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Henmyr, V., Carlberg, D., Manderstedt, E., Lind-Halldén, C., Säll, T., Cardell, L. O. & Halldén, C. (2017). Genetic variation of the toll-like receptors in a Swedish allergic rhinitis case population. BMC Medical Genetics, 18(1), Article ID 18.
Open this publication in new window or tab >>Genetic variation of the toll-like receptors in a Swedish allergic rhinitis case population
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2017 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 18, no 1, article id 18Article in journal (Refereed) Published
Abstract [en]

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

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

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

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

Keywords
Allergic rhinitis, Mutation spectrum, Next-generation sequencing, Rare variants, Toll-like receptor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:hkr:diva-16592 (URN)10.1186/s12881-017-0379-6 (DOI)000397484800001 ()28228119 (PubMedID)
Funder
Swedish Research Council
Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2017-11-29Bibliographically approved
Henmyr, V., Lind-Halldén, C., Halldén, C., Säll, T., Carlberg, D., Bachert, C. & Cardell, L.-O. (2016). Chronic rhinosinusitis patients show accumulation of genetic variants in PARS2. PLoS ONE, 11(6), Article ID e0158202.
Open this publication in new window or tab >>Chronic rhinosinusitis patients show accumulation of genetic variants in PARS2
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, article id e0158202Article in journal (Refereed) Published
Abstract [en]

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

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:hkr:diva-16091 (URN)10.1371/journal.pone.0158202 (DOI)000378801200050 ()27348859 (PubMedID)
Available from: 2016-09-28 Created: 2016-09-28 Last updated: 2017-11-21Bibliographically approved
Mårtensson, A., Letelier, A., Halldén, C. & Ljung, R. (2016). Mutation analysis of Swedish haemophilia B families: high frequency of unique mutations. Haemophilia, 22(3), 440-445
Open this publication in new window or tab >>Mutation analysis of Swedish haemophilia B families: high frequency of unique mutations
2016 (English)In: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 22, no 3, p. 440-445Article in journal (Refereed) Published
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.

Keywords
F9 gene, factor IX, haemophilia B, haplotype analysis, inhibitor, mutation, point mutations, population, series, heterogenity, transitions, prevalence, deletions, sequence
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:hkr:diva-15682 (URN)10.1111/hae.12854 (DOI)000379715000042 ()26612714 (PubMedID)
Funder
Region SkåneSwedish Research Council
Available from: 2016-08-11 Created: 2016-08-11 Last updated: 2017-04-24Bibliographically approved
Mårtensson, A., Ivarsson, S., Letelier, A., Manderstedt, E., Halldén, C. & Ljung, R. (2016). Origin of mutation in sporadic cases of severe haemophilia A in Sweden. Clinical Genetics, 90(1), 63-68
Open this publication in new window or tab >>Origin of mutation in sporadic cases of severe haemophilia A in Sweden
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2016 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 90, no 1, p. 63-68Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:hkr:diva-16090 (URN)10.1111/cge.12709 (DOI)000378652000008 ()26661908 (PubMedID)
Funder
Swedish Research Council, K2013-64X-22298-01-03Region Skåne
Available from: 2016-09-28 Created: 2016-09-28 Last updated: 2017-11-21Bibliographically approved
Henmyr, V., Lind-Halldén, C., Carlberg, D., Halldén, C., Melén, E., Wickman, M., . . . Cardell, L. O. (2015). Characterization of genetic variation in TLR8 in relation to allergic rhinitis. Allergy. European Journal of Allergy and Clinical Immunology
Open this publication in new window or tab >>Characterization of genetic variation in TLR8 in relation to allergic rhinitis
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2015 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995Article in journal (Refereed) Published
Abstract [en]

