| 1. |
- Do, Ron, et al.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 2. |
- van der Harst, Pim, et al.
(författare)
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Seventy-five genetic loci influencing the human red blood cell
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7429, s. 369-375
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Tidskriftsartikel (refereegranskat)abstract
- Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
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| 3. |
- Willer, Cristen J., et al.
(författare)
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Discovery and refinement of loci associated with lipid levels
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1274-1283
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Tidskriftsartikel (refereegranskat)abstract
- Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
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| 4. |
- Biermann, Frank, et al.
(författare)
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Transforming governance and institutions for global sustainability : key insights from the Earth System Governance Project
- 2012
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Ingår i: Current Opinion in Environmental Sustainability. - : Elsevier BV. - 1877-3435 .- 1877-3443. ; 4:1, s. 51-60
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Tidskriftsartikel (refereegranskat)abstract
- The current institutional framework for sustainable development is by far not strong enough to bring about the swift transformative progress that is needed. This article contends that incrementalism-the main approach since the 1972 Stockholm Conference-will not suffice to bring about societal change at the level and speed needed to mitigate and adapt to earth system transformation. Instead, the article argues that transformative structural change in global governance is needed, and that the 2012 United Nations Conference on Sustainable Development in Rio de Janeiro must turn into a major stepping stone for a much stronger institutional framework for sustainable development. The article details core areas where urgent action is required. The article is based on an extensive social science assessment conducted by 32 members of the lead faculty, scientific steering committee, and other affiliates of the Earth System Governance Project. This Project is a ten-year research initiative under the auspices of the International Human Dimensions Programme on Global Environmental Change (IHDP), which is sponsored by the International Council for Science (ICSU), the International Social Science Council (ISSC), and the United Nations University (UNU).
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| 5. |
- Bolton, Kelly L., et al.
(författare)
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Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer
- 2012
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Ingår i: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598. ; 307:4, s. 382-390
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Tidskriftsartikel (refereegranskat)abstract
- Context Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. Objective To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. Design, Setting, and Participants A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n=909) or BRCA2 (n=304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). Main Outcome Measure Five-year overall mortality. Results The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P<.001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P<.001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P<.001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P<.001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity=.003). Conclusion Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis. JAMA. 2012;307(4):382-390
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| 6. |
- Kwiecinski, Jakub, 1985, et al.
(författare)
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Activation of plasminogen by staphylokinase reduces the severity of Staphylococcus aureus systemic infection.
- 2010
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Ingår i: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 202:7, s. 1041-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Staphylokinase (SAK) is produced by the majority of Staphylococcus aureus strains. It is an extracellular protein that activates the conversion of human plasminogen (plg) to plasmin. The role played by SAK in staphylococcal infection is unclear. METHODS: Wild-type S. aureus strain LS-1, which lacks the ability to produce SAK, was modified by an insertion of the sak gene into its chromosome. The sak gene was integrated in 2 forms--(1) linked to its own promoter and (2) fused to the promoter of the protein A gene--which resulted in the overexpression of SAK. SAK is highly specific for human plg and exhibits almost no activity toward murine plg. To investigate the role played by SAK in a murine infection model, human plg transgenic mice and their wild-type counterparts were inoculated intravenously with congenic S. aureus strains differing in SAK production. RESULTS: Human plg transgenic mice inoculated with SAK-expressing strains displayed significantly reduced mortality, less weight loss, and lower bacterial loads in kidneys than did the wild-type mice. No difference in the severity of sepsis was observed between transgenic and wild-type mice infected with a SAK-deficient strain. CONCLUSIONS: The results suggest that expression of SAK followed by activation of plg alleviates the course of S. aureus sepsis.
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| 7. |
- Laven, Daniel, 1973, et al.
(författare)
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From Models to Management: Lessons learned from evaluating U.S. National Heritage Landscapes
- 2011
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Ingår i: 10th Nordic Environmental Social Science Conference, Stockholm 14-16 juni 2011.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- In many parts of the world there is a growing interest in how to manage, protect and develop landscapes as evidenced by the advancement of the European Landscape Convention (ELC) during the last decade. In Sweden, the ELC was recently ratified and decision makers have now turned their attention to implementing the Convention. The ELC underlines the importance of local perspectives and democratic processes to successful and sustainable landscape management. This paper will present experiences from a landscape-scale management and governance program in the United States, and discuss if and how these experiences may inform the ELC process currently underway in Sweden. U.S. National Heritage Areas (NHAs) are one of the oldest and most well-established federal landscape scale programs in the United States. NHAs operate through partnerships with the U.S. National Park Service (NPS), local communities, private and third sector organizations, as well as other governmental agencies and seek to integrate resource conservation with social and economic objectives. Previous research on NHAs reveals the importance of heritage as a discourse tool, inter-sectoral networks and network governance, and entrepreneurial approaches to managing and decision-making. Despite important differences between the NHA environment and the ELC, the NHA experience may be sufficiently similar to the ELC such that thoughtful treatment of these issues will be necessary for successful implementation efforts. We conclude by offering our perspectives on future research.
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