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  • 51.
    Nilsson, Daniel
    et al.
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap. Högskolan Kristianstad, Forskningsmiljön Biomedicin.
    Andiappan, Anand Kumar
    Department of Biological Sciences, National University of Singapore.
    Halldén, Christer
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap. Högskolan Kristianstad, 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 associations2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 1, s. e53975-Artikel i tidskrift (Refereegranskat)
    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.

  • 52.
    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
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap. Högskolan Kristianstad, 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 study2012Ingår i: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 13, nr 1, s. 66-Artikel i tidskrift (Refereegranskat)
    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.

  • 53.
    Nilsson, Daniel
    et al.
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap. Högskolan Kristianstad, Forskningsmiljön Biomedicin.
    Henmyr, Viktor
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap. Högskolan Kristianstad, Forskningsmiljön Biomedicin.
    Halldén, Christer
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap. Högskolan Kristianstad, 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 rhinitis2014Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, nr 11, s. 1506-1514Artikel i tidskrift (Refereegranskat)
    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.

  • 54. 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 beet1997Ingår i: Genome, ISSN 0831-2796, E-ISSN 1480-3321, Vol. 40, nr 5, s. 644-651Artikel i tidskrift (Refereegranskat)
    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.

  • 55.
    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
    Högskolan Kristianstad, Sektionen för lärande och miljö.
    Giwercman, Yvonne Lundberg
    Department of Clinical Sciences, Lund University, Malmö.
    Estrogen receptor α single nucleotide polymorphism modifies the risk of azoospermia in childhood cancer survivors2011Ingår i: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 21, nr 5, s. 263-269Artikel i tidskrift (Refereegranskat)
    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.

  • 56.
    Sjödahl, Gottfrid
    et al.
    Department of Clinical Sciences, Oncology, Lund University.
    Lauss, Martin
    Department of Clinical Sciences, Oncology, Lund University.
    Gudjonsson, Sigurdur
    Department of Clinical Sciences, Urology, Skåne University Hospital, Malmö.
    Liedberg, Fredrik
    Department of Clinical Sciences, Urology, Skåne University Hospital, Malmö.
    Halldén, Christer
    Department of Laboratory Medicine, Clinical Chemistry, Lund University.
    Chebil, Gunilla
    Department of Pathology, Helsingborg Hospital.
    Månsson, Wiking
    Department of Clinical Sciences, Urology, Skåne University Hospital, Malmö.
    Höglund, Mattias
    Department of Clinical Sciences, Oncology, Lund University.
    Lindgren, David
    Department of Clinical Sciences, Oncology, Lund University.
    A systematic study of gene mutations in urothelial carcinoma: inactivating mutations in TSC2 and PIK3R12011Ingår i: PloS ONE, ISSN 1932-6203, Vol. 6, nr 4, s. e18583-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Our data demonstrate a significant association between FGFR3 and PIK3CA mutations in UC. Moreover, the identification of mutations in PIK3R1 further emphasizes the importance of the PI3-kinase pathway in UC. The presence of TSC2 mutations, in addition to TSC1 mutations, underlines the involvement of mTOR signaling in UC.

  • 57.
    Säll, T.
    et al.
    Department of Cell and Organism Biology, Genetics, Lund University.
    Jakobsson, M.
    Department of Cell and Organism Biology, Genetics, Lund University.
    Lind-Halldén, Christina
    Högskolan Kristianstad, Institutionen för matematik och naturvetenskap.
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital.
    Chloroplast DNA indicates a single origin of the allotetraploid Arabidopsis suecica2003Ingår i: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 16, nr 5, s. 1019-1029Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 58.
    Säll, T.
    et al.
    Department of Genetics, Lund University.
    Lind-Halldén, Christina
    Högskolan Kristianstad, Institutionen för matematik och naturvetenskap.
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital,.
    Primer mixtures in RAPD analysis2000Ingår i: Hereditas, ISSN 0018-0661, E-ISSN 1601-5223, Vol. 132, nr 3, s. 203-208Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 59.
    Säll, Torbjörn
    et al.
    Department of Cell and Organism Biology, Genetics, Lund University.
    Lind-Halldén, Christina
    Högskolan Kristianstad, Institutionen för matematik och naturvetenskap.
    Jakobsson, Mattias
    Department of Cell and Organism Biology, Genetics, Lund University.
    Halldén, Christer
    Department of Clinical Chemistry, Malmö University Hospital.
    Mode of reproduction in Arabidopsis suecica2004Ingår i: Hereditas, ISSN 0018-0661, E-ISSN 1601-5223, Vol. 141, nr 3, s. 313-317Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 60. Sävblom, C
    et al.
    Giwercman, A
    Malm, J
    Halldén, Christer
    Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Malmö University Hospital.
    Lundin, K
    Lilja, H
    Giwercman, Y
    Association between polymorphisms in the prostate-specific antigen (PSA) promoter and release of PSA2009Ingår i: International Journal of Andrology, ISSN 0105-6263, E-ISSN 1365-2605, Vol. 32, nr 5, s. 479-485Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Variations in serum prostate-specific antigen (PSA) have been ascribed to A/G nucleotide polymorphisms located at -158 bp (rs266882) and -4643 bp (rs925013), relative to the transcription start site within the promoter of the PSA gene. PSA is also an androgen receptor target (AR) gene and polymorphisms in AR gene are known to affect AR function. Our objective was to compare the impact of these A/G polymorphisms separately or in combination with AR CAG micro satellite on regulation of PSA secretion into seminal plasma and blood in young men. Leukocyte DNA was extracted from 291 conscripts and genotyping performed with the Sequenom Mass Array System. PSA was measured with an immunofluorometric assay. Linear regression analysis was used to test the association of polymorphism frequencies with serum and seminal plasma levels of PSA. PSA gene polymorphisms at -158 bp or -4643 bp did not alone influence total PSA (tPSA) levels in seminal plasma or in blood. Homozygotes for the A-allele at -158 bp in combination with CAG > 22 had significantly higher serum levels of tPSA than subjects carrying the G-allele (p = 0.01). In conclusion, the PSA gene polymorphisms did not importantly influence the levels of tPSA in seminal plasma or in blood. tPSA in serum was influenced by interactions between PSA promoter variants and AR CAG polymorphism.

