. In contrast, the genetic basis of allergic rhinitis (AR) has not been evaluated as extensively. It is well known that asthma is closely related with AR since a large proportion of individuals with asthma also present symptoms of AR, and patients with AR have a 5-6 fold increased risk of developing asthma. Thus, the relevance of asthma candidate genes as predisposing factors for AR is worth investigating. The present study was designed to investigate if SNPs in highly replicated asthma genes are associated with the occurrence of AR.

    METHODS: A total of 192 SNPs from 21 asthma candidate genes reported to be associated with asthma in 6 or more unrelated studies were genotyped in a Swedish population with 246 AR patients and 431 controls. Genotypes for 429 SNPs from the same set of genes were also extracted from a Singapore Chinese genome-wide dataset which consisted of 456 AR cases and 486 controls. All SNPs were subsequently analyzed for association with AR and their influence on allergic sensitization to common allergens.

    RESULTS: A limited number of potential associations were observed and the overall pattern of P-values corresponds well to the expectations in the absence of an effect. However, in the tests of allele effects in the Chinese population the number of significant P-values exceeds the expectations. The strongest signals were found for SNPs in NPSR1 and CTLA4. In these genes, a total of nine SNPs showed P-values <0.001 with corresponding Q-values <0.05. In the NPSR1 gene some P-values were lower than the Bonferroni correction level. Reanalysis after elimination of all patients with asthmatic symptoms excluded asthma as a confounding factor in our results. Weaker indications were found for IL13 and GSTP1 with respect to sensitization to birch pollen in the Swedish population.

    CONCLUSIONS: Genetic variation in the majority of the highly replicated asthma genes were not associated to AR in our populations which suggest that asthma and AR could have less in common than previously anticipated. However, NPSR1 and CTLA4 can be genetic links between AR and asthma and associations of polymorphisms in NPSR1 with AR have not been reported previously.

  • 3. Bachert, C
    et al.
    Van Bruaene, N
    Toskala, E
    Zhang, N
    Olze, H
    Scadding, G
    Van Drunen, C M
    Mullol, J
    Cardell, L
    Gevaert, P
    Van Zele, T
    Claeys, S
    Halldén, Christer
    Malmö University Hospital.
    Kostamo, K
    Foerster, U
    Kowalski, M
    Bieniek, K
    Olszewska-Ziaber, A
    Nizankowska-Mogilnicka, E
    Szczeklik, A
    Swierczynska, M
    Arcimowicz, M
    Lund, V
    Fokkens, W
    Zuberbier, T
    Akdis, C
    Canonica, G
    Van Cauwenberge, P
    Burney, P
    Bousquet, J
    Important research questions in allergy and related diseases: 3-chronic rhinosinusitis and nasal polyposis - a GALEN study2009In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 64, no 4, p. 520-533Article in journal (Refereed)
    Abstract [en]

    Chronic rhinosinusitis is one of the most common health care challenges, with significant direct medical costs and severe impact on lower airway disease and general health outcomes. The diagnosis of chronic rhinosinusitis (CRS) currently is based on clinical signs, nasal endoscopy and CT scanning, and therapeutic recommendations are focussing on 2 classes of drugs, corticosteroids and antibiotics. A better understanding of the pathogenesis and the factors amplifying mucosal inflammation therefore seems to be crucial for the development of new diagnostic and therapeutic tools. In an effort to extend knowledge in this area, the WP 2.7.2 of the GA(2)LEN network of excellence currently collects data and samples of 1000 CRS patients and 250 control subjects. The main objective of this project is to characterize patients with upper airway disease on the basis of clinical parameters, infectious agents, inflammatory mechanisms and remodeling processes. This collaborative research will result in better knowledge on patient phenotypes, pathomechanisms, and subtypes in chronic rhinosinusitis. This review summarizes the state of the art on chronic rhinosinusitis and nasal polyposis in different aspects of the disease. It defines potential gaps in the current research, and points to future research perspectives and targets.

  • 4. Benson, M
    et al.
    Mobini, R
    Barrenäs, F
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital.
    Naluai, A T
    Säll, T
    Cardell, L O
    A haplotype in the inducible T-cell tyrosine kinase is a risk factor for seasonal allergic rhinitis2009In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 64, no 9, p. 1286-1291Article in journal (Refereed)
    Abstract [en]

    Background:  Identification of disease-associated single nucleotide polymorphisms (SNPs) in seasonal allergic rhinitis (SAR) may be facilitated by focusing on genes in a disease-associated pathway.

    Objective:  To search for SNPs in genes that belong to the T-cell receptor (TCR) pathway and that change in expression in allergen-challenged CD4+ cells from patients with SAR.

    Methods:  CD4+ cells from patients with SAR were analysed with gene expression microarrays. Allele, genotype and haplotype frequencies were compared in 251 patients and 386 healthy controls.

    Results:  Gene expression microarray analysis of allergen-challenged CD4+ cells from patients with SAR showed that 25 of 38 TCR pathway genes were differentially expressed. A total of 62 SNPs were analysed in eight of the 25 genes; ICOS, IL4, IL5, IL13, CSF2, CTLA4, the inducible T-cell tyrosine kinase (ITK) and CD3D. Significant chi-squared values were identified for several markers in the ITK kinase gene region. A total of five SNPs were nominally significant at the 5% level. Haplotype analysis of the five significant SNPs showed increased frequency of a haplotype that covered most of the coding part of ITK. The functional relevance of ITK was supported by analysis of an independent material, which showed increased expression of ITK in allergen-challenged CD4+ cells from patients, but not from controls.

    Conclusion:  Analysis of SNPs in TCR pathway genes revealed that a haplotype that covers a major part of the coding sequence of ITK is a risk factor for SAR.

  • 5. Bryborn, M.
    et al.
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital.
    Säll, T.
    Cardell, L.O.
    CLC- a novel susceptibility gene for allergic rhinitis?2010In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 65, no 2, p. 220-228Article in journal (Refereed)
    Abstract [en]

    Background:  Studies of the nasal lavage fluid proteome have previously identified proteins differently expressed in patients with symptomatic allergic rhinitis, e.g. S100A7, prolactin-inducible protein (PIP), wingless-type MMTV integration site family, member 2B (WNT2B), Charcot-Leyden crystal protein (CLC) and palate lung nasal epithelial clone (PLUNC). The aim of the present study was to investigate if genetic variation associated with allergic rhinitis can be found in these genes.

    Methods:  Peripheral blood was collected from 251 patients with birch and/or grass pollen-induced allergic rhinitis and 386 nonatopic healthy controls. A total of 39 single nucleotide polymorphisms (SNPs) distributed over the genes PIP, WNT2B, CLC and PLUNC were selected from dbSNP, genotyped and investigated for associations with allergic rhinitis. Twelve additional SNPs were subsequently analysed for CLC.

    Results:  All 22 investigated SNPs in CLC were polymorphic. Ten SNPs yielded significant differences between cases and controls with respect to genotype frequencies. Homozygotes for the minor allele were more common in allergic individuals compared to healthy controls. The minor alleles of these SNPs were all located on the same haplotype. Furthermore, homozygotes for the minor allele of two of the promoter SNPs had higher average scores for birch in skin prick test. In contrast, for seven SNPs within the gene, heterozygotes and homozygotes for the major allele had higher average scores for grass. None of the other three genes showed association.

    Conclusion:  Genetic variation in CLC was found to be associated with allergic rhinitis. The pattern of variation is compatible with a recessive inheritance model and the previously observed altered protein levels detected in patients with allergic rhinitis.

