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Gyllensten, Ulf B.
Alternative names
Publications (10 of 175) Show all publications
Jiang, J., Thalamuthu, A., Ho, J. E., Mahajan, A., Ek, W. E., Brown, D. A., . . . Mather, K. A. (2018). A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood. Frontiers in Genetics, 9, Article ID 97.
Open this publication in new window or tab >>A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood
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2018 (English)In: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 9, article id 97Article in journal (Refereed) Published
Abstract [en]

Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of similar to 5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 x 10(-35)), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the "COPI-mediated anterograde transport" gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
genome-wide association study, growth differentiation factor-15, macrophage inhibitory cytokine-1, community-based individuals, chromosome 19
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-354354 (URN)10.3389/fgene.2018.00097 (DOI)000428198300001 ()
Funder
Knut and Alice Wallenberg FoundationEU, European Research CouncilSwedish Research Council, 2012-1397Swedish Research Council, 2012-1727Swedish Research Council, 2012-2215Swedish Research Council, 80576801Swedish Research Council, 70374401Swedish Foundation for Strategic Research Australian Research Council, DP0774213Australian Research Council, DP0773584Australian Research Council, LP0669645
Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-08-08Bibliographically approved
Enroth, S., Berggrund, M., Lycke, M., Lundberg, M., Assarsson, E., Olovsson, M., . . . Gyllensten, U. B. (2018). A two-step strategy for identification of plasma protein biomarkers for endometrial and ovarian cancer. Clinical Proteomics, 15, Article ID 38.
Open this publication in new window or tab >>A two-step strategy for identification of plasma protein biomarkers for endometrial and ovarian cancer
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2018 (English)In: Clinical Proteomics, ISSN 1542-6416, E-ISSN 1559-0275, Vol. 15, article id 38Article in journal (Refereed) Published
Abstract [en]

Background: Over 500,000 women worldwide are diagnosed with ovarian or endometrial cancer each year. We have used a two-step strategy to identify plasma proteins that could be used to improve the diagnosis of women with an indication of gynecologic tumor and in population screening.

Methods: In the discovery step we screened 441 proteins in plasma using the proximity extension assay (PEA) and five Olink Multiplex assays (CVD II, CVD III, INF I, ONC II, NEU I) in women with ovarian cancer (n=106), endometrial cancer (n=74), benign ovarian tumors (n=150) and healthy population controls (n=399). Based on the discovery analyses a set of 27 proteins were selected and two focused multiplex PEA assays were developed. In a replication step the focused assays were used to study an independent set of cases with ovarian cancer (n=280), endometrial cancer (n=228), women with benign ovarian tumors (n=76) and healthy controls (n=57).

Results: In the discovery step, 27 proteins that showed an association to cancer status were identified. In the replication analyses, the focused assays distinguished benign tumors from ovarian cancer stage III-IV with a sensitivity of 0.88 and specificity of 0.92 (AUC=0.92). The assays had a significantly higher AUC for distinguishing benign tumors from late stage ovarian cancer than using CA125 and HE4 (p=9.56e-22). Also, population controls could be distinguished from ovarian cancer stage III-IV with a sensitivity of 0.85 and a specificity of 0.92 (AUC=0.89).

Conclusion: The PEA assays represent useful tools for identification of new biomarkers for gynecologic cancers. The selected protein assays could be used to distinguish benign tumors from ovarian and endometrial cancer in women diagnosed with an unknown suspicious pelvic mass. The panels could also be used in population screening, for identification of women in need of specialized gynecologic transvaginal ultrasound examination.

Place, publisher, year, edition, pages
BMC, 2018
Keywords
Ovarian cancer, Endometrial cancer, Proximity extension assay (PEA), Sensitivity, Specificity, Diagnostics
National Category
Obstetrics, Gynecology and Reproductive Medicine Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-372376 (URN)10.1186/s12014-018-9216-y (DOI)000451777900001 ()30519148 (PubMedID)
Funder
Swedish Foundation for Strategic Research Swedish Research CouncilVINNOVASwedish Cancer Society
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-01-08Bibliographically approved
Lindström, A., Sanchez Hermansson, R., Gustavsson, I. M., Lindberg, J. H., Gyllensten, U. B. & Olovsson, M. (2018). Cervical dysplasia in elderly women performing repeated self-sampling for HPV testing. PLoS ONE, 13(12), Article ID e0207714.
Open this publication in new window or tab >>Cervical dysplasia in elderly women performing repeated self-sampling for HPV testing
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0207714Article in journal (Refereed) Published
Abstract [en]