  • 61.
    Sävblom, Charlotta
    et al.
    Lund University, Skåne University Hospital, Malmö.
    Halldén, Christer
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap.
    Cronin, Angel M
    Memorial Sloan-Kettering Cancer Center, New York.
    Säll, Torbjörn
    Department of Cell and Organism Biology, Lund University, Lund.
    Savage, Caroline
    Memorial Sloan-Kettering Cancer Center, New York.
    Vertosick, Emily A
    Memorial Sloan-Kettering Cancer Center, New York.
    Klein, Robert J
    Memorial Sloan-Kettering Cancer Center, New York.
    Giwercman, Aleksander
    Memorial Sloan-Kettering Cancer Center, New York.
    Lilja, Hans
    Lund University, Skåne University Hospital, Malmö.
    Genetic variation in KLK2 and KLK3 is associated with concentrations of hK2 and PSA in serum and seminal plasma in young men2014Ingår i: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 60, nr 3, s. 490-499Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Genetic variants in KLK2 and KLK3 have been associated with increased serum concentrations of their encoded proteins, human kallikrein-related peptidase 2 (hK2) and prostate-specific antigen (PSA), and with prostate cancer in older men. Low PSA concentrations in seminal plasma (SP) have been associated with low sperm motility. To evaluate whether KLK2 and KLK3 genetic variants affect physiological prostatic secretion, we studied the association of SNPs with hK2 and PSA concentrations in SP and serum of young, healthy men.

    METHODS: Leukocyte DNA was extracted from 303 male military conscripts (median age 18.1 years). Nine SNPs across KLK2-KLK3 were genotyped. We measured PSA and hK2 in SP and serum using immunofluorometric assays. The association of genotype frequencies with hK2 and PSA concentrations was tested with the Kruskal-Wallis test.

    RESULTS: Four KLK2 SNPs (rs198972, rs198977, rs198978, and rs80050017) were strongly associated with hK2 concentrations in SP and serum, with individuals homozygous for the major alleles having 3- to 7-fold higher concentrations than the intermediate concentrations found in other homozygotes and heterozygotes (all P < 0.001). Three of these SNPs were significantly associated with percentage of free PSA (%fPSA) in serum (all P < 0.007). Three KLK3 SNPs showed associations with PSA in SP, and the rs1058205 SNP was associated with total PSA in serum (P = 0.001) and %fPSA (P = 0.015).

    CONCLUSIONS: Associations observed in young, healthy men between the SP and serum concentrations of hK2 and PSA and several genetic variants in KLK2 and KLK3 could be useful to refine models of PSA cutoff values in prostate cancer testing.

  • 62. Xu, Xing
    et al.
    Valtonen-André, Camilla
    Sävblom, Charlotta
    Halldén, Christer
    Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University.
    Lilja, Hans
    Klein, Robert J.
    Polymorphisms at the Microseminoprotein-beta locus associated with physiologic variation in beta-microseminoprotein and prostate-specific antigen levels2010Ingår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, nr 8, s. 2035-2042Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: rs10993994, a single nucleotide polymorphism (SNP) at the genetic locus encoding β-microseminoprotein (β-MSP), is associated with both prostate cancer risk and levels of blood prostate-specific antigen (PSA), a biomarker used in prostate cancer screening. Therefore, we wished to determine the association between SNPs at MSMB, the gene encoding β-MSP, and the levels of prostate-produced biomarkers β-MSP, PSA, and human kallikrein 2 (hK2) in blood and semen.

    Methods: Blood and semen from 304 healthy young Swedish men (ages 18-21) were assayed for β-MSP, PSA, and hK2. SNPs around MSMB were genotyped from matched DNA and analyzed for quantitative association with biomarker levels. Empirical P values were multiple test–corrected and the independence of each SNP's effect was determined.

    Results: rs10993994 was significantly associated with the blood and semen levels of β-MSP (both P < 1.0 × 10−7) and PSA (P = 0.00014 and P = 0.0019), and semen levels of hK2 (P = 0.00027). Additional copies of the prostate cancer risk allele resulted in lower β-MSP but higher PSA levels, and singly explained 23% and 5% of the variation seen in semen β-MSP and PSA, respectively. Additional SNPs at MSMB are associated with β-MSP and PSA independently of rs10993994.

    Conclusions: SNPs at MSMB correlate with physiologic variation in β-MSP and PSA levels in the blood and semen of healthy young Swedish men. In particular, rs10993994 has a strong effect on β-MSP levels.

    Impact: Our results suggest a mechanism by which rs10993994 might predispose to prostate cancer and raise the possibility that genetic variation might need to be considered in interpreting the levels of these biomarkers.

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