  • 6. Bryborn, Malin
    et al.
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital.
    Säll, Torbjörn
    Adner, Mikael
    Cardell, Lars Olaf
    Comprehensive evaluation of genetic variation in S100A7 suggests an association with the occurrence of allergic rhinitis2008In: Respiratory research (Online), ISSN 1465-9921, E-ISSN 1465-993X, Vol. 9, no 1, p. 29-Article in journal (Refereed)
    Abstract [en]

    Background S100A7 is a calcium-binding protein with chemotactic and antimicrobial properties. S100A7 protein levels are decreased in nasal lavage fluid from individuals with ongoing allergic rhinitis, suggesting a role for S100A7 in allergic airway inflammation. The aims of this study were to describe genetic variation in S100A7 and search for associations between this variation and allergic rhinitis. Methods Peripheral blood was collected from 184 atopic patients with a history of pollen-induced allergic rhinitis and 378 non-atopic individuals, all of Swedish origin. DNA was extracted and the S100A7 gene was resequenced in a subset of 47 randomly selected atopic individuals. Nine polymorphisms were genotyped in 184 atopic and 378 non-atopic individuals and subsequently investigated for associations with allergic rhinitis as well as skin prick test results. Haplotypes were estimated and compared in the two groups. Results Thirteen polymorphisms were identified in S100A7, of which 7 were previously undescribed. rs3014837 (G/C), which gives rise to an Asp → Glu amino acid shift, had significantly increased minor allele frequency in atopic individuals. The major haplotype, containing the major allele at all sites, was more common in non-atopic individuals, while the haplotype containing the minor allele at rs3014837 was equally more common among the atopic individuals. Additionally, heterozygotes at this site had significantly higher scores in skin prick tests for 9 out of 11 tested allergens, compared to homozygotes. Conclusion This is the first study describing genetic variation, associated with allergy, in S100A7. The results indicate that rs3014837 is linked to allergic rhinitis in our Swedish population and render S100A7 a strong candidate for further investigations regarding its role in allergic inflammation.

  • 7. Dahlman, A.
    et al.
    Edsjö, A.
    Halldén, Christer
    Division of Clinical Chemistry, Lund University.
    Persson, J.L.
    Fine, S.W.
    Lilja, H.
    Gerald, W.
    Bjartell, A.
    Effect of androgen deprivation therapy on the expression of prostate cancer biomarkers MSMB and MSMB-binding protein CRISP32010In: Prostate Cancer and Prostatic Diseases, ISSN 1365-7852, E-ISSN 1476-5608, Vol. 13, no 4, p. 369-375Article in journal (Refereed)
    Abstract [en]

    We have investigated the effects of short-term neoadjuvant and long-term androgen deprivation therapies (ADTs) on β-microseminoprotein (MSMB) and cysteine-rich secretory protein-3 (CRISP3) expression in prostate cancer patients. We also studied if MSMB expression was related to genotype and epigenetic silencing. Using an Affymetrix cDNA microarray analysis, we investigated the expression of MSMB, CRISP3, androgen receptor (AR), KLK3 and Enhancer of Zeste Homologue-2 (EZH2) in tissue from prostate cancer patients receiving (n=17) or not receiving (n=23) ADT before radical prostatectomy. MSMB, CRISP3 and AR were studied in tissue from the same patients undergoing TURP before and during ADT (n=16). MSMB genotyping of these patients was performed by TaqMan PCR. MSMB and KLK3 expression levels decreased during ADT. Expression levels of AR and CRISP3 were not affected by short-term ADT but were high in castration-resistant prostate cancer (CRPC) and metastases. Levels of EZH2 were also high in metastases, where MSMB was low. Genotyping of the MSMB rs10993994 polymorphism showed that the TT genotype conveys poor MSMB expression. MSMB expression is influenced by androgens, but also by genotype and epigenetic silencing. AR and CRISP3 expression are not influenced by short-term ADT, and high levels were found in CRPC and metastases.

  • 8. Gallagher, David J.
    et al.
    Vijai, Joseph
    Cronin, Angel M.
    Bhatia, Jasmine
    Vickers, Andrew J.
    Gaudet, Mia M.
    Fine, Samson
    Reuter, Victor
    Scher, Howard I.
    Halldén, Christer
    Memorial Sloan-Kettering Cancer Center.
    Dutra-Clarke, Ana
    Klein, Robert J.
    Scardino, Peter T.
    Eastham, James A.
    Lilja, Hans
    Kirchhoff, Tomas
    Offit, Kenneth
    Susceptibility loci associated with prostate cancer progression and mortality2010In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 10, p. 2819-2832Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Prostate cancer is a heterogeneous disease with a variable natural history that is not accurately predicted by currently used prognostic tools.

    EXPERIMENTAL DESIGN:

    We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and prostate-specific antigen. We investigated associations between 29 single nucleotide polymorphisms (SNP) and biochemical recurrence, castration-resistant metastasis, and prostate cancer-specific survival. Subsequently, we did an independent analysis using a high-resolution panel of 13 SNPs.

    RESULTS:

    On univariate analysis, two SNPs were associated (P<0.05) with biochemical recurrence, three SNPs were associated with clinical metastases, and one SNP was associated with prostate cancer-specific mortality. Applying a Bonferroni correction (P<0.0017), one association with biochemical recurrence (P=0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer-specific mortality in KLK3 (P<0.0005 by both univariate and multivariable analysis).

    CONCLUSIONS:

    We identified associations between prostate cancer susceptibility SNPs and clinical end points. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region were strongly associated with prostate cancer-specific survival, and rs10486567 in the 7JAZF1 gene were associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models.

  • 9. Goodeve, Anne
    et al.
    Eikenboom, Jeroen
    Castaman, Giancarlo
    Rodeghiero, Francesco
    Federici, Augusto B.
    Batlle, Javier
    Meyer, Dominique
    Mazurier, Claudine
    Goudemand, Jenny
    Schneppenheim, Reinhard
    Budde, Ulrich
    Ingerslev, Jorgen
    Habart, David
    Vorlova, Zdena
    Holmberg, Lars
    Lethagen, Stefan
    Pasi, John
    Hill, Frank
    Hashemi Soteh, Mohammad
    Baronciani, Luciano
    Halldén, Christer
    Department for Coagulation Disorders, University of Lund, Malmö.
    Guilliatt, Andrea
    Lester, Will
    Peake, Ian
    Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD)2007In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 109, no 1, p. 112-121Article in journal (Refereed)
    Abstract [en]

    Type 1 von Willebrand disease (VWD) is characterized by a personal and family history of bleeding coincident with reduced levels of normal plasma von Willebrand factor (VWF). The molecular basis of the disorder is poorly understood. The aims of this study were to determine phenotype and genotype and their relationship in patients historically diagnosed with type 1 VWD. Families were recruited in 9 European countries based on previous type 1 VWD diagnosis. Bleeding symptoms were recorded, plasma phenotype analyzed, and VWF mutation analysis performed in all index cases (ICs). Phenotypic and molecular analysis stratified patients into those with or without phenotypes suggestive of qualitative VWF defects (abnormal multimers) and with or without mutations. A total of 105 of 150 ICs (70%) had mutations identified. A subgroup with abnormal multimers (38% of ICs, 57 of 150) showed a high prevalence of VWF gene mutations (95% of ICs, 54 of 57), whereas in those with qualitatively normal VWF, fewer mutations were identified (55% of ICs, 51 of 93). About one third of the type 1 VWD cases recruited could be reconsidered as type 2. The remaining group could be considered "true" type 1 VWD, although mutations were found in only 55%.