Background About 30% of the cervical cancer cases in Sweden occur in women older than 60. The primary aim was to evaluate the acceptability of repeated self-sampling at home for HPV-testing in elderly women. The prevalence of HPV and HPV related dysplasia as well as the sensitivity of cytology was evaluated. Methods Repeated self-sampling at home for HPV testing was offered 375 women in each of the four age groups 60, 65, 70 and 75 years. Women with two consecutive positive HPV tests were examined with sampling for histology and cytology. Findings A self-sample was provided by 59.5% (893/1500) of the invited women. The overall prevalence of HPV was 4.4% (95% CI 3.2-6.0, n = 39) in the first test, and 2.5% were persistent positive in the second test (95% C 1.6-3.8, n = 22) collected on average 5.5 months later. Dysplasia, was found in 1.8% (16/893) (95% CI 1.1-3.0) and CIN 2+ in 1.0% (9/893) (95% CI 0.5-2.0) of the women. Of the 16 women with dysplasia in histology, 13 (81.2%) had a normal cytology. Interpretation Repeated self-sampling at home combined with HPV testing was well accepted among elderly women. A high prevalence of CIN was diagnosed by histology. Cytology showed extremely low sensitivity and should not be recommended for this age group.

National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-372761 (URN)10.1371/journal.pone.0207714 (DOI)000452212400061 ()30517176 (PubMedID)
Available from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-01-14Bibliographically approved
Ameur, A., Che, H., Martin, M., Bunikis, I., Dahlberg, J., Höijer, I., . . . Gyllensten, U. B. (2018). De Novo Assembly of Two Swedish Genomes Reveals Missing Segments from the Human GRCh38 Reference and Improves Variant Calling of Population-Scale Sequencing Data. Genes, 9(10), Article ID 486.
Open this publication in new window or tab >>De Novo Assembly of Two Swedish Genomes Reveals Missing Segments from the Human GRCh38 Reference and Improves Variant Calling of Population-Scale Sequencing Data
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2018 (English)In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 9, no 10, article id 486Article in journal (Refereed) Published
Abstract [en]

The current human reference sequence (GRCh38) is a foundation for large-scale sequencing projects. However, recent studies have suggested that GRCh38 may be incomplete and give a suboptimal representation of specific population groups. Here, we performed a de novo assembly of two Swedish genomes that revealed over 10 Mb of sequences absent from the human GRCh38 reference in each individual. Around 6 Mb of these novel sequences (NS) are shared with a Chinese personal genome. The NS are highly repetitive, have an elevated GC-content, and are primarily located in centromeric or telomeric regions. Up to 1 Mb of NS can be assigned to chromosome Y, and large segments are also missing from GRCh38 at chromosomes 14, 17, and 21. Inclusion of NS into the GRCh38 reference radically improves the alignment and variant calling from short-read whole-genome sequencing data at several genomic loci. A re-analysis of a Swedish population-scale sequencing project yields > 75,000 putative novel single nucleotide variants (SNVs) and removes > 10,000 false positive SNV calls per individual, some of which are located in protein coding regions. Our results highlight that the GRCh38 reference is not yet complete and demonstrate that personal genome assemblies from local populations can improve the analysis of short-read whole-genome sequencing data.

Keywords
de novo assembly, SMRT sequencing, GRCh38, human reference genome, human whole-genome sequencing, population sequencing, Swedish population
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-369762 (URN)10.3390/genes9100486 (DOI)000448656700024 ()30304863 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, 2014.0272Swedish Research Council
Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2018-12-17Bibliographically approved
Höijer, I., Tsai, Y.-C., Clark, T. A., Kotturi, P., Dahl, N., Stattin, E., . . . Ameur, A. (2018). Detailed analysis of HTT repeat elements in human blood using targeted amplification-free long-read sequencing. Human Mutation, 39(9), 1262-1272
Open this publication in new window or tab >>Detailed analysis of HTT repeat elements in human blood using targeted amplification-free long-read sequencing
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2018 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 39, no 9, p. 1262-1272Article in journal (Refereed) Published
Abstract [en]

