| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Ade, P. A. R., et al.
(författare)
-
Planck 2015 results XIV. Dark energy and modified gravity
- 2016
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 594
-
Tidskriftsartikel (refereegranskat)abstract
- We study the implications of Planck data for models of dark energy (DE) and modified gravity (MG) beyond the standard cosmological constant scenario. We start with cases where the DE only directly affects the background evolution, considering Taylor expansions of the equation of state w(a), as well as principal component analysis and parameterizations related to the potential of a minimally coupled DE scalar field. When estimating the density of DE at early times, we significantly improve present constraints and find that it has to be below similar to 2% (at 95% confidence) of the critical density, even when forced to play a role for z < 50 only. We then move to general parameterizations of the DE or MG perturbations that encompass both effective field theories and the phenomenology of gravitational potentials in MG models. Lastly, we test a range of specific models, such as k-essence, f(R) theories, and coupled DE. In addition to the latest Planck data, for our main analyses, we use background constraints from baryonic acoustic oscillations, type-Ia supernovae, and local measurements of the Hubble constant. We further show the impact of measurements of the cosmological perturbations, such as redshift-space distortions and weak gravitational lensing. These additional probes are important tools for testing MG models and for breaking degeneracies that are still present in the combination of Planck and background data sets. All results that include only background parameterizations (expansion of the equation of state, early DE, general potentials in minimally-coupled scalar fields or principal component analysis) are in agreement with ACDM. When testing models that also change perturbations (even when the background is fixed to ACDM), some tensions appear in a few scenarios: the maximum one found is similar to 2 sigma for Planck TT + lowP when parameterizing observables related to the gravitational potentials with a chosen time dependence; the tension increases to, at most, 3 sigma when external data sets are included. It however disappears when including CMB lensing.
|
|
| 7. |
- Aghanim, N., et al.
(författare)
-
Planck 2018 results I. Overview and the cosmological legacy of Planck
- 2020
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 641
-
Tidskriftsartikel (refereegranskat)abstract
- The European Space Agency's Planck satellite, which was dedicated to studying the early Universe and its subsequent evolution, was launched on 14 May 2009. It scanned the microwave and submillimetre sky continuously between 12 August 2009 and 23 October 2013, producing deep, high-resolution, all-sky maps in nine frequency bands from 30 to 857 GHz. This paper presents the cosmological legacy of Planck, which currently provides our strongest constraints on the parameters of the standard cosmological model and some of the tightest limits available on deviations from that model. The 6-parameter Lambda CDM model continues to provide an excellent fit to the cosmic microwave background data at high and low redshift, describing the cosmological information in over a billion map pixels with just six parameters. With 18 peaks in the temperature and polarization angular power spectra constrained well, Planck measures five of the six parameters to better than 1% (simultaneously), with the best-determined parameter (theta (*)) now known to 0.03%. We describe the multi-component sky as seen by Planck, the success of the Lambda CDM model, and the connection to lower-redshift probes of structure formation. We also give a comprehensive summary of the major changes introduced in this 2018 release. The Planck data, alone and in combination with other probes, provide stringent constraints on our models of the early Universe and the large-scale structure within which all astrophysical objects form and evolve. We discuss some lessons learned from the Planck mission, and highlight areas ripe for further experimental advances.
|
|
| 8. |
- Aghanim, N., et al.
(författare)
-
Planck 2018 results VI. Cosmological parameters
- 2020
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 641
-
Tidskriftsartikel (refereegranskat)abstract
- We present cosmological parameter results from the final full-mission Planck measurements of the cosmic microwave background (CMB) anisotropies, combining information from the temperature and polarization maps and the lensing reconstruction. Compared to the 2015 results, improved measurements of large-scale polarization allow the reionization optical depth to be measured with higher precision, leading to significant gains in the precision of other correlated parameters. Improved modelling of the small-scale polarization leads to more robust constraints on many parameters, with residual modelling uncertainties estimated to affect them only at the 0.5 sigma level. We find good consistency with the standard spatially-flat 6-parameter Lambda CDM cosmology having a power-law spectrum of adiabatic scalar perturbations (denoted base Lambda CDM in this paper), from polarization, temperature, and lensing, separately and in combination. A combined analysis gives dark matter density Omega (c)h(2)=0.120 +/- 0.001, baryon density Omega (b)h(2)=0.0224 +/- 0.0001, scalar spectral index n(s)=0.965 +/- 0.004, and optical depth tau =0.054 +/- 0.007 (in this abstract we quote 68% confidence regions on measured parameters and 95% on upper limits). The angular acoustic scale is measured to 0.03% precision, with 100 theta (*)=1.0411 +/- 0.0003. These results