| 1. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 2. |
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| 3. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 4. |
- Culverhouse, R. C., et al.
(författare)
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Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression
- 2018
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 23:1, s. 133-142
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Tidskriftsartikel (refereegranskat)abstract
- The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.
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| 5. |
- Romagnoni, A, et al.
(författare)
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Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10351-
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Tidskriftsartikel (refereegranskat)abstract
- Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
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| 6. |
- Craddock, Nick, et al.
(författare)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 8. |
- Tye, Andrew M., et al.
(författare)
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Dissolved inorganic carbon export from rivers of Great Britain : Spatial distribution and potential catchment-scale controls
- 2022
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Ingår i: Journal of Hydrology. - : Elsevier. - 0022-1694 .- 1879-2707. ; 615
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Tidskriftsartikel (refereegranskat)abstract
- Dissolved inorganic carbon (DIC) fluxes from the land to ocean have been quantified for many rivers globally. However, CO2 fluxes to the atmosphere from inland waters are quantitatively significant components of the global carbon cycle that are currently poorly constrained. Understanding, the relative contributions of natural and human-impacted processes on the DIC cycle within catchments may provide a basis for developing improved management strategies to mitigate free CO2 concentrations in rivers and subsequent evasion to the atmosphere. Here, a large, internally consistent dataset collected from 41 catchments across Great Britain (GB), accounting for ∼36% of land area (∼83,997 km2) and representative of national land cover, was used to investigate catchment controls on riverine dissolved inorganic carbon (DIC), bicarbonate (HCO3−) and free CO2 concentrations, fluxes to the coastal sea and annual yields per unit area of catchment. Estimated DIC flux to sea for the survey catchments was 647 kt DIC yr−1 which represented 69% of the total dissolved carbon flux from these catchments. Generally, those catchments with large proportions of carbonate and sedimentary sandstone were found to deliver greater DIC and HCO3− to the ocean. The calculated mean free CO2 yield for survey catchments (i.e. potential CO2 emission to the atmosphere) was 0.56 t C km−2 yr−1. Regression models demonstrated that whilst river DIC (R2 = 0.77) and HCO3− (R2 = 0.77) concentrations are largely explained by the geology of the landmass, along with a negative correlation to annual precipitation, free CO2 concentrations were strongly linked to catchment macronutrient status. Overall, DIC dominates dissolved C inputs to coastal waters, meaning that estuarine carbon dynamics are sensitive to underlying geology and therefore are likely to be reasonably constant. In contrast, potential losses of carbon to the atmosphere via dissolved CO2, which likely constitute a significant fraction of net terrestrial ecosystem production and hence the national carbon budget, may be amenable to greater direct management via altering patterns of land use.
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| 12. |
- Garcia-Martin, E. Elena, et al.
(författare)
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Sources, Composition, and Export of Particulate Organic Matter Across British Estuaries
- 2023
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Ingår i: Journal of Geophysical Research - Biogeosciences. - : American Geophysical Union (AGU). - 2169-8953 .- 2169-8961. ; 128:4
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Tidskriftsartikel (refereegranskat)abstract
- Estuaries receive and process a large amount of particulate organic carbon (POC) prior to its export into coastal waters. Studying the origin of this POC is key to understanding the fate of POC and the role of estuaries in the global carbon cycle. Here, we evaluated the concentrations of POC, as well as particulate organic nitrogen (PON), and used stable carbon and nitrogen isotopes to assess their sources across 13 contrasting British estuaries during five different sampling campaigns over 1 year. We found a high variability in POC and PON concentrations across the salinity gradient, reflecting inputs, and losses of organic material within the estuaries. Catchment land cover appeared to influence the contribution of POC to the total organic carbon flux from the estuary to coastal waters, with POC contributions >36% in estuaries draining catchments with a high percentage of urban/suburban land, and <11% in estuaries draining catchments with a high peatland cover. There was no seasonal pattern in the isotopic composition of POC and PON, suggesting similar sources for each estuary over time. Carbon isotopic ratios were depleted (-26.7 +/- 0.42 parts per thousand, average +/- sd) at the lowest salinity waters, indicating mainly terrigenous POC (TPOC). Applying a two-source mixing model, we observed high variability in the contribution of TPOC at the highest salinity waters between estuaries, with a median value of 57%. Our results indicate a large transport of terrigenous organic carbon into coastal waters, where it may be buried, remineralized, or transported offshore. Plain Language Summary Estuaries transport and process a large amount terrigenous particulate organic matter (i.e., carbon and nitrogen) prior to its export to coastal waters. In order to understand the fate of organic carbon and the role of estuaries in the global carbon cycle it is essential to improve our knowledge on its composition, origin, and amount of carbon transported. We quantified the elemental concentrations and stable isotopes composition of carbon and nitrogen to quantify the amount of terrigenous particulate organic matter transported by 13 British estuaries, which drain catchments of diverse land cover under different hydrological conditions. We found a great variability in particulate organic carbon (POC) and particulate organic nitrogen concentrations across the salinity gradient, implying inputs, and losses of material within the estuaries. Each estuary had similar sources of particulate material throughout the year. In most of the estuaries, the POC had a terrigenous origin at the lowest salinity waters. The terrigenous organic carbon contribution decreased toward coastal waters with an average contribution of 57% at the highest salinity waters, indicating a large transport of terrigenous organic carbon into coastal waters.
