| 1. |
- Ntalla, Ioanna, et al.
(författare)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 2. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 3. |
- Nordanstig, Joakim, et al.
(författare)
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Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease.
- 2020
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Ingår i: The New England journal of medicine. - : Massachusetts Medical Society. - 1533-4406 .- 0028-4793. ; 383, s. 2538-46
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Tidskriftsartikel (refereegranskat)abstract
- The results of a recent meta-analysis aroused concern about an increased risk of death associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral artery disease.We conducted an unplanned interim analysis of data from a multicenter, randomized, open-label, registry-based clinical trial. At the time of the analysis, 2289 patients had been randomly assigned to treatment with drug-coated devices (the drug-coated-device group, 1149 patients) or treatment with uncoated devices (the uncoated-device group, 1140 patients). Randomization was stratified according to disease severity on the basis of whether patients had chronic limb-threatening ischemia (1480 patients) or intermittent claudication (809 patients). The single end point for this interim analysis was all-cause mortality.No patients were lost to follow-up. Paclitaxel was used as the coating agent for all the drug-coated devices. During a mean follow-up of 2.49 years, 574 patients died, including 293 patients (25.5%) in the drug-coated-device group and 281 patients (24.6%) in the uncoated-device group (hazard ratio, 1.06; 95% confidence interval, 0.92 to 1.22). At 1 year, all-cause mortality was 10.2% (117 patients) in the drug-coated-device group and 9.9% (113 patients) in the uncoated-device group. During the entire follow-up period, there was no significant difference in the incidence of death between the treatment groups among patients with chronic limb-threatening ischemia (33.4% [249 patients] in the drug-coated-device group and 33.1% [243 patients] in the uncoated-device group) or among those with intermittent claudication (10.9% [44 patients] and 9.4% [38 patients], respectively).In this randomized trial in which patients with peripheral artery disease received treatment with paclitaxel-coated or uncoated endovascular devices, the results of an unplanned interim analysis of all-cause mortality did not show a difference between the groups in the incidence of death during 1 to 4 years of follow-up. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT02051088.).
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| 4. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 5. |
- Ahlstrand, Erik, 1974-, et al.
(författare)
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Highly Reduced Survival in Essential Thrombocythemia and Polycythemia Vera Patients with Vascular Complications during Follow-up
- 2020
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Ingår i: European Journal of Haematology. - : Munksgaard Forlag. - 0902-4441 .- 1600-0609. ; 104:3, s. 271-278
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To explore the relative importance of risk factors, treatments and blood counts for the occurrence of vascular complications and their impact on life expectancy in Essential Thrombocythemia (ET) and Polycythemia Vera (PV).METHODS: Nested case-control study within the Swedish MPN registry. From a cohort of 922 ET patients and 763 PV patients, 71 ET and 81 PV cases with vascular complications were compared to matched controls.RESULTS: Incidence of vascular complications were 2.0 and 3.4 events per 100 patient-years in ET and PV, respectively. At diagnosis, no significant risk factor differences were observed between cases and controls in neither of the diseases. At the time of vascular event, ET complication cases did not differ significantly from controls but in PV, cases had significantly higher WBCs and were to a lesser extent treated with antithrombotic and cytoreductive therapy. Life expectancy was significantly decreased in both ET and PV cases compared to controls.CONCLUSIONS: The risk of vascular complications is high in both ET and PV and these complications have a considerable impact on life expectancy. The protective effect of antithrombotic and cytoreductive therapy for vascular complications in PV underscores the importance of avoiding undertreatment.
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| 6. |
- Angelison, Leif, et al.
(författare)
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Short and long-term efficacy of adalimumab in ulcerative colitis : a real-life study
- 2020
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 55:2, s. 154-162
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Randomized controlled trials have shown the effectiveness of Adalimumab in ulcerative colitis. However, real-life data is scarce. We aimed to assess the effectiveness and predictive factors of effectiveness in a large Swedish cohort. Methods: Retrospective capture of data from local registries at five Swedish IBD centers. Clinical response and remission rates were assessed at three months after starting adalimumab treatment and patients were followed until colectomy or need for another biological. Bio-naive patients were compared to bio experienced patients. Factors associated with short term responses were assessed using logistic regression model. Failure on drug was assessed using a Cox proportional hazards regression model. Results: 118 patients (59 males, 59 females) with median age 34.4 years (IQR 27.0–51.4) were included. Median disease duration was 4.3 years (IQR 2.0–9.0) and follow-up 1.27 years (IQR 0.33–4.1). A clinical corticosteroid-free remission was achieved by 38/118 (32.2%) and response by 91/118 (77%) after three months. CRP >3 mg/l at baseline was predictive of short-term failure to reach corticosteroid-free remission. Factors associated with survival on the drug were male gender, CRP <3 mg/l and absence of primary sclerosing cholangitis. Patients >42 years of age at diagnosis were more likely to respond to adalimumab and remain on treatment compared to patients <20 years. Conclusions: An elevated CRP-level, primary sclerosing cholangitis and female gender were predictors of treatment failure. In contrast older age at diagnosis was a predictor of short-term clinical response and drug survival. Prior infliximab failure, regardless of cause, did not influence the outcome of adalimumab treatment.
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| 7. |
- Bergman, Lina, 1982, et al.
