| 1. |
- Jones, Gregory T., et al.
(författare)
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Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci
- 2017
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Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 120:2, s. 341-
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
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| 2. |
- Haycock, Philip C., et al.
(författare)
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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study
- 2017
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Ingår i: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 3:5, s. 636-651
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [ 95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [ 95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [ 95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [ 95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
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| 3. |
- Axfors, Cathrine, et al.
(författare)
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Association between convalescent plasma treatment and mortality in COVID-19 : a collaborative systematic review and meta-analysis of randomized clinical trials
- 2021
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Ingår i: BMC Infectious Diseases. - : BioMed Central (BMC). - 1471-2334. ; 21:1
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Forskningsöversikt (refereegranskat)abstract
- Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, ). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I-2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.
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| 4. |
- Schulte, Peter, et al.
(författare)
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Cretaceous Extinctions: Evidence Overlooked Response
- 2010
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 328:5981, s. 975-976
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Schulte, Peter, et al.
(författare)
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The Chicxulub Asteroid Impact and Mass Extinction at the Cretaceous-Paleogene Boundary
- 2010
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 327:5970, s. 1214-1218
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Tidskriftsartikel (refereegranskat)abstract
- The Cretaceous-Paleogene boundary similar to 65.5 million years ago marks one of the three largest mass extinctions in the past 500 million years. The extinction event coincided with a large asteroid impact at Chicxulub, Mexico, and occurred within the time of Deccan flood basalt volcanism in India. Here, we synthesize records of the global stratigraphy across this boundary to assess the proposed causes of the mass extinction. Notably, a single ejecta-rich deposit compositionally linked to the Chicxulub impact is globally distributed at the Cretaceous-Paleogene boundary. The temporal match between the ejecta layer and the onset of the extinctions and the agreement of ecological patterns in the fossil record with modeled environmental perturbations (for example, darkness and cooling) lead us to conclude that the Chicxulub impact triggered the mass extinction.
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| 6. |
- Edgar, Kirsty M., et al.
(författare)
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New composite bio- and isotope stratigraphies spanning the Middle Eocene Climatic Optimum at tropical ODP Site 865 in the Pacific Ocean
- 2020
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Ingår i: Journal of Micropalaeontology. - : Copernicus GmbH. - 0262-821X .- 2041-4978. ; 39:2, s. 117-138
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Tidskriftsartikel (refereegranskat)abstract
- The Middle Eocene Climatic Optimum (MECO) at ca. 40 Ma is one of the largest of the transient Eocene global warming events. However, it is relatively poorly known from tropical settings since few sites span the entirety of the MECO event and/or host calcareous microfossils, which are the dominant proxy carrier for palaeoceanographic reconstructions. Ocean Drilling Program (ODP) Pacific Ocean Site 865 in the low-latitude North Pacific (Allison Guyot) has the potential to provide a useful tropical MECO reference, but detailed stratigraphic and chronological constraints needed to evaluate its completeness were previously lacking. We have addressed this deficit by generating new high-resolution biostratigraphic, stable isotope, and X-ray fluorescence (XRF) records spanning the MECO interval ( similar to 38.0-43.0 Ma) in two holes drilled at Site 865. XRF-derived strontium / calcium (Sr/Ca) and barium / strontium (Ba/Sr) ratios and Fe count records allow correlation between holes and reveal pronounced rhythmicity, enabling us to develop the first composite section for Holes 865B and 865C and a preliminary cyclostratigraphy for the MECO. Using this new framework, the sedimentary record is interpreted to be continuous across the event, as identified by a pronounced transient benthic foraminiferal delta O-18 shift of similar to 0.8 parts per thousand. Calcareous microfossil biostratigraphic events from widely used zonation schemes are recognized, with generally good agreement between the two holes, highlighting the robustness of the new composite section and allowing us to identify planktic foraminiferal Zones E10-E15 and calcareous nannofossil Zones NP15-18. However, discrepancies in the relative position and ordering of several primary and secondary bioevents with respect to published schemes are noted. Specifically, the stratigraphic highest occurrences of planktic foraminifera, Acarinina bullbrooki, Guembelitrioides nuttalli, and Morozovella aragonensis, and calcareous nannofossils, Chiasmolithus solitus and Sphenolithus furcatolithoides, and the lowest occurrence of Reticulofenestra reticulata all appear higher in the section than would be predicted relative to other bioevents. We also note conspicuous reworking of older microfossils (from planktic foraminiferal Zones E5-E9 and E13) into younger sediments (planktic foraminiferal Zones E14-15) within our study interval consistent with reworking above the MECO interval. Regardless of reworking, the high-quality XRF records enable decimetre-scale correlation between holes and highlight the potential of Site 865 for constraining tropical environmental and biotic changes, not just across the MECO but also throughout the Palaeocene and early-to-middle Eocene interval.