  • 10.
    Halldén, Christer
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Knobe, K. E.
    Departments of Pediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Malmö.
    Sjörin, E.
    Departments of Pediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Malmö.
    Nilsson, Daniel
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Ljung, R.
    Departments of Pediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Malmö.
    Investigation of disease-associated factors in haemophilia A patients without detectable mutations2012In: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 18, no 3, p. e132-e137Article in journal (Refereed)
    Abstract [en]

    To investigate disease causing mechanism in haemophilia A patients without detectable mutation. Screening for F8 mutations in 307 haemophilia A patients using: re-sequencing and inversion PCR, reverse transcription (RT-PCR) of mRNA, MLPA analysis, haplotyping using SNP and microsatellite markers. No F8 mutations were detected in 9 of the 307 patients (2.9%) using re-sequencing and inversion PCR. MLPA analysis detected duplication in exon 6 in one patient and RT-PCR showed no products for different regions of mRNA in four other patients, indicating failed transcription. No obvious associations were observed between the phenotypes of the nine patients, their F8 haplotypes and the putative mutations detected. The mutation-positive patients carrying the same haplotypes as the mutation-negative patients show a multitude of different mutations, emphasizing the lack of associations at the haplotype level. VWF mutation screening and factor V measurements ruled out type 2N VWD and combined factor V and VIII deficiency respectively. To further investigate a possible role for FVIII interacting factors the haplotypes/diplotypes of F2, F9, F10 and VWF were compared. The nine patients had no specific haplotype/diplotype combination in common that can explain disease. Duplications and faulty transcription contribute to the mutational spectrum of haemophilia A patients where conventional mutation screening fail to identify mutations.

  • 11.
    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.

  • 12.
    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.

  • 13.
    Halldén, Christer
    et al.
    Hilleshög AB, Landskrona.
    Nilsson, N. O.
    Hjerdin, A.
    Rading, I. M.
    A gel electrophoresis system adapted for large-scale molecular marker analysis1996In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 242, no 1, p. 145-7Article in journal (Refereed)
  • 14.
    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.

  • 15. 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.

  • 16.
    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.

  • 17.
    Henmyr, Viktor
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Vandeplas, Griet
    University Hospital Ghent.
    Halldén, Christer
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Säll, Torbjörn
    Lund University.
    Olze, Heidi
    Charité Berlin.
    Bachert, Claus
    Karolinska Institutet.
    Cardell, Lars Olaf
    Karolinska Institutet.
    Replication study of genetic variants associated with chronic rhinosinusitis and nasal polyposis2014In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 133, no 1, p. 273-275Article in journal (Refereed)
  • 18.
    Hjerdin, A
    et al.
    Hilleshög AB.
    Säll, T
    Lunds universitet.
    Nilsson, N.O.
    Lunds universitet.
    Bornman, C.H.
    Hilleshög AB.
    Halldén, Christer
    Hilleshög AB.
    Genetic Variation Among Wild and Cultivated Beets of the Section Beta as Revealed by RFLP Analysis1994In: Journal of sugarbeet research, ISSN 0899-1502, Vol. 31, no 1&2, p. 59-67Article in journal (Refereed)
    Abstract [en]

    The level of genetic variation detected among 7 sugar beet and 4 fodder beet breeding lines was compared to the variation found among 21 accessions of wild beets of the section Beta. RFLP analysis used a set of 32 sugar beet DNA sequences as probes to score a total of 351 bands over all accessions. The band data was used to calculate genetic distances between all pairs of accessions. The distance estimates were subsequently used in a cluster analysis to produce a dendrogram of genetic distances. The analysis unambiguously defined all accessions and clearly defined a fodder beet cluster within the sugar beet cluster. The cultivated beets were all separated from the wild beets. The sugar beet breeding lines showed a considerable amount of genetic variation, comparable with the level of variation detected among the wild beet accessions.

  • 19.
    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.

  • 20.
    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.

  • 21.
    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.

  • 22. Johansson, Anna M.
    et al.
    Halldén, Christer
    Department of Clinical Chemistry, University Hospital, Malmö.
    Säll, Torbjorn
    Detecting deletions in families affected by a dominant disease by use of marker data2005In: Human Heredity, ISSN 0001-5652, E-ISSN 1423-0062, Vol. 60, no 1, p. 26-35Article in journal (Refereed)
    Abstract [en]

    A method of testing for whether inherited deletions are a cause of a single-locus dominant disease was derived, involving analysis of the marker segregation within the pedigree of a single family that segregates for the disease. It is shown that markers can be used to test deductively for the presence of an inherited deletion. The probabilities of confirming or rejecting the presence of a deletion in an arbitrary pedigree without inbreeding are then derived. The power of the test is shown to be limited in single trios but to increase rapidly as the size of the pedigree increases. For larger pedigrees, the probabilities of confirming or rejecting a deletion are higher than 0.9 for SNPs having a minor allele frequency greater than 0.4. The probabilities are higher using multiallelic markers such as microsatellites, reaching levels as high as 0.9 in even rather small pedigrees. In certain cases the test outcome is not deductive, a deletion being neither confirmed nor rejected. It is shown to still be possible then to employ a statistical test for the presence of a deletion by use of an a priori probability for a deletion.

  • 23.
    Johansson, Anna M.
    et al.
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala.
    Halldén, Christer
    Kristianstad University, School of Health and Society.
    Säll, Torbjörn
    Department of Biology, Lund University.
    Lethagen, Stefan
    Department for Coagulation Disorders, University Hospital, Malmö.
    Variation in the VWF Gene in Swedish patients with type 1 von Willebrand Disease2011In: Annals of Human Genetics, ISSN 0003-4800, E-ISSN 1469-1809, Vol. 75, no 4, p. 447-455Article in journal (Refereed)
    Abstract [en]

    The spectrum of mutations in the von Willebrand factor (VWF) gene in a Swedish type 1 von Willebrand disease (VWD) population was investigated. To gain more knowledge about the dynamics of VWD mutations, the data were analyzed from a population genetics perspective. The VWF gene was resequenced in 54 Swedish patients diagnosed with type 1 VWD. Fifty-five variable sites were located in exons, 10 in the promoter and 38 in introns. The spectrum of mutations was similar to a European study, but included 10 new candidate mutations. The synonymous sites were evenly distributed along the coding sequence, whereas nonsynonymous sites were located into three clusters. Overall, 44% of patients had no mutations or candidate mutations and no promoter haplotype was significantly associated with disease. In 11 patients (20%), more than one mutation or candidate mutation was detected. The allelic identity for the putative disease-causing mutations was approximately 0.1, compatible with an overall disease frequency of 1%. VWF sequences for exon 28 from eight monkey species were compared with the variable positions found in our patients. Positions classified as mutations were overrepresented among sites that were fixed in all eight monkey species. No general increase of the mutation rate was found for the pseudogene region.

