| 31. |
- Manning, Alisa, et al.
(författare)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 32. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 33. |
- Gorini, Giacomo, et al.
(författare)
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Engagement of monocytes, NK cells, and CD4(+) Th1 cells by ALVAC-SIV vaccination results in a decreased risk of SIVmac251 vaginal acquisition
- 2020
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 16:3
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Tidskriftsartikel (refereegranskat)abstract
- The ALVAC-HIV/gp120/alum regimen tested in 8,197 human volunteers (61.4% males, 38.6% females) in the RV144 trial decreased the risk of HIV infection similarly in both sexes. The ALVAC-SIV/gp120/alum vaccine also reduced the risk of intrarectal SIVmac251 acquisition in both female and male vaccinated macaques at an average of 44% per exposure. In the current work, we tested whether this vaccine modality could also reduce the risk of intravaginal SIVmac251 exposure. In order to detect correlates of risk, we administered the virus by the intravaginal route and tested another vaccine regimen based on the vaccinia derivative poxvirus NYVAC in parallel. We demonstrate here that the ALVAC-SIV/gp120/alum regimen decreases the risk of vaginal SIVmac251 acquisition (50% vaccine efficacy) and, importantly, we confirmed that subsets of monocytes and CD4(+) T cells are correlates of risk of acquisition. In addition, we uncovered cytotoxic vaginal NKG2A(+) cells and gut-homing alpha(4)beta(7) positive plasmablasts as novel correlates of risk of intravaginal virus acquisition. In contrast, NYVAC-SIV vaccination induced high levels of activated T cells and did not protect against SIVmac251 acquisition. We examined the contrasting immune responses to better understand the correlate of protection and found that the unique ability of ALVAC-SIV to activate early interferon responses and the inflammasome during priming differentiates the two poxvirus vectors. This work demonstrates the reproducibility of the efficacy observed in the ALVAC-based regimen and defines novel correlates of risk in the rigorous SIVmac251 macaque model, establishing a benchmark for future improvement of this vaccine approach. The recombinant Canarypox ALVAC-HIV/gp120/alum vaccine regimen was the first to significantly decrease the risk of HIV acquisition in humans, with equal effectiveness in both males and females. Similarly, an equivalent SIV-based ALVAC vaccine regimen decreased the risk of virus acquisition in Indian rhesus macaques of both sexes following intrarectal exposure to low doses of SIVmac251. Here, we demonstrate that the ALVAC-SIV/gp120/alum vaccine is also efficacious in female Chinese rhesus macaques following intravaginal exposure to low doses of SIVmac251 and we confirm that CD14(+) classical monocytes are a strong correlate of decreased risk of virus acquisition. Furthermore, we demonstrate that the frequency of CD14(+) cells and/or their gene expression correlates with blood Type 1 CD4(+) T helper cells, alpha(4)beta(+)(7) plasmablasts, and vaginal cytocidal NKG2A(+) cells. To better understand the correlate of protection, we contrasted the ALVAC-SIV vaccine with a NYVAC-based SIV/gp120 regimen that used the identical immunogen. We found that NYVAC-SIV induced higher immune activation via CD4(+)Ki67(+)CD38(+) and CD4(+)Ki67(+)alpha(4)beta(+)(7) T cells, higher SIV envelope-specific IFN-gamma producing cells, equivalent ADCC, and did not decrease the risk of SIVmac251 acquisition. Using the systems biology approach, we demonstrate that specific expression profiles of plasmablasts, NKG2A(+) cells, and monocytes elicited by the ALVAC-based regimen correlated with decreased risk of virus acquisition.
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| 34. |
- Odenrick, Per, et al.
(författare)
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Continuous Improvements at Work - a Programme in an Inter-Disciplinary Research Centre on Humans, Technology and Change at Work
- 1996
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Ingår i: Human Factors in Organizational Design and Management - V. ; , s. 489-492
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Konferensbidrag (refereegranskat)abstract
- The aim of this programme is to contribute to the scientific and practical knowledge about continuous improvements (CI) at work. Some of the principles of CI like: the emphasis on small and incremental changes, the use of structured tools for problem-solving and the monitoring of improvements, and the responsibility of operative personnel for the CI activity rather than experts and task-forces, are combined with methods and principles from Scandinavian research about work environments, participation and workteams.
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| 35. |
- Smith, Bradley N., et al.
(författare)
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The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder
- 2013
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Ingår i: European Journal of Human Genetics. - London : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 21:1, s. 102-108
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Tidskriftsartikel (refereegranskat)abstract
- A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n = 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n = 434) and controls (n = 856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.
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