Amplification of DNA is required as a mandatory step during library preparation in most targeted sequencing protocols. This can be a critical limitation when targeting regions that are highly repetitive or with extreme guanine-cytosine (GC) content, including repeat expansions associated with human disease. Here, we used an amplification-free protocol for targeted enrichment utilizing the CRISPR/Cas9 system (No-Amp Targeted sequencing) in combination with single molecule, real-time (SMRT) sequencing for studying repeat elements in the huntingtin (HTT) gene, where an expanded CAG repeat is causative for Huntington disease. We also developed a robust data analysis pipeline for repeat element analysis that is independent of alignment of reads to a reference genome. The method was applied to 11 diagnostic blood samples, and for all 22 alleles the resulting CAG repeat count agreed with previous results based on fragment analysis. The amplification-free protocol also allowed for studying somatic variability of repeat elements in our samples, without the interference of PCR stutter. In summary, with No-Amp Targeted sequencing in combination with our analysis pipeline, we could accurately study repeat elements that are difficult to investigate using PCR-based methods.

Keywords
amplification-free sequencing, HTT, Huntington disease, No-Amp Targeted sequencing, repeat expansion, SMRT sequencing, somatic mosaicism, targeted enrichment, targeted sequencing
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-364189 (URN)10.1002/humu.23580 (DOI)000443229000010 ()29932473 (PubMedID)
Available from: 2018-11-07 Created: 2018-11-07 Last updated: 2018-11-16Bibliographically approved
Evangelou, E., Warren, H. R., Mosen-Ansorena, D., Mifsud, B., Pazoki, R., Gao, H., . . . Caulfield, M. J. (2018). Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.. Nature Genetics, 50(10), 1412-1425
Open this publication in new window or tab >>Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
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2018 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 10, p. 1412-1425Article in journal (Refereed) Published
Abstract [en]

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-367084 (URN)10.1038/s41588-018-0205-x (DOI)000446047000013 ()30224653 (PubMedID)
Funder
EU, European Research CouncilNovo Nordisk, NNF15CC0018486EU, FP7, Seventh Framework Programme, HEALTH-F2-2013-601456Wellcome trust, RE/13/1/30181Wellcome trust, WT098051
Available from: 2018-11-28 Created: 2018-11-28 Last updated: 2018-12-05Bibliographically approved
Ek, W. E., Rask-Andersen, M., Karlsson, T., Enroth, S., Gyllensten, U. B. & Johansson, Å. (2018). Genetic variants influencing phenotypic variance heterogeneity. Human Molecular Genetics, 27(5), 799-810
Open this publication in new window or tab >>Genetic variants influencing phenotypic variance heterogeneity
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2018 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 5, p. 799-810Article in journal (Refereed) Published
Abstract [en]

Most genetic studies identify genetic variants associated with disease risk or with the mean value of a quantitative trait. More rarely, genetic variants associated with variance heterogeneity are considered. In this study, we have identified such variance single-nucleotide polymorphisms (vSNPs) and examined if these represent biological gene x gene or gene x environment interactions or statistical artifacts caused by multiple linked genetic variants influencing the same phenotype. We have performed a genome-wide study, to identify vSNPs associated with variance heterogeneity in DNA methylation levels. Genotype data from over 10 million single-nucleotide polymorphisms (SNPs), and DNA methylation levels at over 430 000 CpG sites, were analyzed in 729 individuals. We identified vSNPs for 7195 CpG sites (P < 9.4 x 10(-11)). This is a relatively low number compared to 52 335 CpG sites for which SNPs were associated with mean DNA methylation levels. We further showed that variance heterogeneity between genotypes mainly represents additional, often rare, SNPs in linkage disequilibrium (LD) with the respective vSNP and for some vSNPs, multiple low frequency variants co-segregating with one of the vSNP alleles. Therefore, our results suggest that variance heterogeneity of DNA methylation mainly represents phenotypic effects by multiple SNPs, rather than biological interactions. Such effects may also be important for interpreting variance heterogeneity of more complex clinical phenotypes.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-350890 (URN)10.1093/hmg/ddx441 (DOI)000426838200003 ()29325024 (PubMedID)
Funder
Swedish Research Council, 2011-2354, 2015-03327Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Society for Medical Research (SSMF)Åke Wiberg Foundation
Available from: 2018-05-28 Created: 2018-05-28 Last updated: 2018-07-06Bibliographically approved
Enroth, S., Maturi, V., Berggrund, M., Bosdotter Enroth, S., Moustakas, A., Johansson, Å. & Gyllensten, U. B. (2018). Systemic and specific effects of antihypertensive and lipid-lowering medication on plasma protein biomarkers for cardiovascular diseases. Scientific Reports, 8, Article ID 5531.
Open this publication in new window or tab >>Systemic and specific effects of antihypertensive and lipid-lowering medication on plasma protein biomarkers for cardiovascular diseases
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 5531Article in journal (Refereed) Published
Abstract [en]