  • 24. Johansson, Anna M.
    et al.
    Hillarp, Andreas
    Säll, Torbjörn
    Zöller, Bengt
    Dahlbäck, Björn
    Halldén, Christer
    Department of Clinical Chemistry, University Hospital, Malmö.
    Large deletions of the PROS1 gene in a large fraction of mutation-negative patients with protein S deficiency2005In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 94, no 5, p. 951-957Article in journal (Refereed)
    Abstract [en]

    Protein S deficiency is an autosomal dominant disorder that results from mutations in the PROS1 gene. Conventional mutation detection techniques fail to detect a pathogenic PROS1 mutation in approximately 50% of cases. The present study investigates whether large deletions of PROS1 are found in families where mutations in the PROS1 gene have not been found despite sequencing. For this purpose,a dense set of SNP and microsatellite markers were used in segregation analysis to identify deletions. Large deletions were identified by this technique in three out of eight investigated families (38%). The deletions encompassed at least 35 kb, 437 kb and 449 kb respectively. The deletions were confirmed by quantitative PCR. Haplotype analysis showed that the three large deletions and the five other disease haplotypes were all different. All of the eight disease haplotypes co-segregated with protein S deficiency, but each of the five non-deletion haplotypes were present also in normal individuals. In conclusion: Large deletions of PROS1 are relatively common in protein S deficiency patients and screening for large deletions in PROS1 mutation-negative individuals are therefore warranted.

  • 25.
    Johansson, Anna M.
    et al.
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala.
    Lanke, Elsa
    Department for Coagulation Disorders, University Hospital, Malmö.
    Säll, Torbjörn
    Department of Biology, Lund University.
    Lethagen, Stefan
    Department for Coagulation Disorders, University Hospital, Malmö.
    Halldén, Christer
    Kristianstad University, School of Teacher Education.
    A large deletion identified in a Swedish family with type 1 VWD2011In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 105, no 4, p. 733-734Article in journal (Refereed)
  • 26. Klein, R.J.
    et al.
    Halldén, Christer
    Department of Laboratory Medicine, Lund University.
    Gupta, A.
    Savage, C.J.
    Dahlin, A.
    Bjartell, A.
    Manjer, J.
    Scardina, P.T.
    Ulmert, D.
    Wallström, P.
    Vickers, A.J.
    Lilja, H.
    Evaluation of multiple risk-associated single nucleotide polymorphisms versus prostate-specific antigen at baseline to predict prostate cancer in unscreened men2012In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 61, no 3, p. 471-477Article in journal (Refereed)
  • 27. Klein, Robert J.
    et al.
    Halldén, Christer
    Departments of Laboratory Medicine (Clinical Chemistry) and Clinical Sciences (Urology) in Malmö, Lund University.
    Cronin, Angel M.
    Ploner, Alexander
    Wiklund, Fredrik
    Bjartell, Anders S.
    Stattin, Pär
    Xu, Jianfeng
    Scardino, Peter T.
    Offit, Kenneth
    Vickers, Andrew J.
    Grönberg, Henrik
    Lilja, Hans
    Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms: kallikreins and prostate cancer2010In: Cancer prevention research (Philadelphia, Pa.), ISSN 1940-6215, Vol. 3, no 5, p. 611-619Article in journal (Refereed)
    Abstract [en]

    Polymorphisms associated with prostate cancer include those in three genes encoding major secretory products of the prostate: KLK2 (encoding kallikrein-related peptidase 2; hK2), KLK3 (encoding prostate-specific antigen; PSA), and MSMB (encoding beta-microseminoprotein). PSA and hK2, members of the kallikrein family, are elevated in sera of men with prostate cancer. In a comprehensive analysis that included sequencing of all coding, flanking, and 2 kb of putative promoter regions of all 15 kallikrein (KLK) genes spanning approximately 280 kb on chromosome 19q, we identified novel single-nucleotide polymorphisms (SNP) and genotyped 104 SNPs in 1,419 cancer cases and 736 controls in Cancer Prostate in Sweden 1, with independent replication in 1,267 cases and 901 controls in Cancer Prostate in Sweden 2. This verified prior associations of SNPs in KLK2 and in MSMB (but not in KLK3) with prostate cancer. Twelve SNPs in KLK2 and KLK3 were associated with levels of PSA forms or hK2 in plasma of control subjects. Based on our comprehensive approach, this is likely to represent all common KLK variants associated with these phenotypes. A T allele at rs198977 in KLK2 was associated with increased cancer risk and a striking decrease of hK2 levels in blood. We also found a strong interaction between rs198977 genotype and hK2 levels in blood in predicting cancer risk. Based on this strong association, we developed a model for predicting prostate cancer risk from standard biomarkers, rs198977 genotype, and rs198977 x hK2 interaction; this model had greater accuracy than did biomarkers alone (area under the receiver operating characteristic curve, 0.874 versus 0.866), providing proof in principle to clinical application for our findings.

  • 28. Kraft, T.
    et al.
    Säll, T.
    Fridlund, B.
    Hjerdin, A.
    Tuvesson, S.
    Halldén, Christer
    Hilleshög AB, Landskrona.
    Estimating genetic variation in sugar beets and wild beets using pools of individuals1997In: Genome, ISSN 0831-2796, E-ISSN 1480-3321, Vol. 40, no 4, p. 527-533Article in journal (Refereed)
    Abstract [en]

    The study describes the genetic structure in sugar beets and in wild beets (Beta vulgaris) using 30 RFLP markers. Samples consisting of pooled plant material of 100 individuals from each line and population were used to analyse 120 sugar beet breeding lines and 91 wild beet populations. Greater variation was found among the wild populations than among the breeding lines. Although the two major groups of breeding lines, monogerm and multigerm, had approximately equal amounts of genetic variation, in the monogerm group more of this variation was partitioned among the lines than within the lines. Furthermore, despite most of the variation being shared by the two groups, the two groups were found to be separated along the first two components in a principal component analysis. Computer simulations were carried out to evaluate the usefulness of the pooled-sample strategy employed in the investigation. These simulations showed the use of pooled samples to be a better alternative than that of analysing a few plants individually.

  • 29. Kraft, T.
    et al.
    Säll, T.
    Magnusson-Rading, I.
    Nilsson, N. O.
    Halldén, Christer
    Department of Genetics, Lund University.
    Positive correlation between recombination rates and levels of genetic variation in natural populations of sea beet (Beta vulgaris subsp. maritima)1998In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 150, no 3, p. 1239-1244Article in journal (Refereed)
    Abstract [en]

    The relation between the level of genetic variation and the rate of recombination per physical unit was investigated in sea beet (Beta vulgaris subsp. maritima). The rate of recombination per physical unit was estimated indirectly through marker density in an RFLP linkage map of sugar beet. From this map, we also selected RFLP markers covering two of the nine chromosomes in Beta. The markers were used to estimate the level of genetic variation in three populations of sea beet, two from Italy and one from England. Two estimates of genetic variation were employed, one based on the number of alleles in the sample and the other on heterozygosity. A statistically significant positive correlation was found between recombination rate and genetic variation. Several theoretical explanations for this are discussed, background selection being one. A correlation similar to this has been observed previously in Drosophila, one that was higher than what we obtained for Beta. This is consistent with various biological differences between the two species.

