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Clark, D. W., Karlsson, T., Sennblad, B., Gyllensten, U. B., Johansson, Å. & Wilson, J. F. (2019). Associations of autozygosity with a broad range of human phenotypes. Nature Communications, 10, Article ID 4957.
Open this publication in new window or tab >>Associations of autozygosity with a broad range of human phenotypes
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 4957Article in journal (Refereed) Published
Abstract [en]

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-397418 (URN)10.1038/s41467-019-12283-6 (DOI)000493438700005 ()31673082 (PubMedID)
Note

For complete list of authors see http://dx.doi.org/10.1038/s41467-019-12283-6

Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2019-11-20Bibliographically approved
Gustavsson, I. M., Aarnio, R., Myrnäs, M., Lindberg, J. H., Taku, O., Meiring, T., . . . Gyllensten, U. B. (2019). Clinical validation of the HPVIR high-risk HPV test on cervical samples according to the international guidelines for human papillomavirus DNA test requirements for cervical cancer screening. Virology Journal, 16(1), Article ID 107.
Open this publication in new window or tab >>Clinical validation of the HPVIR high-risk HPV test on cervical samples according to the international guidelines for human papillomavirus DNA test requirements for cervical cancer screening
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2019 (English)In: Virology Journal, ISSN 1743-422X, E-ISSN 1743-422X, Vol. 16, no 1, article id 107Article in journal (Refereed) Published
Abstract [en]

Background

The indicating FTA card is a dry medium used for collection of cervical samples. HPVIR is a multiplex real-time PCR test that detects 12 high-risk human papillomavirus types (hrHPV) and provides single genotype information for HPV16, − 31, − 35, − 39, − 51, − 56, and − 59 and pooled type information for HPV18/45 and HPV33/52/58. The aim of this study was to evaluate whether a strategy with cervical samples collected on the FTA card and subsequently analysed with the HPVIR test complies with the criteria of the international guidelines for a clinically validated method for cervical screening.

Methods

We performed a non-inferiority test comparing the clinical sensitivity and specificity of the candidate test (FTA card and HPVIR) with a clinically validated reference test (Cobas® HPV test) based on liquid-based cytology (LBC) samples. Two clinical samples (LBC and FTA) were collected from 896 participants in population-based screening. For evaluation of the specificity we used 799 women without ≥ CIN2, and for clinical sensitivity we used 67 women with histologically confirmed ≥ CIN2. The reproducibility was studied by performing inter- and intra-laboratory tests of 558 additional clinical samples.

Results

The clinical sensitivity and specificity for samples collected on the FTA card and analysed using the HPVIR test were non-inferior to samples analysed with the Cobas® HPV test based on LBC samples (non-inferiority test score, p = 1.0 × 10− 2 and p = 1.89 × 10− 9, respectively). Adequate agreement of > 87% was seen in both the intra- and inter-laboratory comparisons.

Conclusions

Samples collected on the indicating FTA card and analysed with HPVIR test fulfil the requirements of the international guidelines and can therefore be used in primary cervical cancer screening.

Keywords
HPV, DNA testing, Primary cervical cancer screening, International guidelines
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-394268 (URN)10.1186/s12985-019-1216-7 (DOI)000483382500001 ()31438976 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and WelfareSwedish Cancer Society
Available from: 2019-10-09 Created: 2019-10-09 Last updated: 2019-10-09Bibliographically approved
Aarnio, R., Wikström, I., Gustavsson, I. M., Gyllensten, U. B. & Olovsson, M. (2019). Diagnostic excision of the cervix in women over 40 years with human papilloma virus persistency and normal cytology. European journal of obstetrics & gynecology and reproductive biology: X, 3, Article ID 100042.
Open this publication in new window or tab >>Diagnostic excision of the cervix in women over 40 years with human papilloma virus persistency and normal cytology
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2019 (English)In: European journal of obstetrics & gynecology and reproductive biology: X, ISSN 2590-1613, Vol. 3, article id 100042Article in journal (Refereed) Published
Abstract [en]

Objective: Persistent infection with human papillomavirus (HPV) is recognized as the main risk factor of cervical cancer. Investigation via cytology and colposcopy have lower sensitivity than HPV testing in the diagnosis of high-grade cervical intraepithelial neoplasia (CIN2+). Despite normal cytology and colposcopy findings women with persistent HPV infection have an increased risk of CIN2+. The aim of the study was to evaluate the proportion of histologically confirmed CIN2+ in women with persistent HPV infection and normal Pap smears.