are only weakly dependent on the cosmological model and remain stable, with somewhat increased errors, in many commonly considered extensions. Assuming the base-Lambda CDM cosmology, the inferred (model-dependent) late-Universe parameters are: Hubble constant H-0=(67.4 +/- 0.5) km s(-1) Mpc(-1); matter density parameter Omega (m)=0.315 +/- 0.007; and matter fluctuation amplitude sigma (8)=0.811 +/- 0.006. We find no compelling evidence for extensions to the base-Lambda CDM model. Combining with baryon acoustic oscillation (BAO) measurements (and considering single-parameter extensions) we constrain the effective extra relativistic degrees of freedom to be N-eff=2.99 +/- 0.17, in agreement with the Standard Model prediction N-eff=3.046, and find that the neutrino mass is tightly constrained to Sigma m(nu)< 0.12 eV. The CMB spectra continue to prefer higher lensing amplitudes than predicted in base CDM at over 2 sigma, which pulls some parameters that affect the lensing amplitude away from the Lambda CDM model; however, this is not supported by the lensing reconstruction or (in models that also change the background geometry) BAO data. The joint constraint with BAO measurements on spatial curvature is consistent with a flat universe, Omega (K)=0.001 +/- 0.002. Also combining with Type Ia supernovae (SNe), the dark-energy equation of state parameter is measured to be w(0)=-1.03 +/- 0.03, consistent with a cosmological constant. We find no evidence for deviations from a purely power-law primordial spectrum, and combining with data from BAO, BICEP2, and Keck Array data, we place a limit on the tensor-to-scalar ratio r(0.002)< 0.06. Standard big-bang nucleosynthesis predictions for the helium and deuterium abundances for the base-CDM cosmology are in excellent agreement with observations. The Planck base-Lambda CDM results are in good agreement with BAO, SNe, and some galaxy lensing observations, but in slight tension with the Dark Energy Survey's combined-probe results including galaxy clustering (which prefers lower fluctuation amplitudes or matter density parameters), and in significant, 3.6 sigma, tension with local measurements of the Hubble constant (which prefer a higher value). Simple model extensions that can partially resolve these tensions are not favoured by the Planck data.
|
|
| 9. |
- Pezzotta, A., et al.
(författare)
-
Euclid preparation XLI. Galaxy power spectrum modelling in real space
- 2024
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 687
-
Tidskriftsartikel (refereegranskat)abstract
- We investigate the accuracy of the perturbative galaxy bias expansion in view of the forthcoming analysis of the Euclid spectroscopic galaxy samples. We compare the performance of a Eulerian galaxy bias expansion using state-of-the-art prescriptions from the effective field theory of large-scale structure (EFTofLSS) with a hybrid approach based on Lagrangian perturbation theory and high-resolution simulations. These models are benchmarked against comoving snapshots of the flagship I N-body simulation at z = (0.9, 1.2, 1.5, 1.8), which have been populated with H alpha galaxies leading to catalogues of millions of objects within a volume of about 58 h(-3) Gpc(3). Our analysis suggests that both models can be used to provide a robust inference of the parameters (h, omega c) in the redshift range under consideration, with comparable constraining power. We additionally determine the range of validity of the EFTofLSS model in terms of scale cuts and model degrees of freedom. From these tests, it emerges that the standard third-order Eulerian bias expansion - which includes local and non-local bias parameters, a matter counter term, and a correction to the shot-noise contribution - can accurately describe the full shape of the real-space galaxy power spectrum up to the maximum wavenumber of k(max) = 0.45 h Mpc(-1), and with a measurement precision of well below the percentage level. Fixing either of the tidal bias parameters to physically motivated relations still leads to unbiased cosmological constraints, and helps in reducing the severity of projection effects due to the large dimensionality of the model. We finally show how we repeated our analysis assuming a volume that matches the expected footprint of Euclid, but without considering observational effects, such as purity and completeness, showing that we can get constraints on the combination (h, omega c) that are consistent with the fiducial values to better than the 68% confidence interval over this range of scales and redshifts.
|
|
| 10. |
|
|
| 11. |
- Pucella, G., et al.
(författare)
-
Overview of the FTU results
- 2022
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 62:4
-
Forskningsöversikt (refereegranskat)abstract
- Since the 2018 IAEA FEC Conference, FTU operations have been devoted to several experiments covering a large range of topics, from the investigation of the behaviour of a liquid tin limiter to the runaway electrons mitigation and control and to the stabilization of tearing modes by electron cyclotron heating and by pellet injection. Other experiments have involved the spectroscopy of heavy metal ions, the electron density peaking in helium doped plasmas, the electron cyclotron assisted start-up and the electron temperature measurements in high temperature plasmas. The effectiveness of the laser induced breakdown spectroscopy system has been demonstrated and the new capabilities of the runaway electron imaging spectrometry system for in-flight runaways studies have been explored. Finally, a high resolution saddle coil array for MHD analysis and UV and SXR diamond detectors have been successfully tested on different plasma scenarios.
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
- Reimerdes, H., et al.