  • 30. Lahermo, Päivi
    et al.
    Liljedahl, Ulrika
    Alnaes, Grethe
    Axelsson, Tomas
    Brookes, Anthony J.
    Ellonen, Pekka
    Groop, Per-Henrik
    Halldén, Christer
    Clinical Chemistry, Malmö University Hospital.
    Holmberg, Dan
    Holmberg, Kristina
    Keinänen, Mauri
    Kepp, Katrin
    Kere, Juha
    Kiviluoma, Päivi
    Kristensen, Vessela
    Lindgren, Cecilia
    Odeberg, Jacob
    Osterman, Pia
    Parkkonen, Maija
    Saarela, Janna
    Sterner, Maria
    Strömqvist, Linda
    Talas, Ulvi
    Wessman, Maija
    Palotie, Aarno
    Syvänen, Ann-Christine
    A quality assessment survey of SNP genotyping laboratories2006In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 27, no 7, p. 711-714Article in journal (Refereed)
    Abstract [en]

    To survey the quality of SNP genotyping, a joint Nordic quality assessment (QA) round was organized between 11 laboratories in the Nordic and Baltic countries. The QA round involved blinded genotyping of 47 DNA samples for 18 or six randomly selected SNPs. The methods used by the participating laboratories included all major platforms for small- to medium-size SNP genotyping. The laboratories used their standard procedures for SNP assay design, genotyping, and quality control. Based on the joint results from all laboratories, a consensus genotype for each DNA sample and SNP was determined by the coordinator of the survey, and the results from each laboratory were compared to this genotype. The overall genotyping accuracy achieved in the survey was excellent. Six laboratories delivered genotype data that were in full agreement with the consensus genotype. The average accuracy per SNP varied from 99.1 to 100% between the laboratories, and it was frequently 100% for the majority of the assays for which SNP genotypes were reported. Lessons from the survey are that special attention should be given to the quality of the DNA samples prior to genotyping, and that a conservative approach for calling the genotypes should be used to achieve a high accuracy.

  • 31. Lanke, E.
    et al.
    Johansson, A. M.
    Halldén, Christer
    Department of Clinical Chemistry, University Hospital, Malmö.
    Lethagen, S.
    Genetic analysis of 31 Swedish type 1 von Willebrand disease families reveals incomplete linkage to the von Willebrand factor gene and a high frequency of a certain disease haplotype2005In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 3, no 12, p. 2656-2663Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The most common type of von Willebrand disease (VWD), type 1, has in only a few cases been explained by an identified causative mutation in the von Willebrand factor (VWF) gene. The ABO blood group and other modifier loci outside the VWF gene may contribute to the development of type 1 VWD.

    OBJECTIVES AND METHODS:

    Our aim was to determine whether there was genetic linkage to the VWF gene in 31 Swedish type 1 VWD families. Stringent diagnostic criteria in accordance with ISTH guidelines were used. Genetic linkage was investigated by using two highly informative dinucleotide microsatellite markers, which we have recently identified, located in introns six and 15 of the VWF gene. We also investigated the existence of common disease haplotypes and the relation between type 1 VWD and ABO blood group.

    RESULTS:

    We found genetic linkage to the VWF gene in 27 (87%) of the families. However, in four (13%) of the families, there was clearly no genetic linkage. We found the 4751A>G (Tyr1584Cys) sequence variation in exon 28, which is a common mutation in the Canadian VWD population (14.3%), in only one of the 31 families (3.2%). A possible common mutation was identified in six of the 27 (22%) families with genetic linkage. Blood group O was over-represented among type 1 VWD patients.

    CONCLUSION:

    We conclude that there is linkage between the VWF gene and hereditary type 1 VWD in a majority of families.

  • 32. Lanke, E.
    et al.
    Johansson, A. M.
    Hillarp, A.
    Lethagen, S.
    Zöller, B.
    Dahlbäck, B.
    Halldén, Christer
    Department of Clinical Chemistry, University Hospital, Malmö.
    Co-segregation of the PROS1 locus and protein S deficiency in families having no detectable mutations in PROS12004In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 2, no 11, p. 1918-1923Article in journal (Refereed)
    Abstract [en]

    Inherited deficiency of protein S constitutes an important risk factor of venous thrombosis. Many reports have demonstrated that causative mutations in the protein S gene are found only in approximately 50% of the cases with protein S deficiency. It is uncertain whether the protein S gene is causative in all cases of protein S deficiency or if other genes are involved in cases where no mutation is identified. The aim of the current study was to determine whether haplotypes of the protein S gene cosegregate with the disease phenotype in cases where no mutations have been found. Eight protein S-deficient families comprising 115 individuals where previous DNA sequencing had failed to detect any causative mutations were analyzed using four microsatellite markers in the protein S gene region. Co-segregation between microsatellite haplotypes and protein S deficiency was found in seven of the investigated families, one family being uninformative. This suggests that the causative genetic defects are located in or close to the protein S gene in a majority of such cases where no mutations have been found.

  • 33. Lethagen, Stefan
    et al.
    Hillarp, Andreas
    Ekholm, Caroline
    Mattson, Eva
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital.
    Friberg, Britt
    Distribution of von Willebrand factor levels in young women with and without bleeding symptoms: influence of ABO blood group and promoter haplotypes2008In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 99, no 6, p. 1013-1018Article in journal (Refereed)
    Abstract [en]

    The normal distribution of von Willebrand factor (VWF) levels is wide. Low levels are associated with bleeding symptoms and von Willebrand disease (VWD). We have recently described a high prevalence of bleeding symptoms in a whole age group of young females (n = 1,019) from Malmo, Sweden. It was the objective of the present study to evaluate the distribution of VWF levels in young females with or without bleeding symptoms in this population, and the influence of ABO blood group and promoter haplotypes on VWF levels and to identify a possible increased prevalence of VWD in females with bleeding symptoms. A random selection of the female age group (n = 246), into a study group (n = 176) with, and a control group (n = 70) without bleeding symptoms, was evaluated. Eighteen girls had VWF:RCo below the reference range, of which 17 belonged to the study group (17/176, 9.7%), and one to the control group (1/70, 1.4%) (p = 0.017). Blood group O was found in 14/18 girls with low VWF:RCo. There was a highly significant correlation between VWF:RCo and blood group O and non-O genotypes. Two common VWF promoter haplotypes did not contribute to the VWF:RCo variation. VWF levels did not correlate with time during menstrual cycle, or the use of oral contraceptives. No case fulfilled the diagnostic criteria for VWD. In conclusion, low VWF:RCo was significantly more frequent in females with bleeding symptoms. However, we found no case fulfilling strict diagnostic criteria for VWD. The ABO blood group was a strong modifier, but VWF promoter haplotypes had no association to VWF levels in this population.

  • 34.
    Lindahl, Pernilla
    et al.
    Kristianstad University, Forskningsmiljön Biomedicin.
    Säll, Torbjörn
    Department of Biology, Lund University.
    Bjartell, Anders
    Department of Urology, Skåne University Hospital, Malmö.
    Johansson, Anna M
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala.
    Lilja, Hans
    Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Skåne University Hospital, Malmö.
    Halldén, Christer
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Copy number variants in the kallikrein gene cluster2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e69097-Article in journal (Refereed)
    Abstract [en]

    The kallikrein gene family (KLK1-KLK15) is the largest contiguous group of protease genes within the human genome and is associated with both risk and outcome of cancer and other diseases. We searched for copy number variants in all KLK genes using quantitative PCR analysis and analysis of inheritance patterns of single nucleotide polymorphisms. Two deletions were identified: one 2235-bp deletion in KLK9 present in 1.2% of alleles, and one 3394-bp deletion in KLK15 present in 4.0% of alleles. Each deletion eliminated one complete exon and created out-of-frame coding that eliminated the catalytic triad of the resulting truncated gene product, which therefore likely is a non-functional protein. Deletion breakpoints identified by DNA sequencing located the KLK9 deletion breakpoint to a long interspersed element (LINE) repeated sequence, while the deletion in KLK15 is located in a single copy sequence. To search for an association between each deletion and risk of prostate cancer (PC), we analyzed a cohort of 667 biopsied men (266 PC cases and 401 men with no evidence of PC at biopsy) using short deletion-specific PCR assays. There was no association between evidence of PC in this cohort and the presence of either gene deletion. Haplotyping revealed a single origin of each deletion, with most recent common ancestor estimates of 3000-8000 and 6000-14 000 years for the deletions in KLK9 and KLK15, respectively. The presence of the deletions on the same haplotypes in 1000 Genomes data of both European and African populations indicate an early origin of both deletions. The old age in combination with homozygous presence of loss-of-function variants suggests that some kallikrein-related peptidases have non-essential functions.