Study design: From April 2013 until March 2016 we prospectively recruited 91 women over 40 years with persistent HPV infection without any abnormalities in cytology. Of these, 40 women attended a gynecological examination including an HPV test, Pap smear, endocervical cytology, colposcopy with biopsies and diagnostic loop electrosurgical excision procedure (LEEP). Biopsy and LEEP samples were subjected to histological examination.

Results: CIN2+ was verified by histological examination of the LEEP sample in 6/40 (15%) of the women. All the cytological samples were normal and none of the biopsies confirmed CIN2+. Only 19/40 women still had a persistent HPV infection at the study visit. None of the 21/40 women who had cleared their HPV infection at the study visit had CIN2+ in histology of the LEEP sample.

Conclusions: A persistent HPV infection needs to be monitored despite normal Pap smears, since 6/40 (15%) women older than 40 years, was revealed to have an undiagnosed CIN2+ when LEEP was performed. Counseling women regarding the risk of cervical cancer and the expected effect of an eventual LEEP can help them to make an optimal informed choice.

Keywords
Cervical intraepithelial neoplasia, Colposcopy, Human papillomavirus, Loop electrical excision procedure, Transformation zone
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-400770 (URN)10.1016/j.eurox.2019.100042 (DOI)31404426 (PubMedID)
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-03-18Bibliographically approved
Imboden, M., Wielscher, M., Rezwan, F. I., Amaral, A. F., Schaffner, E., Jeong, A., . . . Probst-Hensch, N. M. (2019). Epigenome-wide association study of lung function level and its change. European Respiratory Journal, 54(1), Article ID 1900457.
Open this publication in new window or tab >>Epigenome-wide association study of lung function level and its change
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2019 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 54, no 1, article id 1900457Article in journal (Refereed) Published
Abstract [en]

Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, 6-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10-7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute β-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10-21 and pcombined=7.22×10-50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10-20).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and in children.

Place, publisher, year, edition, pages
European Respiratory Society, 2019
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-392910 (URN)10.1183/13993003.00457-2019 (DOI)000486537500022 ()31073081 (PubMedID)
Funder
EU, Horizon 2020, 633212
Available from: 2019-09-11 Created: 2019-09-11 Last updated: 2019-10-30Bibliographically approved
Sakornsakolpat, P., Prokopenko, D., Lamontagne, M., Reeve, N. F., Guyatt, A. L., Jackson, V. E., . . . Zeigler-Heitbrock, L. (2019). Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations. Nature Genetics, 51(3), 494-505
Open this publication in new window or tab >>Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 494-505Article in journal (Refereed) Published
Abstract [en]

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 x 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.

National Category
Respiratory Medicine and Allergy Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379346 (URN)10.1038/s41588-018-0342-2 (DOI)000459947200017 ()30804561 (PubMedID)
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Enroth, S., Berggrund, M., Lycke, M., Broberg, J., Lundberg, M., Assarsson, E., . . . Gyllensten, U. B. (2019). High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer. Communications biology, 2, Article ID 221.
Open this publication in new window or tab >>High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer
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2019 (English)In: Communications biology, ISSN 2399-3642, Vol. 2, article id 221Article in journal (Refereed) Published
Abstract [en]

Ovarian cancer is usually detected at a late stage and the overall 5-year survival is only 30-40%. Additional means for early detection and improved diagnosis are acutely needed. To search for novel biomarkers, we compared circulating plasma levels of 593 proteins in three cohorts of patients with ovarian cancer and benign tumors, using the proximity extension assay (PEA). A combinatorial strategy was developed for identification of different multivariate biomarker signatures. A final model consisting of 11 biomarkers plus age was developed into a multiplex PEA test reporting in absolute concentrations. The final model was evaluated in a fourth independent cohort and has an AUC = 0.94, PPV = 0.92, sensitivity = 0.85 and specificity = 0.93 for detection of ovarian cancer stages I-IV. The novel plasma protein signature could be used to improve the diagnosis of women with adnexal ovarian mass or in screening to identify women that should be referred to specialized examination.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
Keywords
Diagnostic markers, Machine learning, Ovarian cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-388611 (URN)10.1038/s42003-019-0464-9 (DOI)000472439200002 ()31240259 (PubMedID)
Funder
Swedish Foundation for Strategic Research Swedish Research CouncilSwedish Cancer SocietyVinnova
Note