(författare)
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Study for Improving Maternal Pregnancy And Child ouTcomes (IMPACT): a study protocol for a Swedish prospective multicentre cohort study
- 2020
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Ingår i: BMJ Open. - : BMJ. - 2044-6055 .- 2044-6055. ; 10:9, s. e033851-e033851
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Tidskriftsartikel (refereegranskat)abstract
- Introduction First-trimester pregnancy risk evaluation facilitates individualised antenatal care, as well as application of preventive strategies for pre-eclampsia or birth of a small for gestational age infant. A range of early intervention strategies in pregnancies identified as high risk at the end of the first trimester has been shown to decrease the risk of preterm pre-eclampsia (<37 gestational weeks). The aim of this project is to create the Improving Maternal Pregnancy And Child ouTcomes (IMPACT) database; a nationwide database with individual patient data, including predictors recorded at the end of the first trimester and later pregnancy outcomes, to identify women at high risk of pre-eclampsia. A second aim is to link the IMPACT database to a biobank with first-trimester blood samples. Methods and analysis This is a Swedish prospective multicentre cohort study. Women are included between the 11th and 14th weeks of pregnancy. At inclusion, pre-identified predictors are retrieved by interviews and medical examinations. Blood samples are collected and stored in a biobank. Additional predictors and pregnancy outcomes are retrieved from the Swedish Pregnancy Register. Inclusion in the study began in November 2018 with a targeted sample size of 45 000 pregnancies by end of 2021. Creation of a new risk prediction model will then be developed, validated and implemented. The database and biobank will enable future research on prediction of various pregnancy-related complications. Ethics and dissemination Confidentiality aspects such as data encryption and storage comply with the General Data Protection Regulation and with ethical committee requirements. This study has been granted national ethical approval by the Swedish Ethical Review Authority (Uppsala 2018-231) and national biobank approval at Uppsala Biobank (18237 2 2018 231). Results from the current as well as future studies using information from the IMPACT database will be published in peer-reviewed journals.
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| 8. |
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| 9. |
- Erlandsson, Lena, et al.
(författare)
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Exposure to wood smoke particles leads to inflammation, disrupted proliferation and damage to cellular structures in a human first trimester trophoblast cell line
- 2020
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Ingår i: Environmental Pollution. - : Elsevier. - 0269-7491 .- 1873-6424. ; 264
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Tidskriftsartikel (refereegranskat)abstract
- The ongoing transition to renewable fuel sources has led to increased use of wood and other biomass fuels. The physiochemical characteristics of biomass combustion derived aerosols depends on appliances, fuel and operation procedures, and particles generated during incomplete combustion are linked to toxicity. Frequent indoor wood burning is related to severe health problems such as negative effects on airways and inflammation, as well as chronic hypoxia and pathological changes in placentas, adverse pregnancy outcome, preterm delivery and increased risk of preeclampsia. The presence of combustion-derived black carbon particles at both the maternal and fetal side of placentas suggests that particles can reach the fetus. Air pollution particles have also been shown to inhibit trophoblast migration and invasion, which are vital functions for the development of the placenta during the first trimester. In this study we exposed a placental first trimester trophoblast cell line to wood smoke particles emitted under Nominal Burn rate (NB) or High Burn rate (HB). The particles were visible inside exposed cells and localized to the mitochondria, causing ultrastructural changes in mitochondria and endoplasmic reticulum. Exposed cells showed decreased secretion of the pregnancy marker human chorionic gonadotropin, increased secretion of IL-6, disrupted membrane integrity, disrupted proliferation and contained specific polycyclic aromatic hydrocarbons (PAHs) from the particles. Taken together, these results suggest that wood smoke particles can enter trophoblasts and have detrimental effects early in pregnancy by disrupting critical trophoblast functions needed for normal placenta development and function. This could contribute to the underlying mechanisms leading to pregnancy complications such as miscarriage, premature birth, preeclampsia and/or fetal growth restriction. This study support the general recommendation that more efficient combustion technologies and burning practices should be adopted to reduce some of the toxicity generated during wood burning.
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| 10. |
- Gerding, Henrik, et al.
(författare)
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The Republican Forum Romanum
- 2020
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The Forum Romanum constituted the religious, political, economic and administrative centre of Rome for more than a millennium. During this time it went through several changes. It transformed from a liminal zone in the periphery of the Iron Age settlements into a communal space and sacred ground; later into an arena for political struggle and civic ambition; and finally into a showcase for Imperial power and authority. New buildings were constantly being added and old ones rebuilt or replaced. This project deals with the architectural and spatial development of the Republican Forum Romanum. Of particular interest is the spatial configuration of the central Forum area in the mid- and late Republican periods. Thus, in a way, the study connects to the very first archaeological excavation in the Forum Romanum, conducted by the Swedish diplomat Carl Fredrik Fredenheim in 1788–89.The built environment that present day visitors to the Forum experience basically represents the late Augustan phase, interspersed with later additions and modifications. Earlier structures have only been excavated to a limited extent and the few remains that have been uncovered are now situated in deep trenches or underground compartments with little or no intervisibility. The fragmented state of the archaeological record constitutes a further hindrance to a satisfactory understanding of the earlier phases of the Forum. However, renewed investigations of previously excavated remains, supported by digital documentation techniques, holds the potential of revealing new features and providing a more comprehensive picture. By integrating separate and spatially isolated remains in a coherent and georeferenced three-dimensional model, the spatial relationship between various elements can be visualised and accurately assessed. The model will also be used to analyse the hydrological situation, a crucial aspect of the urban layout.In the field campaign of 2016 the architectural remains of the Basilica Sempronia and the Basilica Fulvia were investigated and documented. These contemporary buildings played an important role in defining the Forum. The ongoing study explores how they were related to each other and interacted with the intermediate and surrounding environment.The project has been financed by the Stiftelsen Enboms donationsfond, Carl Stadlers fond, Stiftelsen Torsten och Ingrid Ghils fond. We are also grateful to the Soprintendenza Speciale per i Beni Archeologici di Roma for graciously giving us the permission to carry out the investigation and for lending us support.
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