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- Beecham, Ashley H, et al.
(author)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Journal article (peer-reviewed)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.
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- Sawcer, Stephen, et al.
(author)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Journal article (peer-reviewed)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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- Ahokas, E K, et al.
(author)
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Minimal effect of water immersion on markers of inflammation and muscle damage after intensive exercise
- 2019
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In: Proc Physiol Soc 44.
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Conference paper (peer-reviewed)abstract
- Water immersion methods, such as cold water immersion and contrast water therapy are popular recovery interventions after athletic training and competition. Nevertheless, post-exercise cold water immersion may actually inhibit hypertrophic signalling pathways and muscle adaptation to training (1). It is has been commonly assumed that the mechanism of impaired training adaptation is mediated by blunted inflammatory responses to muscle-damaging exercise, although this assumption has been questioned by recent data (2). A weakness of previous studies is omission of active recovery in water immersion interventions, which would arguably be utilised in addition to water immersion by athletic populations. The aim of this study was to compare the influence of three water immersion methods, performed after active recovery, on inflammatory responses to muscle-damaging exercise. Nine male participants (age 20-35 y) performed an intensive exercise protocol, consisting of maximal jumps and sprinting, on four occasions. After each trial, participants completed one of four recovery protocols in a randomised, crossover design (ACT, active recovery only, 10 min cycling; heart rate 120-140 b/min; CWI, active recovery followed by 10 min cold water immersion, 10°C; TWI, active recovery followed by 10 min temperate water immersion, 24°C and CWT, active recovery followed by contrast water therapy, 10 min alternating 10°C and 38°C in 1 min cycles). The study was conducted in accordance with the Declaration of Helsinki and approved by the local ethical review board. Venous blood samples were collected pre-exercise and 5 min, 60 min, 24 h, 48 h and 96 h post-exercise, then analysed for myocyte chemoattractant protein 1 (MCP-1) and creatine kinase (CK) using ELISA and high-sensitivity C-reactive protein (hs-CRP) using a chemiluminescence assay. Two-way repeated measures ANOVA was used to compare biomarker concentrations between groups over time. There were no differences in biomarker concentrations during exercise and recovery between groups across the six time points, however main effects of time were present for all three markers (MCP-1: F(2.32, 18.56) = 23.1, p < 0.0001; CK: F(2.059, 16.47) = 8.74, p = 0.002; hs-CRP: F(1.07, 8.57 = 13.8, p = 0.005). Tukey’s post-hoc analysis of simple time effects revealed increases in MCP-1 at post-5 min versus pre in all groups except CWT. In TWI and CWI, MCP-1 was still elevated above pre at 60 min post-exercise. hs-CRP peaked at 24 h post-exercise in all groups. CK was elevated at post-60 versus pre in all groups and at post-24 except in CWT. Our findings suggest that use of cold or thermoneutral water immersion in combination with active recovery may slightly prolong the immediate post-exercise elevation in MCP-1 but have minimal overall effect on markers of inflammation and muscle damage.
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| 8. |
- Ahokas, E. K., et al.
(author)
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Water immersion methods do not alter muscle damage and inflammation biomarkers after high-intensity sprinting and jumping exercise
- 2020
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In: European Journal of Applied Physiology. - : Springer Science and Business Media LLC. - 1439-6319 .- 1439-6327. ; 120, s. 2625-2634
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Journal article (peer-reviewed)abstract
- Purpose: The aim of this study was to compare the efficacy of three water immersion interventions performed after active recovery compared to active recovery only on the resolution of inflammation and markers of muscle damage post-exercise. Methods: Nine physically active men (n = 9; age 20‒35 years) performed an intensive loading protocol, including maximal jumps and sprinting on four occasions. After each trial, one of three recovery interventions (10 min duration) was used in a random order: cold-water immersion (CWI, 10 °C), thermoneutral water immersion (TWI, 24 °C), contrast water therapy (CWT, alternately 10 °C and 38 °C). All of these methods were performed after an active recovery (10 min bicycle ergometer), and were compared to active recovery only (ACT). 5 min, 1, 24, 48, and 96 h after exercise bouts, immune response and recovery were assessed through leukocyte subsets, monocyte chemoattractant protein-1, myoglobin and high-sensitivity C-reactive protein concentrations. Results: Significant changes in all blood markers occurred at post-loading (p < 0.05), but there were no significant differences observed in the recovery between methods. However, retrospective analysis revealed significant trial-order effects for myoglobin and neutrophils (p < 0.01). Only lymphocytes displayed satisfactory reliability in the exercise response, with intraclass correlation coefficient > 0.5. Conclusions: The recovery methods did not affect the resolution of inflammatory and immune responses after high-intensity sprinting and jumping exercise. It is notable that the biomarker responses were variable within individuals. Thus, the lack of differences between recovery methods may have been influenced by the reliability of exercise-induced biomarker responses.
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- Hart, Traver, et al.
(author)
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High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities
- 2015
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In: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 163:6
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Journal article (peer-reviewed)abstract
- The ability to perturb genes in human cells is crucial for elucidating gene function and holds great potential for finding therapeutic targets for diseases such as cancer. To extend the catalog of human core and context-dependent fitness genes, we have developed a high-complexity second-generation genome-scale CRISPR-Cas9 gRNA library and applied it to fitness screens in five human cell lines. Using an improved Bayesian analytical approach, we consistently discover 5-fold more fitness genes than were previously observed. We present a list of 1,580 human core fitness genes and describe their general properties. Moreover, we demonstrate that context-dependent fitness genes accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and reveal cell-type-specific dependencies for specific receptor tyrosine kinases, even in oncogenic KRAS backgrounds. Thus, rigorous identification of human cell line fitness genes using a high-complexity CRISPR-Cas9 library affords a high-resolution view of the genetic vulnerabilities of a cell.
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