| 1. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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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.
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| 2. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 3. |
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| 4. |
- Su, Zhan, et al.
(författare)
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Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Tidskriftsartikel (refereegranskat)abstract
- Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
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| 5. |
- Thanabalasingham, Gaya, et al.
(författare)
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Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile
- 2013
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 62:4, s. 1329-1337
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Tidskriftsartikel (refereegranskat)abstract
- A recent genome-wide association study identified hepatocyte nuclear factor 1-alpha (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MOD?) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCE)-MODY (n = 118), hepatocyte nuclear factor 4-alpha (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic >= 0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction.
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| 6. |
- DeVita, Michael A., et al.
(författare)
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"Identifying the hospitalised patient in crisis"-A consensus conference on the afferent limb of Rapid Response Systems
- 2010
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Ingår i: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 81:4, s. 375-382
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most reports of Rapid Response Systems (RRS) focus on the efferent, response component of the system, although evidence suggests that improved vital sign monitoring and recognition of a clinical crisis may have outcome benefits. There is no consensus regarding how best to detect patient deterioration or a clear description of what constitutes patient monitoring. Methods: A consensus conference of international experts in safety, RRS, healthcare technology, education, and risk prediction was convened to review current knowledge and opinion on clinical monitoring. Using established consensus procedures, four topic areas were addressed: (1) To what extent do physiologic abnormalities predict risk for patient deterioration? (2) Do workload changes and their potential stresses on the healthcare environment increase patient risk in a predictable manner? (3) What are the characteristics of an "ideal" monitoring system, and to what extent does currently available technology meet this need? and (4) How can monitoring be categorized to facilitate comparing systems? The major findings include: (1) vital sign aberrations predict risk, (2) monitoring patients more effectively may improve outcome, although some risk is random, (3) the workload implications of monitoring on the clinical workforce have not been explored, but are amenable to study and should be investigated, (4) the characteristics of an ideal monitoring system are identifiable, and it is possible to categorize monitoring modalities. It may also be possible to describe monitoring levels, and a system is proposed. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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| 7. |
- Lind, Lars, et al.
(författare)
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Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin.
- 2014
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
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| 8. |
- Stahl, Günter K., et al.
(författare)
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Sociocultural integration in mergers and acquisitions: Unresolved paradoxes and directions for future research
- 2013
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Ingår i: Thunderbird International Business Review. - : Wiley. - 1096-4762 .- 1520-6874. ; 55:4, s. 333-356
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Tidskriftsartikel (refereegranskat)abstract
- Despite decades of research, the key factors for success in mergers and acquisitions (M&As) and the reasons why M&As often fail remain poorly understood. While attempts to explain M&A success and failure have traditionally focused on strategic and financial factors, an emergent field of inquiry has been directed at the sociocultural and human resources issues involved in the integration of acquired or merging firms. This research has sought to explain M&A performance and underperformance in terms of the impact that variables such as cultural fit, management style similarity, the pattern of dominance between merging firms, the acquirer's degree of cultural tolerance, and the social climate surrounding a takeover have on the postmerger integration process. In this article, we attempt to take stock of, and synthesize, the findings from research on sociocultural and human resources integration in M&A, to identify conflicting perspectives and unresolved questions as well as several underresearched areas, and then use our analyses to propose an agenda for the next stage of research in this field. © 2013 Wiley Periodicals, Inc.
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| 9. |
- Viers, Joshua H., et al.
(författare)
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Vinecology: pairing wine with nature
- 2013
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Ingår i: Conservation Letters. - : Wiley. - 1755-263X. ; 6:5, s. 287-299
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Forskningsöversikt (refereegranskat)abstract
- With some of the highest biodiversity on the planet, the Mediterranean Biome is experiencing a conservation crisis driven by high human population density, development, and habitat fragmentation. While protected areas safeguard some critical habitat, economic realities require conservation efforts in human-dominated landscapes to maintain biodiversity in practice. As an essential component of food security for a growing human population, agricultural landscapes must play a key role in such efforts because they occupy large areas of land, are adjacent to critical habitat, and both depend on and provide ecosystem services. Winegrapes are a high-value specialty crop that can both benefit from and contribute to conservation, as producers and consumers increasingly value environmental stewardship. At the same time, potential expansion of cultivated areas, either to meet future wine demand or in response to climate change, means that decreasing the environmental impact of viticulture is critical for biodiversity conservation. We propose that vinecologythe integration of ecological and viticultural practicescan produce win-win solutions for wine production and nature conservation, where the goal is a diverse landscape that yields sustainable economic benefits, species and habitat protection, and long-term provision of a full range of ecosystem services.
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