  • 35. Lindgren, David
    et al.
    Frigyesi, Attila
    Gudjonsson, Sigurdur
    Sjödahl, Gottfrid
    Halldén, Christer
    Department of Laboratory Medicine, Clinical Chemistry, Malmö University Hospital.
    Chebil, Gunilla
    Veerla, Srinivas
    Ryden, Tobias
    Månsson, Wiking
    Liedberg, Fredrik
    Höglund, Mattias
    Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 9, p. 3463-3472Article in journal (Refereed)
    Abstract [en]

    In the present investigation, we sought to refine the classification of urothelial carcinoma by combining information on gene expression, genomic, and gene mutation levels. For these purposes, we performed gene expression analysis of 144 carcinomas, and whole genome array-CGH analysis and mutation analyses of FGFR3, PIK3CA, KRAS, HRAS, NRAS, TP53, CDKN2A, and TSC1 in 103 of these cases. Hierarchical cluster analysis identified two intrinsic molecular subtypes, MS1 and MS2, which were validated and defined by the same set of genes in three independent bladder cancer data sets. The two subtypes differed with respect to gene expression and mutation profiles, as well as with the level of genomic instability. The data show that genomic instability was the most distinguishing genomic feature of MS2 tumors, and that this trait was not dependent on TP53/MDM2 alterations. By combining molecular and pathologic data, it was possible to distinguish two molecular subtypes of T(a) and T(1) tumors, respectively. In addition, we define gene signatures validated in two independent data sets that classify urothelial carcinoma into low-grade (G(1)/G(2)) and high-grade (G(3)) tumors as well as non-muscle and muscle-invasive tumors with high precisions and sensitivities, suggesting molecular grading as a relevant complement to standard pathologic grading. We also present a gene expression signature with independent prognostic effect on metastasis and disease-specific survival. We conclude that the combination of molecular and histopathologic classification systems might provide a strong improvement for bladder cancer classification and produce new insights into the development of this tumor type.

  • 36.
    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.

  • 37.
    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.

  • 38.
    Ljung, R.
    et al.
    Lund University, Department of Paediatrics.
    Halldén, Christer
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Hemophilia A families with the same mutation are often related: a survey of the Swedish population2012In: Haemophilia (ISSN 1351-8216) 2012: 18 (supplement 3), p. 109, 2012, Vol. 18, no Suppl. 3, p. 109-109Conference paper (Other academic)
    Abstract [en]

    Aim: To study if families with hemophilia A in Sweden carrying the same mutation are identical by descent (IBD) or the result of independent mutations (RM).

    Study group: A total of 284 presumed unrelated and unselected Swedish families with hemophilia A comprising all clinical severities. Control group of 254 healthy individuals.

    Methods: Haplotyping was performed using 90 SNP markers (18 within the F8 gene) and 5 microsatellite markers. The frequencies of shared haplotypes were determined in the control group and the ages of the shared haplotypes determined using the program ESTIAGE.

    Results: Analysis of the mutations gave the following results: inversions in introns 1 or 22 were detected in 71 cases, large deletions in 5, small deletions/insertions in 4, and substitutions in 204 patients. For substitutions, a total of 107 mutations occurred in a single individual only, whereas the remaining 35 mutations occurred in 2 or more individuals; 20 mutations occurred in 2 individuals, 9 mutations occurred in 3 individuals, m4 mutations occurred in 4 individuals, and 2 mutations occurred in 7 individuals each, i.e., 97 mutations out of 204 (47%) were either IBD or recurrent mutation. Haplotyping and comparisons with the control group classified 51 of the 97 mutations as IBD. The phenotypes of the 51 individuals were mild (31), moderate (5), and severe (8), and the corresponding mutations had age estimates varying between 150 and 700 years. Inhibitors occurred in both RM and IBD families. One IBD family with mild hemophilia (2105 Tyr>Cys) had 3 members who developed inhibitors.

    Conclusion: Many families with hemophilia A, in particular those with milder forms, carrying the same mutation are IBD, i.e., revision of ‘‘hot-spots’’ for mutation is needed. Few ‘‘clusters of inhibitors’’ were found.

  • 39.
    Ljung, R.
    et al.
    Lund University, Department of Paediatrics.
    Lidén, Annika
    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.
    Hemophilia B families with the same mutation are often related: a survey of the Swedish population2012In: Haemophilia (ISSN 1351-8216) 2012: 18 (supplement 3), p. 109, 2012, Vol. 18, no Suppl. 3, p. 109-109Conference paper (Other academic)
    Abstract [en]

    Aim: To study if families with hemophilia B in Sweden carrying the same mutation are identical by descent (IBD) or the result of independent mutations (RM).

    Study group: A total of 77 presumed unrelated and unselected Swedish families with hemophilia B comprising all clinical severities (total and large deletions not included). Control group of 256 healthy individuals.

    Methods: Haplotyping was performed using 90 SNP markers (11 within the F9 gene) and 1 microsatellite marker. The frequencies of shared haplotypes were determined in the control group, and the ages of the shared haplotypes will be determined using the program ESTIAGE.

    Results: Analysis of the mutations gave the following results: 5 small deletions (<10bp), 2 small insertions (<10bp), 3 splice site mutations, 14 nonsense mutations, and 53 missense mutations. A total of 30 mutations (39%) occurred in a single individual only, whereas the remaining 47 mutations occurred in 2 or more individuals; 7 mutations occurred in 2 individuals, 4 mutations occurred in 3 individuals, 2 mutations occurred in 4 individuals, 1 mutation occurred in 6 individuals, and 1 mutation occurred in 7 individuals each, i.e., 47 mutations out of 77 (61%) were either IBD or recurrent mutation. Haplotyping and comparisons with the control group classified 21/47 mutations as IBD and 25/47 as RM. The phenotypes of the 21 IBD individuals were mild (17), moderate 2), and severe (1); those of the 25 RM individuals were mild (7), moderate (7), and severe (12). Age estimation of the mutations is ongoing.

    Conclusion: Many families with hemophilia B, in particular those with milder forms, carrying the same mutation are IBD, i.e., revision of ‘‘hot-spots’’ for mutation is needed.

  • 40. Lundwall, Åke
    et al.
    Giwercman, Aleksander
    Ruhayel, Yasir
    Giwercman, Yvonne
    Lilja, Hans
    Halldén, Christer
    Department of Laboratory Medicine, University Hospital MAS, Malmö.
    Malm, Johan
    A frequent allele codes for a truncated variant of semenogelin I, the major protein component of human semen coagulum2003In: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 9, no 6, p. 345-350Article in journal (Refereed)
    Abstract [en]

    Human semen coagulum predominantly consists of high molecular mass complexes of the seminal vesicle secreted semenogelin I (SgI) and semenogelin II (SgII). Here we describe a previously unknown variant of the SgI gene that is present at an allele frequency of approximately 3% in the Swedish population. It gives rise to a protein with a molecular mass of 43 kDa, SgI(43), which compared with the 50 kDa variant, SgI(50), is lacking a tandem repeat of 60 amino acid residues that was probably deleted by homologous recombination. In spite of the size difference, SgI(43) has many properties in common with SgI(50), such as a very high iso-electric point and susceptibility to proteolytic degradation by prostate-specific antigen. Heterozygous carriers of the SgI(43) allele neither show impaired fertility nor do they significantly differ from individuals homozygous for SgI(50) with respect to sperm parameters such as semen volume, sperm count and fraction of motile spermatozoa.

