| 1. |
- Johansson, Anna Maria, et al.
(författare)
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Variation in the VWF Gene in Swedish Patients with Type 1 von Willebrand Disease.
- 2011
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Ingår i: Annals of Human Genetics. - : Wiley. - 1469-1809 .- 0003-4800. ; 75, s. 447-455
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Lindahl, Pernilla, et al.
(författare)
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Copy number variants in the kallikrein gene cluster.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Manderstedt, Eric, et al.
(författare)
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Thrombotic Risk Determined by Protein C Receptor (PROCR) Variants among Middle-Aged and Older Adults : A Population-Based Cohort Study
- 2022
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 122:8, s. 1326-1332
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Tidskriftsartikel (refereegranskat)abstract
- Background The protein C (PC) anticoagulant system has a key role in maintaining hemostatic balance. One missense (Ser219Gly) variant in the PC receptor (PROCR) was associated with venous thromboembolism (VTE) in genome-wide association studies. Objectives This study aimed to determine the thrombotic risk of rare and common PROCR variants in a large population-based cohort of middle-aged and older adults. Methods The exonic sequence of PROCR was analyzed for the Ser219Gly variant and other qualifying variants in 28,794 subjects (born 1923-1950, 60% women) without previous VTE, who participated in the Malmö Diet and Cancer study (1991-1996). Incidence of VTE was followed up until 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequencies (MAFs) <0.1%. Results Re-sequencing identified 36 PROCR variants in the study population (26,210 non-VTE exomes and 2,584 VTE exomes), 11 synonymous, 22 missense, and three loss-of-function variants. Kaplan-Meier analysis of the known Ser219Gly variant (rs867186) showed that homozygosity for this variant increased the risk of disease, whereas heterozygosity showed no effect. Cox multivariate regression analysis revealed an adjusted hazard ratio (HR) of 1.5 (95% confidence interval [CI]: 1.1-2.0). Fifteen rare variants were classified as qualifying and were included in collapsing analysis (burden test and SKAT-O). They did not contribute to risk. However, a Arg113Cys missense variant (rs146420040; MAF = 0.004) showed an increased VTE risk (HR = 1.3; 95% CI: 1.0-1.9). Conclusion Homozygosity for the Ser219Gly variant and a previously identified functional PROCR variant (Arg113Cys) was associated with VTE. Other variants did not contribute to VTE.
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| 4. |
- Nilsson, D., et al.
(författare)
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Replication of genomewide associations with allergic sensitization And allergic rhinitis
- 2014
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 69:11, s. 1506-1514
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Andiappan, Anand Kumar, et al.
(författare)
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Investigating highly replicated asthma genes as candidate genes for allergic rhinitis
- 2013
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Zöller, Bengt, et al.
(författare)
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Genetic risk factors for venous thromboembolism
- 2020
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Ingår i: Expert Review of Hematology. - : Informa UK Limited. - 1747-4086 .- 1747-4094. ; 13:9, s. 971-981
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Forskningsöversikt (refereegranskat)abstract
- Introduction: Venous thromboembolism (VTE) is a complex disease that aggregates in families. Both acquired and genetic risk factors are important. Proper recognition and management of high-risk individuals are important. Areas covered: The genetic risk factors for VTE, the clinical consequences, and future perspectives are summarized. Classical thrombophilia i.e., factor V Leiden (rs6025), the prothrombin G20210A mutation (rs1799963), deficiencies of antithrombin, protein C, and protein S and the recent findings from genome wide association studies (GWAS), transcriptome-wide association studies (TWAS), genetic risk score (GRS), VTE candidate genes, expression studies, animal studies, studies using next generation sequencing, pathway analysis, and clinical implications are discussed. Expert opinion: Screening of inherited thrombophilia should be performed in special cases. Identification of strong risk variants might affect the management. The increasing number of genetic risk variants is likely to change management of VTE.
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| 7. |
- Manderstedt, Eric, et al.
(författare)
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Thrombotic risk determined by rare and common SERPINA1 variants in a population-based cohort study
- 2022
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 20:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case-control study. Objectives: This study aimed to determine the genetic variation in the SERPINA1 gene and a possible thrombotic risk of these variants in a population-based cohort study. Patients/Methods: The coding sequence of SERPINA1 was analyzed for the Z (rs28929474), S (rs17580), and other qualifying variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer study (1991–1996). Individuals were followed from baseline until the first event of VTE, death, or 2018. Results: Resequencing the coding sequence of SERPINA1 identified 84 variants in the total study population, 21 synonymous, 62 missense, and 1 loss-of-function variant. Kaplan-Meier analysis showed that homozygosity for the Z allele increased the risk of VTE whereas heterozygosity showed no effect. The S (rs17580) variant was not associated with VTE. Thirty-one rare variants were qualifying and included in collapsing analysis using the following selection criteria, loss of function, in frame deletion or non-benign (PolyPhen-2) missense variants with minor allele frequency (MAF)
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| 8. |
- Nilsson, Daniel, et al.
(författare)
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Toll-like receptor gene polymorphisms are associated with allergic rhinitis: a case control study
- 2012
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 13:66
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Tidskriftsartikel (refereegranskat)abstract
- 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 risk-associated 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.
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| 9. |
- Manderstedt, Eric, et al.
(författare)
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Genetic variation of the blood coagulation regulator tissue factor pathway inhibitor and venous thromboembolism among middle-aged and older adults: A population-based cohort study
- 2022
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Ingår i: Research and practice in thrombosis and haemostasis. - : Elsevier BV. - 2475-0379. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tissue factor is the main initiator of blood coagulation, and tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the initiation of blood coagulation. The genetic variation of TFPI and the relation to venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, remains to be clarified. This exome sequencing study aimed to determine the molecular epidemiology of the TFPI gene and the relation to VTE in a large population-based cohort of middle-aged and older adults. Methods: The exomes of TFPI were analyzed for variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer Study (1991–1996). Patients were followed until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequency less than 0.1%. Results: No common variant was associated with VTE. Nine rare variants (two loss-of-function and seven nonbenign missense) were classified as qualifying and included in collapsing analysis. Prevalence of qualifying variants was 0.09%. Five individuals with VTE compared to 17 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and ancestry showed a hazard ratio of 2.9 (95% CI, 1.2–7.1) for rare qualifying variants. Conclusion: Rare qualifying TFPI variants were associated with VTE, suggesting that rare variants in TFPI contribute to the development of VTE. The qualifying TFPI gene variants were very rare, suggesting a constrained gene. © 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).
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| 10. |
- Henmyr, Viktor, et al.
(författare)
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Characterization of genetic variation in TLR8 in relation to allergic rhinitis
- 2015
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995.
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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