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| 21. |
- Rothwell, S, et al.
(författare)
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Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:7, s. 996-1002
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Tidskriftsartikel (refereegranskat)abstract
- Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies.MethodsWe collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups.ResultsWe report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10–5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10–53 and HLA-DRB1*03:01, p=3.25×10–9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10–26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10–11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10–13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10–6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10–64) and position 9 of HLA-B (p=7.03×10–11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies.ConclusionsThese findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.
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| 22. |
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| 23. |
- Williamson, Jennifer L., et al.
(författare)
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Landscape controls on riverine export of dissolved organic carbon from Great Britain
- 2021
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Ingår i: Biogeochemistry. - : Springer Science and Business Media LLC. - 0168-2563 .- 1573-515X.
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Tidskriftsartikel (refereegranskat)abstract
- The dissolved organic carbon (DOC) export from land to ocean via rivers is a significant term in the global C cycle, and has been modified in many areas by human activity. DOC exports from large global rivers are fairly well quantified, but those from smaller river systems, including those draining oceanic regions, are generally under-represented in global syntheses. Given that these regions typically have high runoff and high peat cover, they may exert a disproportionate influence on the global land–ocean DOC export. Here we describe a comprehensive new assessment of the annual riverine DOC export to estuaries across the island of Great Britain (GB), which spans the latitude range 50–60° N with strong spatial gradients of topography, soils, rainfall, land use and population density. DOC yields (export per unit area) were positively related to and best predicted by rainfall, peat extent and forest cover, but relatively insensitive to population density or agricultural development. Based on an empirical relationship with land use and rainfall we estimate that the DOC export from the GB land area to the freshwater-seawater interface was 1.15 Tg C year−1 in 2017. The average yield for GB rivers is 5.04 g C m−2 year−1, higher than most of the world’s major rivers, including those of the humid tropics and Arctic, supporting the conclusion that under-representation of smaller river systems draining peat-rich areas could lead to under-estimation of the global land–ocean DOC export. The main anthropogenic factor influencing the spatial distribution of GB DOC exports appears to be upland conifer plantation forestry, which is estimated to have raised the overall DOC export by 0.168 Tg C year−1. This is equivalent to 15% of the estimated current rate of net CO2 uptake by British forests. With the UK and many other countries seeking to expand plantation forest cover for climate change mitigation, this ‘leak in the ecosystem’ should be incorporated in future assessments of the CO2 sequestration potential of forest planting strategies.
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| 24. |
- Bowes, Heather M, et al.
(författare)
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Swim performance and thermoregulatory effects of wearing clothing in a simulated cold-water survival situation.
- 2016
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Ingår i: European Journal of Applied Physiology. - : Springer. - 1439-6319 .- 1439-6327. ; 116:4, s. 759-67
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Accidental cold-water immersion (CWI) impairs swim performance, increases drowning risk and often occurs whilst clothed. The impact of clothing on thermoregulation and swim performance during CWI was explored with the view of making recommendations on whether swimming is viable for self-rescue; contrary to the traditional recommendations.METHOD: Ten unhabituated males (age 24 (4) years; height 1.80 (0.08) m; mass 78.50 (10.93) kg; body composition 14.8 (3.4) fat %) completed four separate CWIs in 12 °C water. They either rested clothed or naked (i.e. wearing a bathing costume) or swum self-paced clothed or naked for up to 1 h. Swim speed, distance covered, oxygen consumption and thermal responses (rectal temperature (T re), mean skin temperature (T msk) and mean body temperature T b) were measured.RESULTS: When clothed, participants swum at a slower pace and for a significantly shorter distance (815 (482) m, 39 (19) min) compared to when naked (1264 (564) m, 52 (18) min), but had a similar oxygen consumption indicating clothing made them less efficient. Swimming accelerated the rate of T msk and T b cooling and wearing clothing partially attenuated this drop. The impairment to swimming performance caused by clothing was greater than the thermal benefit it provided; participants withdrew due to exhaustion before hypothermia developed.CONCLUSION: Swimming is a viable self-rescue method in 12 °C water, however, clothing impairs swimming capability. Self-rescue swimming could be considered before clinical hypothermia sets in for the majority of individuals. These suggestions must be tested for the wider population.
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| 27. |
- Hinks, A, et al.
(författare)
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Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases
- 2017
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 76:4, s. 765-772
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Tidskriftsartikel (refereegranskat)abstract
- Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides.MethodsDense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed.ResultsWe identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA.ConclusionsThe findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.