  • 41.
    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.

  • 42.
    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.

  • 43.
    Mårtensson, A.
    et al.
    Lund University.
    Ivarsson, S.
    Lund University.
    Letelier, A.
    Lund University.
    Manderstedt, Eric
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Plattformen för molekylär analys.
    Halldén, Christer
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Plattformen för molekylär analys.
    Ljung, R.
    Lund University.
    Origin of mutation in sporadic cases of severe haemophilia A in Sweden2016In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 90, no 1, p. 63-68Article in journal (Refereed)
    Abstract [en]

    Many newly diagnosed Swedish severe haemophilia A (HA) patients are sporadic cases. Some genotypically non-carrier mothers have gone on to have two descendants with the same mutation, presumably because of mosaicism.

    AIMS: To define the origin of mutation in sporadic cases of HA, reveal possible sex-specific differences in mutagenesis and identify potential mosaics among non-carrier mothers.

    METHOD: Sanger sequencing characterized the mutations and microsatellite haplotyping determined the origin of the X chromosome carrying the mutation in 3 generations of 45 families with sporadic severe HA. Droplet digital polymerase chain reaction (ddPCR) was used in five cases to reveal that mosaicism mutations are not found on conventional DNA sequencing.

    RESULTS: In 23 out of 45 families, the mother carried the mutation and in 5 out of 28 families, the grandmother was also a carrier. The X chromosome was of grandpaternal origin in 17 out of 23 cases. One of five tested mothers was a mosaic with a mutation frequency of 7%.

    CONCLUSION: In 40 out of 45 families, the sporadic case resulted from a mutation in the last two generations. In 82% (23/28), the carrier mothers had a de novo mutation where the X chromosome was of paternal origin in 74% (17/23). ddPCR is a potentially powerful and promising analysis for mosaicism in HA.

  • 44.
    Mårtensson, Annika
    et al.
    Lund University.
    Letelier, A.
    Lund University.
    Halldén, Christer
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Ljung, R.
    Lund University.
    Mutation analysis of Swedish haemophilia B families: high frequency of unique mutations2016In: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 22, no 3, p. 440-445Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Haemophilia B is caused by a heterogeneous spectrum of mutations. Mutation characterization is important in genetic counselling, prenatal diagnosis and to predict risk of inhibitor development.

    AIMS: To study the mutation spectrum, frequency of unique recurrent mutations, genotype-phenotype association and inhibitor development in a population-based study of the complete Swedish haemophilia B population.

    METHODS: The study included, facilitated by centralized DNA diagnostics, the complete registered Swedish haemophilia B population (113 families: 47 severe, 22 moderate and 44 mild), each represented by a single patient. Mutation characterization was performed by conventional sequencing of all exons and haplotyping by genotyping of single nucleotide variants and microsatellites.

    RESULTS: A mutation was found in every family: eight had large deletions, three had small deletions (<10 base pair) and 102 had single base pair substitutions (69 missense, 26 nonsense, four splice site and three promoter). Ten novel mutations were found and were predicted to be deleterious. Sixteen mutations (one total gene deletion, 14 substitutions and one acceptor splice site) were present in more than one family. Of the single nucleotide mutations (37/102), 36% arose at CpG sites. Haplotyping of families with identical mutations and present analyses showed that the frequency of unique mutations was at least 65%. Inhibitors developed in 9/47 (19%) patients with severe haemophilia B.

    CONCLUSION: The spectrum of haemophilia B mutations reveals at least 65% of the families carry a unique mutation, but with more inhibitor patients than reported internationally, probably as a result of many 'null' mutations.

  • 45. Möllenkvist, Andrea
    et al.
    Nordström, Therése
    Halldén, Christer
    Clinical Chemistry, Malmö University Hospital.
    Christensen, Jens Jørgen
    Forsgren, Arne
    Riesbeck, Kristian
    The Moraxella catarrhalis immunoglobulin D-binding protein MID has conserved sequences and is regulated by a mechanism corresponding to phase variation2003In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 185, no 7, p. 2285-2295Article in journal (Refereed)
    Abstract [en]

    The prevalence of the Moraxella catarrhalis immunoglobulin D (IgD)-binding outer membrane protein MID and its gene was determined in 91 clinical isolates and in 7 culture collection strains. Eighty-four percent of the clinical Moraxella strains expressed MID-dependent IgD binding. The mid gene was detected in all strains as revealed by homology of the signal peptide sequence and a conserved area in the 3' end of the gene. When MID proteins from five different strains were compared, an identity of 65.3 to 85.0% and a similarity of 71.2 to 89.1% were detected. Gene analyses showed several amino acid repeat motifs in the open reading frames, and MID could be called a putative autotransport protein. Interestingly, homopolymeric [polyguanine [poly(G)]] tracts were detected at the 5' ends within the open reading frames. By flow cytometry, using human IgD and fluorescein isothiocyanate-conjugated anti-IgD polyclonal antibodies, most strains showed two peaks: one high- and one low-intensity peak. All isolates expressing high levels of MID had 1, 2, or 3 triplets of G's in their poly(G) tracts, while strains not expressing MID had 4, 7, 8, or 10 G's in their poly(G) tracts or point mutations causing a putative preterminated translation. Northern blot analysis revealed that the mid gene was regulated at the transcriptional level. Experiments with nonclumping variants of M. catarrhalis proved that bacteria lost their MID expression by removing a G in their poly(G) tracts. Moraxella strains isolated from the nasopharynx or from blood and sputum specimens expressed MID at approximately the same frequency. In addition, no variation was observed between strains of different geographical origins (Australia, Europe, Japan, or the United States). MID and the mid gene were found solely in M. catarrhalis, whereas related Neisseria and Moraxella species did not express MID. Taken together, MID appears to be a conserved protein that can be found in essentially all M. catarrhalis strains. Furthermore, MID is governed by poly(G) tracts when bacteria undergo phase variation.

  • 46.
    Nilsson, Daniel
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Andiappan, Anand Kumar
    Department of Biological Sciences, National University of Singapore.
    Halldén, Christer
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Tim, Chew Fook
    Department of Biological Sciences, National University of Singapore.
    Säll, Torbjörn
    Department of Cell and Organism Biology, Lund University.
    Wang, De Yun
    Department of Otolaryngology, National University of Singapore.
    Cardell, Lars-Olaf
    Division of ENT Diseases, Department of Clinical Science, Intervention and Technology, Karolinska Institutet.
    Poor reproducibility of allergic rhinitis SNP associations2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e53975-Article in journal (Refereed)
    Abstract [en]

    Replication of reported associations is crucial to the investigation of complex disease. More than 100 SNPs have previously been reported as associated with allergic rhinitis (AR), but few of these have been replicated successfully. To investigate the general reproducibility of reported AR-associations in candidate gene studies, one Swedish (352 AR-cases, 709 controls) and one Singapore Chinese population (948 AR-cases, 580 controls) were analyzed using 49 AR-associated SNPs. The overall pattern of P-values indicated that very few of the investigated SNPs were associated with AR. Given published odds ratios (ORs) most SNPs showed high power to detect an association, but no correlations were found between the ORs of the two study populations or with published ORs. None of the association signals were in common to the two genome-wide association studies published in AR, indicating that the associations represent false positives or have much lower effect-sizes than reported.