These authors contributed equally: Stefan Enroth, Malin Berggrund

Available from: 2019-07-02 Created: 2019-07-02 Last updated: 2019-08-07Bibliographically approved
Berggrund, M., Gustavsson, I. M., Aarnio, R., Lindberg, J. H., Sanner, K., Wikström, I., . . . Gyllensten, U. B. (2019). HPV viral load in self-collected vaginal fluid samples as predictor for presence of cervical intraepithelial neoplasia.. Virology Journal, 16, Article ID 146.
Open this publication in new window or tab >>HPV viral load in self-collected vaginal fluid samples as predictor for presence of cervical intraepithelial neoplasia.
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2019 (English)In: Virology Journal, ISSN 1743-422X, E-ISSN 1743-422X, Vol. 16, article id 146Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: This study was performed to evaluate the use of high-risk HPV (hrHPV) viral load in screening tests for cervical cancer to predict persistent infection and presence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+).

METHODS: We followed women between 30 and 60 years of age who performed self-sampling of vaginal fluid and subsequently a hrHPV test. Women who were hrHPV positive in their screening test repeated the hrHPV test 3-6 months later and were included in the present study.

RESULTS: Our results show that women with a persistent HPV16 infection had higher HPV viral load in their primary screening test than women with transient infections (p = 5.33e-03). This was also true for sum of viral load for all hrHPV types in the primary screening test (p = 3.88e-07). 48% of women with persistent HPV16 infection and CIN2+ had an increase in HPV16 titer in the follow-up test, as compared to only 20% of women with persistent infection but without CIN2+ lesions. For the sum of all hrHPV types, 41% of women with persistent infection and CIN2+ had an increase in titer as compared to 26% of women without CIN2 + .

CONCLUSIONS: The results show that hrHPV viral load in the primary screening HPV test is associated with the presence of CIN2+ and could be used in triaging hrHPV positive women for different follow-up strategies or recall times. Serial testing of hrHPV viral load has the potential to distinguish women with CIN2+ lesions from women with persistent infection but without CIN2+ lesions.

Keywords
CIN2+, Cervical cancer, HPV viral load, Self-sampling, hrHPV
National Category
Obstetrics, Gynecology and Reproductive Medicine Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-406972 (URN)10.1186/s12985-019-1253-2 (DOI)000513831600002 ()31771594 (PubMedID)
Funder
Swedish Cancer SocietySwedish Foundation for Strategic Research Swedish Research Council
Available from: 2020-03-17 Created: 2020-03-17 Last updated: 2020-03-20Bibliographically approved
Berggrund, M., Enroth, S., Lundberg, M., Assarsson, E., Stålberg, K., Lindquist, D., . . . Gyllensten, U. (2019). Identification of Candidate Plasma Protein Biomarkers for Cervical Cancer Using the Multiplex Proximity Extension Assay. Molecular & Cellular Proteomics, 18(4), 735-743
Open this publication in new window or tab >>Identification of Candidate Plasma Protein Biomarkers for Cervical Cancer Using the Multiplex Proximity Extension Assay
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2019 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, no 4, p. 735-743Article in journal (Refereed) Published
Abstract [en]