(författare)
-
Overview of the TCV tokamak experimental programme
- 2022
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 62:4
-
Tidskriftsartikel (refereegranskat)abstract
- The tokamak a configuration variable (TCV) continues to leverage its unique shaping capabilities, flexible heating systems and modern control system to address critical issues in preparation for ITER and a fusion power plant. For the 2019-20 campaign its configurational flexibility has been enhanced with the installation of removable divertor gas baffles, its diagnostic capabilities with an extensive set of upgrades and its heating systems with new dual frequency gyrotrons. The gas baffles reduce coupling between the divertor and the main chamber and allow for detailed investigations on the role of fuelling in general and, together with upgraded boundary diagnostics, test divertor and edge models in particular. The increased heating capabilities broaden the operational regime to include T (e)/T (i) similar to 1 and have stimulated refocussing studies from L-mode to H-mode across a range of research topics. ITER baseline parameters were reached in type-I ELMy H-modes and alternative regimes with 'small' (or no) ELMs explored. Most prominently, negative triangularity was investigated in detail and confirmed as an attractive scenario with H-mode level core confinement but an L-mode edge. Emphasis was also placed on control, where an increased number of observers, actuators and control solutions became available and are now integrated into a generic control framework as will be needed in future devices. The quantity and quality of results of the 2019-20 TCV campaign are a testament to its successful integration within the European research effort alongside a vibrant domestic programme and international collaborations.
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
- Sawcer, Stephen, et al.
(författare)
-
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
|
|
| 19. |
- Kuhle, J., et al.
(författare)
-
Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study
- 2015
-
Ingår i: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 21:8, s. 1013-1024
-
Tidskriftsartikel (refereegranskat)abstract
- Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.
|
|
| 20. |
|
|
| 21. |
- Beecham, Ashley H, et al.
(författare)
-
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
-
Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
-
Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
|
|
| 22. |
|
|
| 23. |
- Lam, MT, et al.
(författare)
-
A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function
- 2019
-
Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 216:12, s. 2778-2799
-
Tidskriftsartikel (refereegranskat)abstract
- Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
- Crosby, Jacy, et al.
(författare)
-
Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease
- 2014
-
Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 371:1, s. 22-31
-
Tidskriftsartikel (refereegranskat)abstract
- Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G -> A and IVS3+1G -> T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1x10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8x10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4x10(-6)). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)
|
|
| 29. |
|
|
| 30. |
|
|
| 31. |
|
|
| 32. |
- Patel, Riyaz S., et al.
(författare)
-
Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
- 2019
-
Ingår i: Circulation. - 2574-8300. ; 12:4
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
|
|
| 33. |
- Schunkert, Heribert, et al.
(författare)
-
Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
- 2011
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:4, s. 153-333
-
Tidskriftsartikel (refereegranskat)abstract
- We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 x 10(-8) and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
|
|
| 34. |
|
|
| 35. |
- Webb, Thomas R., et al.
(författare)
-
Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
- 2017
-
Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 69:7, s. 823-836
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.OBJECTIVES This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.METHODS In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.RESULTS We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits.CONCLUSIONS We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
|
|
| 36. |
- White, H, et al.
(författare)
-
A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real time quantitative PCR.
- 2015
-
Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 29:2, s. 369-376
-
Tidskriftsartikel (refereegranskat)abstract
- Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukemia, but there is substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 10(6), 1.08±0.11 × 10(5), 1.03±0.10 × 10(4), 1.02±0.09 × 10(3), 1.04±0.10 × 10(2) and 10.0±1.5 copies/μL. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise the numbers of measured transcripts of e14a2 BCR-ABL1 and three control genes; ABL1, BCR and GUSB. The set of 6 plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (http://irmm.jrc.ec.europa.eu; CRM code ERM-AD623a-f).Leukemia accepted article preview online, 18 July 2014; doi:10.1038/leu.2014.217.
|
|
| 37. |
|
|
| 38. |
|
|
| 39. |
|
|
| 40. |
|
|
| 41. |
|
|
| 42. |
|
|
| 43. |
|
|
| 44. |
|
|
| 45. |
|
|
| 46. |
- Patel, Riyaz S., et al.
(författare)
-
Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events : A GENIUS-CHD Study of Individual Participant Data
- 2019
-
Ingår i: Circulation. - 2574-8300. ; 12:4
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
|
|
| 47. |
- Peloso, Gina M, et al.
(författare)
-
Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.
- 2014
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 223-232
-
Tidskriftsartikel (refereegranskat)abstract
- Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121(∗)], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
|
|
| 48. |
|
|
| 49. |
- Stitziel, Nathan O., et al.
(författare)
-
Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
- 2016
-
Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 374:12, s. 1134-1144
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
|
|
| 50. |
- Voight, Benjamin F, et al.
(författare)
-
Plasma HDL cholesterol and risk of myocardial infarction : a mendelian randomisation study
- 2012
-
Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 380:9841, s. 572-580
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.FINDINGS: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)).INTERPRETATION: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
|
|
