| 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. |
- Marriott, Heather, et al.
(författare)
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Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS
- 2024
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Ingår i: Annals of Clinical and Translational Neurology. - : John Wiley & Sons. - 2328-9503.
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk.Methods: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta-analyses of published case–control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole-genome sequencing data.Results: Fixed-effects meta-analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13–9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14–1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18–1.77, pMadsen–Browning = 0.0007, pSKAT-O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86–4.37, pMadsen–Browning = 0.039), supporting the meta-analysis results. Finally, several tail in-frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricated architecture that requires further investigation.Interpretation: We showed that NEFH tail missense and in-frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.
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| 3. |
- Kondo, Elsuida, et al.
(författare)
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Metabolic profiling of yeast culture using gas chromatography coupled with orthogonal acceleration accurate mass time-of-flight mass spectrometry : Application to biomarker discovery
- 2014
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Ingår i: Analytica Chimica Acta. - : Elsevier. - 0003-2670 .- 1873-4324. ; 807, s. 135-142
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Tidskriftsartikel (refereegranskat)abstract
- Yeast and yeast cultures are frequently used as additives in diets of dairy cows. Beneficial effects from the inclusion of yeast culture in diets for dairy mammals have been reported, and the aim of this study was to develop a comprehensive analytical method for the accurate mass identification of the 'global' metabolites in order to differentiate a variety of yeasts at varying growth stages (Diamond V XP, Yea-Sacc and Levucell). Microwave-assisted derivatization for metabolic profiling is demonstrated through the analysis of differing yeast samples developed for cattle feed, which include a wide range of metabolites of interest covering a large range of compound classes. Accurate identification of the components was undertaken using GC-oa-ToFMS (gas chromatography-orthogonal acceleration-time-of-flight mass spectrometry), followed by principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) for data reduction and biomarker discovery. Semi-quantification (fold changes in relative peak areas) was reported for metabolites identified as possible discriminative biomarkers (p-value <0.05, fold change >2), including d-ribose (four fold decrease), myo-inositol (five fold increase), l-phenylalanine (three fold increase), glucopyranoside (two fold increase), fructose (three fold increase) and threitol (three fold increase) respectively. (C) 2013 Elsevier B. V. All rights reserved.
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| 4. |
- Kouremenos, Konstantinos A, et al.
(författare)
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Advances in gas chromatographic methods for the identification of biomarkers in cancer
- 2012
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Ingår i: Journal of Cancer. - Sydney, Australia : Ivyspring International Publisher. - 1837-9664. ; 3, s. 404-420
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Tidskriftsartikel (refereegranskat)abstract
- Screening complex biological specimens such as exhaled air, tissue, blood and urine to identify biomarkers in different forms of cancer has become increasingly popular over the last decade, mainly due to new instruments and improved bioinformatics. However, despite some progress, the identification of biomarkers has shown to be a difficult task with few new biomarkers (excluding recent genetic markers) being considered for introduction to clinical analysis. This review describes recent advances in gas chromatographic methods for the identification of biomarkers in the detection, diagnosis and treatment of cancer. It presents a general overview of cancer metabolism, the current biomarkers used for cancer diagnosis and treatment, a background to metabolic changes in tumors, an overview of current GC methods, and collectively presents the scope and outlook of GC methods in oncology.
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| 5. |
- Marriott, Philip J, et al.
(författare)
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A review of environmental toxicant analysis by using multidimensional gas chromatography and comprehensive GC
- 2003
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Ingår i: Clinica Chimica Acta. ; 328:1-2, s. 1-19
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this review is to highlight the developments in coupled-column gas chromatography methods for qualitative analysis of selected environmental toxicants such as dioxin, polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), etc. In particular, the new technique of GC×GC will be introduced, and its role, and the promise it offers to this field is discussed. The benefits of enhanced separation to quantitative analysis will be considered.In order to perform an accurate risk assessment, both the dose and biological effects of environmental toxicants have to be determined with a high degree of certainty. This is most often achieved by using chromatographic methods. Given the complexity of most environmental sample extracts, single-column gas chromatography is unable to fully resolve all the components of interest frequently leading to a positive bias in the reported concentrations. Advanced separation tools, such as multidimensional gas chromatography (MDGC), were investigated quite early and demonstrated improvements in separation. However, limitations in the number of target analytes that could be analyzed in a single run as well as insufficient robustness lead to a continued interest in alternative solutions. The parallel development of mass spectrometric identification and quantification strategies proved useful in many cases, although it frequently failed to provide positive identification of chromatographically unresolved isomeric compounds. More recently, comprehensive two-dimensional gas chromatography (GC×GC) may offer a solution to that problem, especially because it offers enhanced resolution for complex mixtures containing trace level environmental toxicants.
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