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

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

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

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

Keywords
Adolescents, depression, school-based program, prevention, cognitive behavior program
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:hkr:diva-15026 (URN)10.1111/all.12805 (DOI)26556310 (PubMedID)
Available from: 2015-11-18 Created: 2015-11-18 Last updated: 2017-12-01Bibliographically approved
Sävblom, C., Halldén, C., Cronin, A. M., Säll, T., Savage, C., Vertosick, E. A., . . . Lilja, H. (2014). Genetic variation in KLK2 and KLK3 is associated with concentrations of hK2 and PSA in serum and seminal plasma in young men. Clinical Chemistry, 60(3), 490-499
Open this publication in new window or tab >>Genetic variation in KLK2 and KLK3 is associated with concentrations of hK2 and PSA in serum and seminal plasma in young men
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2014 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 60, no 3, p. 490-499Article in journal (Refereed) Published
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.

Keywords
Allergic rhinitis, Association, Asthma, Case–control, Replication
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:hkr:diva-12154 (URN)10.1373/clinchem.2013.211219 (DOI)000335146800013 ()24270797 (PubMedID)
Available from: 2014-06-17 Created: 2014-06-17 Last updated: 2017-12-05Bibliographically approved
Nilsson, D., Henmyr, V., Halldén, C., Säll, T., Kull, I., Wickman, M., . . . Cardell, L. O. (2014). Replication of genomewide associations with allergic sensitization and allergic rhinitis. Allergy. European Journal of Allergy and Clinical Immunology, 69(11), 1506-1514
Open this publication in new window or tab >>Replication of genomewide associations with allergic sensitization and allergic rhinitis
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2014 (English)In: 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) Published
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.

National Category
Immunology in the medical area Medical Genetics
Identifiers
urn:nbn:se:hkr:diva-12914 (URN)10.1111/all.12495 (DOI)000343851200009 ()25066275 (PubMedID)
Available from: 2014-09-16 Created: 2014-09-16 Last updated: 2018-01-11Bibliographically approved
Henmyr, V., Vandeplas, G., Halldén, C., Säll, T., Olze, H., Bachert, C. & Cardell, L. O. (2014). Replication study of genetic variants associated with chronic rhinosinusitis and nasal polyposis [Letter to the editor]. Journal of Allergy and Clinical Immunology, 133(1), 273-275
Open this publication in new window or tab >>Replication study of genetic variants associated with chronic rhinosinusitis and nasal polyposis
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2014 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 133, no 1, p. 273-275Article in journal, Letter (Refereed) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:hkr:diva-11678 (URN)10.1016/j.jaci.2013.08.011 (DOI)000329105700041 ()24074519 (PubMedID)
Available from: 2014-01-23 Created: 2014-01-23 Last updated: 2018-01-11Bibliographically approved
Lindahl, P., Säll, T., Bjartell, A., Johansson, A. M., Lilja, H. & Halldén, C. (2013). Copy number variants in the kallikrein gene cluster. PLoS ONE, 8(7), e69097
Open this publication in new window or tab >>Copy number variants in the kallikrein gene cluster
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e69097-Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:hkr:diva-10822 (URN)10.1371/journal.pone.0069097 (DOI)000322132100045 ()23894413 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2013-08-08 Created: 2013-08-08 Last updated: 2017-12-06Bibliographically approved
Andiappan, A. K., Nilsson, D., Halldén, C., Yun, W. D., Säll, T., Cardell, L. O. & Tim, C. F. (2013). Investigating highly replicated asthma genes as candidate genes for allergic rhinitis. BMC Medical Genetics, 14, 51
Open this publication in new window or tab >>Investigating highly replicated asthma genes as candidate genes for allergic rhinitis
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2013 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 14, p. 51-Article in journal (Refereed) Published
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.

Keywords
Allergic rhinitis, Association, Asthma, Case–control, Replication
National Category
Genetics
Identifiers
urn:nbn:se:hkr:diva-10839 (URN)10.1186/1471-2350-14-51 (DOI)000318862500001 ()23663310 (PubMedID)
Available from: 2013-08-09 Created: 2013-08-09 Last updated: 2017-12-06Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9355-3901

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