Human papillomavirus (HPV) is recommended as the primary test in cervical cancer screening, with co-testing by cytology for HPV-positive women to identify cervical lesions. Cytology has low sensitivity and there is a need to identify biomarkers that could identify dysplasia that are likely to progress to cancer. We searched for plasma proteins that could identify women with cervical cancer using the multiplex proximity extension assay (PEA). The abundance of 100 proteins were measured in plasma collected at the time of diagnosis of patients with invasive cervical cancer and in population controls using the Olink Multiplex panels CVD II, INF I, and ONC II. Eighty proteins showed increased levels in cases compared with controls. We identified a signature of 11 proteins (PTX3, ITGB1BP2, AXIN1, STAMPB, SRC, SIRT2, 4E-BP1, PAPPA, HB-EGF, NEMO and IL27) that distinguished cases and controls with a sensitivity of 0.96 at a specificity of 1.0. This signature was evaluated in a prospective replication cohort with samples collected before, at or after diagnosis and achieved a sensitivity of 0.78 and a specificity 0.56 separating samples collected at the time of diagnosis of invasive cancer from samples collected prior to diagnosis. No difference in abundance was seen between samples collected prior to diagnosis or after treatment as compared with population controls, indicating that this protein signature is mainly informative close to time of diagnosis. Further studies are needed to determine the optimal window in time prior to diagnosis for these biomarker candidates.

National Category
Cancer and Oncology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-383873 (URN)10.1074/mcp.RA118.001208 (DOI)000466934700009 ()30692274 (PubMedID)
Funder
Swedish Foundation for Strategic Research Swedish Research CouncilSwedish Cancer Society
Available from: 2019-06-14 Created: 2019-06-14 Last updated: 2020-03-18Bibliographically approved
Cui, T., Enroth, S., Ameur, A., Gustavsson, I., Lindquist, D. & Gyllensten, U. (2019). Invasive cervical tumors with high and low HPV titer represent molecular subgroups with different disease etiology. Carcinogenesis, 40(2), 269-278
Open this publication in new window or tab >>Invasive cervical tumors with high and low HPV titer represent molecular subgroups with different disease etiology
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2019 (English)In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 40, no 2, p. 269-278Article in journal (Refereed) Published
Abstract [en]

Invasive cervical cancer (ICC) with very low titer of high-risk human papillomavirus (HPV) has worse clinical outcome than cases with high titer, indicating a difference in molecular etiology. Fresh-frozen ICC tumors (n = 49) were classified into high- and low-HPV-titer cases using real-time PCR-based HPV genotyping. The mutation spectra were studied using the AmpliSeq Comprehensive Cancer Panel and the expression profiles using total RNA sequencing, and the results were validated using the AmpliSeq Transcriptome assay. HPV DNA genotyping and RNA sequencing showed that 16.6% of ICC tumors contained very low levels of HPV DNA and HPV transcripts. Tumors with low HPV levels had more mutations with a high allele frequency and fewer mutations with low allele frequency relative to tumors with high HPV titer. A number of genes showed significant expression differences between HPV titer groups, including genes with somatic mutations. Gene ontology and pathway analyses implicated the enrichment of genes involved in DNA replication, cell cycle control and extracellular matrix in tumors with low HPV titer. The results indicate that in low titer tumors, HPVs act as trigger of cancer development whereas somatic mutations are clonally selected and become drivers of the tumor development process. In contrast, in tumors with high HPV titer the expression of HPV oncoproteins plays a major role in tumor development and the many low frequency somatic mutations represent passengers. This putative subdivision of invasive cervical tumors may explain the higher radiosensitivity of ICC tumors with high HPV titer and thereby have consequences for clinical management.

National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-388612 (URN)10.1093/carcin/bgy183 (DOI)000472792800012 ()30596972 (PubMedID)
Funder
Swedish Cancer Society, CF23560Swedish Research Council, 2012-2884Swedish Society for Medical Research (SSMF)Knut and Alice Wallenberg Foundation, KAW2011.0205
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2019-07-02 Created: 2019-07-02 Last updated: 2019-08-23Bibliographically approved
Shrine, N., Guyatt, A. L., Erzurumluoglu, A. M., Jackson, V. E., Hobbs, B. D., Melbourne, C. A., . . . Wain, L. V. (2019). New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries. Nature Genetics, 51(3), 481-493
Open this publication in new window or tab >>New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 481-493Article in journal (Refereed) Published
Abstract [en]

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

National Category
Medical Genetics Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-379345 (URN)10.1038/s41588-018-0321-7 (DOI)000459947200016 ()30804560 (PubMedID)
Funder
Wellcome trust, WT202849/Z/16/Z
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6316-3355

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