A large fraction of the adult population is on lifelong medication for cardiovascular disorders, but the metabolic consequences are largely unknown. This study determines the effects of common anti-hypertensive and lipid lowering drugs on circulating plasma protein biomarkers. We studied 425 proteins in plasma together with anthropometric and lifestyle variables, and the genetic profile in a cross-sectional cohort. We found 8406 covariate-protein associations, and a two-stage GWAS identified 17253 SNPs to be associated with 109 proteins. By computationally removing variation due to lifestyle and genetic factors, we could determine that medication, per se, affected the abundance levels of 35.7% of the plasma proteins. Medication either affected a single, a few, or a large number of protein, and were found to have a negative or positive influence on known disease pathways and biomarkers. Anti-hypertensive or lipid lowering drugs affected 33.1% of the proteins. Angiotensin-converting enzyme inhibitors showed the strongest lowering effect by decreasing plasma levels of myostatin. Cell-culture experiments showed that angiotensin-converting enzyme inhibitors reducted myostatin RNA levels. Thus, understanding the effects of lifelong medication on the plasma proteome is important both for sharpening the diagnostic precision of protein biomarkers and in disease management.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-351628 (URN)10.1038/s41598-018-23860-y (DOI)000428999200067 ()29615742 (PubMedID)
Funder
Swedish Foundation for Strategic Research Swedish National Infrastructure for Computing (SNIC), b2011203; b2014145
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2018-07-06Bibliographically approved
Ek, W. E., Ahsan, M., Rask-Andersen, M., Liang, L., Moffatt, M. F., Gyllensten, U. & Johansson, Å. (2017). Epigenome-wide DNA methylation study of IgE concentration in relation to self-reported allergies. Epigenomics, 9(4), 407-418
Open this publication in new window or tab >>Epigenome-wide DNA methylation study of IgE concentration in relation to self-reported allergies
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2017 (English)In: Epigenomics, ISSN 1750-1911, Vol. 9, no 4, p. 407-418Article in journal (Refereed) Published
Abstract [en]

AIM: Epigenetic mechanisms are critical for normal immune development and epigenetic alterations might therefore be possible contributors to immune diseases. To investigate if DNA methylation in whole blood is associated with total and allergen-specific IgE levels.

METHODS: We performed an epigenome-wide association study to investigate the association between DNA methylation and IgE level, allergen-specific IgE and self-reported immune diseases and allergies in 728 individuals.

RESULTS: We identified and replicated 15 CpG sites associated with IgE, mapping to biologically relevant genes, including ACOT7, ILR5A, KCNH2, PRG2 and EPX. A total of 331 loci were associated with allergen-specific IgE, but none of these CpG sites were associated with self-reported allergies and immune diseases.

CONCLUSION: This study shows that IgE levels are associated with DNA methylation levels at numerous CpG sites, which might provide new leads for investigating the links between IgE and allergic inflammation.

Keywords
DNA methylation, Fx5, IgE, Phadiatop, allergy, immune diseases
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-318034 (URN)10.2217/epi-2016-0158 (DOI)000399344700006 ()28322575 (PubMedID)
Funder
Swedish Society of Medicine, 2011-2354 K2007-66X-20270-01-3Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologySwedish Foundation for Strategic Research EU, European Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2018-07-06Bibliographically approved
Aschard, H., Tobin, M. D., Hancock, D. B., Skurnik, D., Sood, A., James, A., . . . Kraft, P. (2017). Evidence for large-scale gene-by-smoking interaction effects on pulmonary function. International Journal of Epidemiology, 46(3), 894-904
Open this publication in new window or tab >>Evidence for large-scale gene-by-smoking interaction effects on pulmonary function
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2017 (English)In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 46, no 3, p. 894-904Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking.

METHODS: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia.

RESULTS: We identified an interaction (βint = -0.036, 95% confidence interval, -0.040 to -0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV 1: /FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect.

CONCLUSIONS: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.

Keywords
FEV1/FVC, genetic risk score, gene–environment interaction, smoking
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-317998 (URN)10.1093/ije/dyw318 (DOI)000406242600023 ()28082375 (PubMedID)
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2017-10-30Bibliographically approved
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