| 1. |
- 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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| 2. |
- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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| 3. |
- 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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| 4. |
- Oliveros, Carl H., et al.
(författare)
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Earth history and the passerine superradiation
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:16, s. 7916-7925
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Tidskriftsartikel (refereegranskat)abstract
- Avian diversification has been influenced by global climate change, plate tectonic movements, and mass extinction events. However, the impact of these factors on the diversification of the hyper-diverse perching birds (passerines) is unclear because family level relationships are unresolved and the timing of splitting events among lineages is uncertain. We analyzed DNA data from 4,060 nuclear loci and 137 passerine families using concatenation and coalescent approaches to infer a comprehensive phylogenetic hypothesis that clarifies relationships among all passerine families. Then, we calibrated this phylogeny using 13 fossils to examine the effects of different events in Earth history on the timing and rate of passerine diversification. Our analyses reconcile passerine diversification with the fossil and geological records; suggest that passerines originated on the Australian landmass ∼47 Ma; and show that subsequent dispersal and diversification of passerines was affected by a number of climatological and geological events, such as Oligocene glaciation and inundation of the New Zealand landmass. Although passerine diversification rates fluctuated throughout the Cenozoic, we find no link between the rate of passerine diversification and Cenozoic global temperature, and our analyses show that the increases in passerine diversification rate we observe are disconnected from the colonization of new continents. Taken together, these results suggest more complex mechanisms than temperature change or ecological opportunity have controlled macroscale patterns of passerine speciation.
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| 5. |
- Pennells, Lisa, et al.
(författare)
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Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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| 6. |
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| 7. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 8. |
- Juell-Skielse, Gustaf, 1964-
(författare)
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ERP adoption in small and medium sized enterprises
- 2006
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Enterprise resource planning (ERP) is established among a majority of small and medium sized companies in Kista Science City and seems to have a positive effect on organizational effectiveness. Kista Science City is Sweden’s largest corporate centre, with more companies and employees in a limited area than anywhere else in Europe. This study looks at the level of adoption of ERP functions, perceived organizational effectiveness and critical success factors. The most common use of ERP is for financial control and reporting, followed by order entry and purchasing. A significant relationship between the level of adoption and organizational effectiveness was found. Although Enterprise Resource Planning has become an established phenomenon the investments in ERP software are far from fully utilized. Most companies have started to use ERP to integrate functional areas but few companies have moved to extended ERP (ERPII). The adoption of functionality for customer relationship management seems to have started, but the use of e-commerce, business intelligence and supply chain management is very low. Different reasons for the low level of adoption are discussed and it is suggested that the interrelationship between SMEs and ERP-consultants be investigated further. ERP-consultants are important change agents and knowledge transfers for ERP and one way to interpret the data is that ERP-consultants are caught in a negative spiral where they focus on installations and technical maintenance of core ERP, which prevents them from developing new, extended ERP competence. An analysis of critical success factors showed that although technical competence was important socially oriented factors such as project teamwork and composition as well as communication had a greater effect on organizational effectiveness. Surprisingly enough, project management did not have any effect on organizational effectiveness. Common implementation methods for ERP focus on project management. It is suggested to further analyse if these methods could be improved by an increased adaptability to differences in company settings and requirements as well as through a better use of critical success factors. Organizational effectiveness can be measured in many ways and it was found that the success factors varied in terms of how they correlated with different measures. In the next step, the doctorial thesis, it is suggested that a prototype environment is developed to stimulate an increased use of extended ERP among small and medium sized companies. Several actors, such as SMEs, consultants, vendors and students would be involved. The prototype environment could facilitate enhancements of implementation methods and reduction of implementation costs through the development of reusable objects such as add-on solutions, process maps and system configurations. It could also help small and medium sized companies to investigate the business benefits of ERP by increasing involvement and familiarity while on the same time decrease costs and risks.
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| 9. |
- Marklund, Matti, et al.
(författare)
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Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality : An Individual-Level Pooled Analysis of 30 Cohort Studies
- 2019
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Ingår i: Circulation. - : American Heart Association. - 0009-7322 .- 1524-4539. ; 139:21, s. 2422-2436
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Tidskriftsartikel (refereegranskat)abstract
- Background:Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.Methods:We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).Results:In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15198 incident cardiovascular events occurred among 68659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.Conclusions:In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.
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| 10. |
- Moraitis, Michail, 1994-
(författare)
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Towards Securing the FPGA Bitstream: Exploiting Vulnerabilities and Implementing Countermeasures
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Field-programmable gate arrays (FPGAs) are used across various industries due to their high performance, energy efficiency, and reconfigurability. However, the major advantage of reconfigurability is also a source of security challenges.The present doctoral thesis investigates the security vulnerabilities of the FPGA configuration file, i.e. the bitstream, focusing on the exploration and mitigation of targeted bitstream modification attacks. The results outlined in the seven chapters of the thesis are based on the appended collection of twelve papers. Out of those papers, seven present novel research on the topic of bitstream modification attacks and countermeasures, with the majority of contributions being on attacks. Four present novel research on the topic of FPGA-based countermeasures against side-channel analysis. The final paper presents a survey on bitstream modification attacks and countermeasures. The motivation behind the papers on side-channel countermeasures is to enhance the FPGA encryption schemes, as strong encryption can thwart targeted bitstream modification attacks. The attack vector of targeted bitstream modification is explored through a series of attacks against cryptographic FPGA implementations. The targets are popular stream ciphers (SNOW 3G, ACORN, and Trivium) and cryptographic primitives (an arbiter-based physical unclonable function and multi-ring-oscillator-based true random number generator). In the attacks on stream ciphers, the bitstream is modified to introduce faults that weaken the keystream by linearizing its generation process. A subsequent analysis of that faulty keystream reveals the secret key of the implementations. In the attacks on cryptographic primitives, the goal of the bitstream modification attack is to lower the bar or enable a side-channel analysis. The aim of the side-channel analysis is to predict the random output values produced by the primitives. To facilitate that, the bitstream modification attack identifies components in the bitstream that produce exploitable information leakage and creates multiple copies of them. The copies have the same values as the targets, but their outputs are not connected, thus having no impact on the functionality of the design. The study on bitstream modification is complemented with the introduction of low-cost obfuscation countermeasures and a general-purpose methodology against obfuscation based on constants. The methodology is able to defeat all the countermeasures we have previously defined, and its application extends to the general field of hardware design obfuscation.On the topic of side-channel analysis countermeasures, the popular methodology of clock randomization is evaluated. The assumed side-channel analysis aims to extract the secret key of the advanced encryption standard (AES) block cipher. The evaluation reveales that clock randomization cannot offer protection when the side-channel measurements are sampled at a frequency significantly higher than the operational frequency of the device. In response to that, the clock randomization technique is coupled with encryption core duplication to form, a novel countermeasure called CRCD (clock randomization with encryption core duplication). The countermeasure is shown to effectively protect implementations of block ciphers such as AES, and post-quantum key encapsulation mechanisms such as CRYSTALS-Kyber. Further analysis of the countermeasure reveals a weakness that is exploited and finally patched in an updated implementation of CRCD.
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