  • 47.
    Nilsson, Daniel
    et al.
    Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet.
    Andiappan, Anand Kumar
    Department of Biological Sciences, National University of Singapore.
    Halldén, Christer
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Yun, Wang De
    Department of Otolaryngology, National University of Singapore.
    Säll, Torbjorn
    Department of Cell and Organism Biology, Lund University.
    Tim, Chew Fook
    Department of Biological Sciences, National University of Singapore.
    Cardell, Lars-Olaf
    Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet.
    Toll-like receptor gene polymorphisms are associated with allergic rhinitis: a case control study2012In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 13, no 1, p. 66-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:The Toll-like receptor proteins are important in host defense and initiation of the innate and adaptive immune responses. A number of studies have identified associations between genetic variation in the Toll-like receptor genes and allergic disorders such as asthma and allergic rhinitis. The present study aim to search for genetic variation associated with allergic rhinitis in the Toll-like receptor genes.

    METHODS:A first association analysis genotyped 73 SNPs in 182 cases and 378 controls from a Swedish population. Based on these results an additional 24 SNPs were analyzed in one Swedish population with 352 cases and 709 controls and one Chinese population with 948 cases and 580 controls.

    RESULTS:The first association analysis identified 4 allergic rhinitis-associated SNPs in the TLR7-TLR8 gene region. Subsequent analysis of 24 SNPs from this region identified 7 and 5 significant SNPs from the Swedish and Chinese populations, respectively. The corresponding riskassociated haplotypes are significant after Bonferroni correction and are the most common haplotypes in both populations. The associations are primarily detected in females in the Swedish population, whereas it is seen in males in the Chinese population. Further independent support for the involvement of this region in allergic rhinitis was obtained from quantitative skin prick test data generated in both populations.

    CONCLUSIONS:Haplotypes in the TLR7-TLR8 gene region were associated with allergic rhinitis in one Swedish and one Chinese population. Since this region has earlier been associated with asthma and allergic rhinitis in a Danish linkage study this speaks strongly in favour of this region being truly involved in the development of this disease.

  • 48.
    Nilsson, Daniel
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Henmyr, Viktor
    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, T.
    Department of Biology, Lund University.
    Kull, I.
    Department of Clinical Science and Education, Karolinska Institutet.
    Wickman, M.
    Institute of Environmental Medicine Karolinska Institutet.
    Melén, E.
    Institute of Environmental Medicine Karolinska Institutet.
    Cardell, L. O.
    Division of ENT Diseases, CLINTEC, Karolinska Institutet.
    Replication of genomewide associations with allergic sensitization and allergic rhinitis2014In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, no 11, p. 1506-1514Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Three genomewide metastudies have recently reported associations with self-reported allergic rhinitis and allergic sensitization. The three studies together identified a set of 37 loci but showed low concordance. This study investigates the reproducibility of the detected single nucleotide polymorphism (SNP) associations in an extensively characterized longitudinal cohort, BAMSE.

    METHODS: Phenotypic evaluation of allergic rhinitis (AR) and allergic sensitization was performed on 2153 children from BAMSE at 8 and 16 years of age. Allele frequencies of 39 SNPs were investigated for association with the exact allergic phenotypes of the metastudies. Odds ratios and false discovery rates were calculated, and the impact of asthma was evaluated. The cases were also evaluated for age at onset effects (≤ or >8 years of age).

    RESULTS: Association tests of the 39 SNPs identified 12 SNPs with P-values < 0.05 and Q-values < 0.10. Two of the four loci (TLR6-TLR1 and HLA-DQA1-HLA-DQB1) identified in all three original studies were also identified in this study. Three SNPs located in the TLR6-TLR1 locus had the lowest P-values and Q-values < 0.1 when using a well-defined AR phenotype. Two loci showed significant age at onset effects, but the effect of asthma on the associations was very limited.

    CONCLUSION: The TLR6-TLR1 locus is likely to have a central role in the development of allergic disease. The association between genetic variation in the SSTR1-MIPOL1 and TSLP-SLC25A46 loci and age at onset is the first report of age at onset effects in allergic rhinitis.

  • 49. Nilsson, N. O.
    et al.
    Halldén, Christer
    Hilleshög AB, Landskrona.
    Hansen, M.
    Hjerdin, A
    Säll, T.
    Comparing the distribution of RAPD and RFLP markers in a high density linkage map of sugar beet1997In: Genome, ISSN 0831-2796, E-ISSN 1480-3321, Vol. 40, no 5, p. 644-651Article in journal (Refereed)
    Abstract [en]

    The distribution of RAPD markers was compared with that of RFLP markers in a high density linkage map of sugar beet. The same mapping population of 161 F2 individuals was used to generate all the marker data. The total map comprises 160 RAPD and 248 RFLP markers covering 508 cM. Both the RAPD and the RFLP markers show a high degree of clustering over the nine linkage groups. The pattern is compatible with a strong distal localization of recombination in the sugar beet. It leads generally to one major cluster of markers in the centre of each linkage group. In regions of high marker density, dominant RAPD markers present in either linkage phase and codominant RFLP markers are subclustered relative to each other. This phenomenon is shown to be attributable to: (i) effects of the mapping procedure when dominant and codominant data are combined, (ii) effects of the mapping procedure when dominant data in both linkage phases are combined, and (iii) genuine differences in the way RAPD and RFLP markers are recruited.

  • 50.
    Romerius, Patrik
    et al.
    Department of Pediatrics, Skåne University Hospital, Lund.
    Giwercman, Aleksander
    Department of Laboratory Medicine, Skåne University Hospital, Lund.
    Moëll, Christian
    Department of Pediatrics, Skåne University Hospital, Lund.
    Relander, Thomas
    Department of Oncology, Skåne University Hospital, Lund.
    Cavallin-Ståhl, Eva
    Department of Oncology, Skåne University Hospital, Lund.
    Wiebe, Thomas
    Department of Pediatrics, Skåne University Hospital, Lund.
    Halldén, Christer
    Kristianstad University, School of Education and Environment.
    Giwercman, Yvonne Lundberg
    Department of Clinical Sciences, Lund University, Malmö.
    Estrogen receptor α single nucleotide polymorphism modifies the risk of azoospermia in childhood cancer survivors2011In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 21, no 5, p. 263-269Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Cancer treatment in childhood leads to permanent azoospermia in a significant number of boys and those who are diagnosed with cancer before puberty do not have the option of pretreatment cryopreservation of spermatozoa. However, there is an interindividual variation in the sensitivity to gonadotoxic effects of cancer therapy, which probably is due to genetic factors. Identification of genetic markers for the risk of azoospermia in childhood cancer survivors may help in identifying boys to whom testicular cryopreservation should be offered.

    METHODS:

    Fifty-one single nucleotide polymorphisms (SNPs) being markers of 12 different haplotype blocks in the androgen receptor, estrogen receptor (ER) α and ER β genes were examined in 127 adult childhood cancer survivors.

    RESULTS:

    In ERα, markers of one specific haplotype block (rs2207396, rs9340958, rs9340978) were associated with an increased risk of azoospermia. Compared with those with the GG genotype, patients being heterozygous for the A allele in rs2207396 had a significantly increased risk of azoospermia [odds ratio (OR): 3.8; 95% confidence interval: 1.5-9.5; P=0.008], this OR being even higher in the subgroup treated with alkylating drugs (OR: 8.8; 95% confidence interval: 2.1-36; P=0.004). In this subgroup, 48% of the patients carried the A allele of rs2207396, this proportion being 70% among the azoospermic patients.

    CONCLUSION:

    Use of genetic markers of high risk of posttreatment azoospermia may, in the future, prove an important clinical tool in selection of boys to whom preservation of testicular tissue before cancer therapy should be offered.

12 1 - 50 of 57
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