| 1. |
- Freitag, Daniel F., et al.
(författare)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Tidskriftsartikel (refereegranskat)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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| 2. |
- Evangelou, Evangelos, et al.
(författare)
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A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
- 2014
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 73:12, s. 2130-2136
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. Results We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9x10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p= 5.6x10(-8)) and follow-up studies (p=7.3x10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9x10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2x10(-6), OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
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| 3. |
- Lindblad-Toh, Kerstin, et al.
(författare)
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Genome sequence, comparative analysis and haplotype structure of the domestic dog.
- 2005
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 438:7069, s. 803-19
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Tidskriftsartikel (refereegranskat)abstract
- Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.
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| 4. |
- Yi, Chuixiang, et al.
(författare)
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Climate control of terrestrial carbon exchange across biomes and continents
- 2010
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Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the relationships between climate and carbon exchange by terrestrial ecosystems is critical to predict future levels of atmospheric carbon dioxide because of the potential accelerating effects of positive climate-carbon cycle feedbacks. However, directly observed relationships between climate and terrestrial CO2 exchange with the atmosphere across biomes and continents are lacking. Here we present data describing the relationships between net ecosystem exchange of carbon (NEE) and climate factors as measured using the eddy covariance method at 125 unique sites in various ecosystems over six continents with a total of 559 site-years. We find that NEE observed at eddy covariance sites is (1) a strong function of mean annual temperature at mid-and high-latitudes, (2) a strong function of dryness at mid-and low-latitudes, and (3) a function of both temperature and dryness around the mid-latitudinal belt (45 degrees N). The sensitivity of NEE to mean annual temperature breaks down at similar to 16 degrees C (a threshold value of mean annual temperature), above which no further increase of CO2 uptake with temperature was observed and dryness influence overrules temperature influence.
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| 5. |
- Ford, Caroline S., et al.
(författare)
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Selection of candidate coding DNA barcoding regions for use on land plants
- 2009
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Ingår i: Botanical journal of the Linnean Society. - : Oxford University Press (OUP). - 0024-4074 .- 1095-8339. ; 159:1, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- An in silico screen of 41 of the 81 coding regions of the Nicotiana plastid genome generated a shortlist of 12 candidates as DNA barcoding loci for land plants. These loci were evaluated for amplification and sequence variation against a reference set of 98 land plant taxa. The deployment of multiple primers and a modified multiplexed tandem polymerase chain reaction yielded 85-94% amplification across taxa, and mean sequence differences between sister taxa of 6.1 from 156 bases of accD to 22 from 493 bases of matK. We conclude that loci should be combined for effective diagnosis, and recommend further investigation of the following six loci: matK, rpoB, rpoC1, ndhJ, ycf5 and accD.
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| 6. |
- Andersen, Naja Steen, et al.
(författare)
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Processes affecting genetic structure and conservation: a case study of wild and cultivated Brassica rapa
- 2009
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Ingår i: Genetic Resources and Crop Evolution. - Dordrecht : Springer Science and Business Media LLC. - 0925-9864 .- 1573-5109. ; 56:2, s. 189-200
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Tidskriftsartikel (refereegranskat)abstract
- When planning optimal conservation strategies for wild and cultivated types of a plant species, a number of influencing biological and environmental factors should be considered from the outset. In the present study Brassica rapa was used to illustrate this: to develop Scandinavian conservation strategies for wild and cultivated B. rapa, DNA-marker analysis was performed on 15 cultivated and 17 wild accessions of B. rapa plus 8 accessions of the cross compatible B. napus. The B. rapa cultivars were bred in Sweden and Finland in 1944-1997 and the wild B. rapa material was collected from Denmark, Sweden and United Kingdom. The B. napus accessions were bred within the last 20 years in the Scandinavian countries. Results were based on scoring of 131 polymorphic ISSR markers in the total plant material. A Bayesian Markov chain Monte Carlo (MCMC) approach implemented in NewHybrids demonstrated a clear distinction of B. rapa and B. napus individuals except for three individuals that seemed to be backcrosses. The backcrossed hybrids descended from two Swedish populations, one wild and one escaped. The overall pattern of genetic variation and structure in B. rapa showed that cultivated and wild B. rapa accessions formed two almost separated clusters. Geographical origin and breeding history of cultivars were reflected in these genetic relationships. In addition, wild populations from Denmark and Sweden seemed to be closely related, except for a Swedish population, which seemingly was an escaped cultivar. The study point to that many processes, e.g. spontaneous introgression, naturalisation, breeding and agricultural practise affected the genetic structure of wild and cultivated B. rapa populations.
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| 7. |
- Frank, Matthias J., et al.
(författare)
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Stromgren uvby photometry of the peculiar globular cluster NGC 2419
- 2015
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 581
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Tidskriftsartikel (refereegranskat)abstract
- NGC 2419 is a peculiar Galactic globular cluster off set from the others in the size-luminosity diagram, and showing several chemical abundance anomalies. Here, we present Stromgren uvby photometry of the cluster. Using the gravity-and metallicity-sensitive c(1) and m(1) indices, we identify a sample of likely cluster members extending well beyond the formal tidal radius. The estimated contamination by cluster non-members is only one per cent, making our catalogue ideally suited for spectroscopic follow-up. We derive photometric [Fe/H] of red giants, and depending on which metallicity calibration from the literature we use, we find reasonable to excellent agreement with spectroscopic [Fe/H], both for the cluster mean metallicity and for individual stars. We demonstrate explicitly that the photometric uncertainties are not Gaussian and this must be accounted for in any analysis of the metallicity distribution function. Using a realistic, non-Gaussian model for the photometric uncertainties, we find a formal internal [Fe/H] spread of sigma = 0.11(-0.01)(+0.02) dex. This is an upper limit to the cluster's true [Fe/H] spread and may partially, and possibly entirely, reflect the limited precision of the photometric metallicity estimation and systematic effects. The lack of correlation between spectroscopic and photometric [Fe/H] of individual stars is further evidence against a [Fe/H] spread on the 0.1 dex level. Finally, the CN-sensitive delta(4), among other colour indices, anti-correlates strongly with magnesium abundance, indicating that the second-generation stars are nitrogen enriched. The absence of similar correlations in some other CN-sensitive indices supports the second generation being enriched in He, which in these indices approximately compensates the shift due to CN. Compared to a single continuous distribution with finite dispersion, the observed delta(4) distribution of red giants is slightly better fit by two distinct populations with no internal spread, with the nitrogen-enhanced second generation accounting for 53 +/- 5 per cent of stars. Despite its known peculiarities, NGC 2419 appears to be very similar to other metal-poor Galactic globular clusters with a similarly nitrogen-enhanced second generation and little or no variation in [Fe/H], which sets it apart from other suspected accreted nuclei such as omega Cen.
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| 8. |
- Wilkinson, Jack, et al.
(författare)
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Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions
- 2024
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare-related interventions.Methods and analysis The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: (1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, (2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, (3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in, (4) a consensus meeting to select checks to be included in a draft tool and to determine its format and (5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies and will help patients by protecting them from the influence of false data on their healthcare.Ethics and dissemination The University of Manchester ethics decision tool was used, and this returned the result that ethical approval was not required for this project (30 September 2022), which incorporates secondary research and surveys of professionals about subjects relating to their expertise. Informed consent will be obtained from all survey participants. All results will be published as open-access articles. The final tool will be made freely available.
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