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- Liang, Liming, et al.
(författare)
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An epigenome-wide association study of total serum immunoglobulin E concentration
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 520:7549, s. 670-U188
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever' and allergic asthma'''. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation'. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations with a meta-analysis false discovery rate less than 10-4 between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies'''. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases.
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- Nordlund, Jessica, et al.
(författare)
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Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia
- 2013
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 14:9, s. r105-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood.RESULTS:We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status.CONCLUSIONS:Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.
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- Dammann, Dyre Oliver, 1985, et al.
(författare)
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Iceberg topography and volume classification using TanDEM-X interferometry
- 2019
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Ingår i: Cryosphere. - : Copernicus GmbH. - 1994-0424 .- 1994-0416. ; 13:7, s. 1861-1875
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Tidskriftsartikel (refereegranskat)abstract
- Icebergs in polar regions affect water salinity, alter marine habitats, and impose serious hazards on maritime operations and navigation. These impacts mainly depend on the iceberg volume, which remains an elusive parameter to measure. We investigate the capability of TanDEM-X bistatic single-pass synthetic aperture radar interferometry (InSAR) to derive iceberg subaerial morphology and infer total volume. We cross-verify InSAR results with Operation IceBridge (OIB) data acquired near Wordie Bay, Antarctica, as part of the OIB/TanDEM-X Antarctic Science Campaign (OTASC). While icebergs are typically classified according to size based on length or maximum height, we develop a new volumetric classification approach for applications where iceberg volume is relevant. For icebergs with heights exceeding 5 m, we find iceberg volumes derived from TanDEM-X and OIB data match within 7 %. We also derive a range of possible iceberg keel depths relevant to grounding and potential impacts on subsea installations. These results suggest that TanDEM-X could pave the way for future single-pass interferometric systems for scientific and operational iceberg mapping and classification based on iceberg volume and keel depth.
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- Paul, Dirk S., et al.
(författare)
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Increased DNA methylation variability in type 1 diabetes across three immune effector cell types
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.
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