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| 7. |
- Freitag, Daniel F., et al.
(författare)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Tidskriftsartikel (refereegranskat)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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| 8. |
- Cappelli, Carlotta, et al.
(författare)
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Middle Eocene large coccolithaceans : Biostratigraphic implications and paleoclimatic clues
- 2020
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Ingår i: Marine Micropaleontology. - : Elsevier BV. - 0377-8398 .- 1872-6186. ; 154
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Tidskriftsartikel (refereegranskat)abstract
- A combined light microscope-scanning electron microscope study of exceptionally well-preserved calcareous nannofossil assemblages from clay-rich middle Eocene sediments recovered at IODP Site U1410 (NW Atlantic Ocean) has enabled us to document a new evolutionary lineage within Coccolithus-like placoliths that have well-developed near-axial or diagonal cross-bars in their central-area. Based on our observations, we describe a new genus Pletolithus, a new species Pletolithus giganteus and four new combinations (Pletolithus opdykei, Pletolithus staurion, Pletolithus mutatus and Pletolithus gigas). The distinctive ultra-structures of the different morphotypes and the presence of transitional morphologies suggest that Pletolithus evolved from a morphological variant of Coccolithus. The evolution of this group of coccolithaceans is initially characterized by increasing size and the appearance of delicate axial cross-bars in the central-area. Size continues to increase in these coccoliths and the orientation of the cross-bars shifts to asymmetric and diagonal in later representatives. Morphometric measurements on P. gigas and the morphologically similar P. giganteus, provide evidence for the presence of two distinct populations allowing for an objective differentiation of these two species, which in turn provides unambiguous taxonomic definition for the important biostratigraphic marker species P. gigas. These data improve the reliability of middle Eocene biostratigraphy and show that this lineage appeared when a new equilibrium in the environmental conditions was reached and intriguingly it coincides with a remarkable change in the deep circulation of the North Atlantic Ocean.
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| 9. |
- Cappelli, Carlotta, et al.
(författare)
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The evolution of Eocene (Ypresian/Lutetian) sphenoliths : biostratigraphic implications and paleoceanographic significance from North Atlantic Site IODP U1410
- 2021
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Ingår i: Newsletters on stratigraphy. - : Schweizerbart. - 0078-0421. ; 54:4, s. 405-431
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Tidskriftsartikel (refereegranskat)abstract
- Sphenoliths are a diverse and evolutionarily dynamic group of Cenozoic nannofossils which are widely used in biostratigraphic and paleoecological studies. We document the early-middle Eocene evolutionary succession of sphenoliths from IODP Site U1410 in the NW Atlantic Ocean (Southeast Newfoundland Ridge). The exquisite nannofossil preservation at this site allows us to better delineate the morphologic and optical features of these sphenoliths and to document new fragile morphotypes. These include forms bearing long and fragile lateral processes (the 'spiny sphenoliths' group) that are the possible ancestors of the Sphenolithus furcatolithoides group, which is characterized by well-developed apical cycles and typically bifurcating spines. New quantitative stratigraphic analyses highlight the biostratigraphic potential of the S. furcatolithoides group throughout Zones NP14-NP15 (Martini 1971) and six key intervals characterized by shifting sphenolith assemblage compositions are identified through the early-middle Eocene. These are: 1) the post-EECO S. moriformis decrease, 2) the S. radians-S. spiniger turnover across the Ypresian-Lutetian transition, 3) the appearance and diversification of the 'spiny sphenoliths' group during the early Lutetian, and 4-6) development of the S. furcatolithoides evolutionary lineage, including S. pseudo-furcatolithoides (sp. nov., former S. furcatolithoides morphotype A), S. cuniculus, S. furcatolithoides (former S. furcatolithoides morphotype B) and S. strigosus. Assemblage compositions shifts and stable isotope records indicate possible environmental forcing on sphenolith evolution, suggesting the group is sensitive to changes in trophic and/or thermal conditions.
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| 10. |
- Gibbs, Samantha J., et al.
(författare)
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Comment on "Calcareous Nannoplankton Response to Surface-Water Acidification Around Oceanic Anoxic Event 1a"
- 2011
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 332:6026, s. 175-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Erba et al. (Reports, 23 July 2010, p. 428) attributed calcareous nannofossil morphology and assemblage changes across Cretaceous Oceanic Anoxic Event 1a to the effects of surface ocean acidification. We argue that the quality of carbonate preservation in these sequences, the unsupported assumptions of the biotic response to acidity, and the absence of independent proxy estimates for ocean pH or atmospheric pCO(2) render this conclusion questionable.
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