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| 28. |
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| 29. |
- Ishigaki, Kazuyoshi, et al.
(författare)
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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:11, s. 1640-1651
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.
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| 30. |
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| 31. |
- Kia, Richard, et al.
(författare)
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MicroRNA-122 : a novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity
- 2015
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Ingår i: Toxicological Sciences. - : Oxford University Press. - 1096-6080 .- 1096-0929. ; 144:1, s. 173-185
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Tidskriftsartikel (refereegranskat)abstract
- Emerging hepatic models for the study of drug-induced toxicity include pluripotent stem cell-derived hepatocyte-like cells (HLCs) and complex hepatocyte-non-parenchymal cellular coculture to mimic the complex multicellular interactions that recapitulate the niche environment in the human liver. However, a specific marker of hepatocyte perturbation, required to discriminate hepatocyte damage from non-specific cellular toxicity contributed by non-hepatocyte cell types or immature differentiated cells is currently lacking, as the cytotoxicity assays routinely used in in vitro toxicology research depend on intracellular molecules which are ubiquitously present in all eukaryotic cell types. In this study, we demonstrate that microRNA-122 (miR-122) detection in cell culture media can be used as a hepatocyte-enriched in vitro marker of drug-induced toxicity in homogeneous cultures of hepatic cells, and a cell-specific marker of toxicity of hepatic cells in heterogeneous cultures such as HLCs generated from various differentiation protocols and pluripotent stem cell lines, where conventional cytotoxicity assays using generic cellular markers may not be appropriate. We show that the sensitivity of the miR-122 cytotoxicity assay is similar to conventional assays that measure lactate dehydrogenase activity and intracellular adenosine triphosphate when applied in hepatic models with high levels of intracellular miR-122, and can be multiplexed with other assays. MiR-122 as a biomarker also has the potential to bridge results in in vitro experiments to in vivo animal models and human samples using the same assay, and to link findings from clinical studies in determining the relevance of in vitro models being developed for the study of drug-induced liver injury.
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| 32. |
- Apel, Maria, et al.
(författare)
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Variants in RUNX3 Contribute to Susceptibility to Psoriatic Arthritis, Exhibiting Further Common Ground With Ankylosing Spondylitis
- 2013
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 65:5, s. 1224-1231
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Tidskriftsartikel (refereegranskat)abstract
- Objective Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris. In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease was not fully explained. Therefore, we undertook this study to investigate further 17 loci from our GWAS that did not reach genome-wide significance levels of association in the initial analysis. Methods Twenty-one of 22 single-nucleotide polymorphisms were successfully genotyped in independent cohorts of 1,398 PsA patients and 6,389 controls and in a group of 964 German patients with psoriasis vulgaris. Results Association with a RUNX3 variant, rs4649038, was replicated in independent patients and controls and resulted in a combined P value of 1.40 x 108 by Cochran-Mantel-Haenszel test and an odds ratio (OR) of 1.24 (95% confidence interval [95% CI] 1.151.33). Further analyses based on linkage disequilibrium (LD) at RUNX3 refined the most significant association to an LD block located in the first intron of one isoform. Weaker evidence for association was detected in German patients with psoriasis vulgaris (P = 5.89 x 102; OR 1.13 [95% CI 1.001.28]), indicating a role in the skin manifestations of psoriasis. Conclusion Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondyloarthritis, although its risk allele is independent from the one for PsA. RUNX-3 is involved in CD8+ T lymphocyte differentiation and is therefore a good candidate for involvement in PsA and psoriasis vulgaris as T cellmediated diseases.
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| 33. |
- Bowes, Rachel E., et al.
(författare)
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Consequences of employing amino acid vs. bulk-tissue, stable isotope analysis : a laboratory trophic position experiment
- 2015
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Ingår i: Ecosphere. - : John Wiley & Sons. - 2150-8925 .- 2150-8925. ; 6:1, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- An important metric of environmental health is food web structure because it reflects species richness, natural history diversity, and resource availability. While bulk-tissue stable isotope analysis has proven valuable for food web studies, field conditions may severely restrict its use and data can be quite variable. Amino acid stable isotope analysis potentially reduces this variability, in part by eliminating the need for signatures near the trophic base because a single top consumer contains both the primary producer signature (constant phenylalanine signature) and information reflecting number of trophic transfers (a progressively increasing d15N signature of glutamic acid). To evaluate the ecological sensitivity and cost/benefits of the techniques, we conducted a laboratory food chain experiment with four trophic levels. Water fleas (Daphnia magna) were cultured on a diet of powdered algae and then fed daily to guppies (Poecilia reticulata) for three months. These invertivorous fishes were then consumed by piscivororus bluegill sunfishes (Lepomis macrochirus) for a subsequent three months. All members of the food web were analyzed for 15N values and degree of fractionation using both bulk-tissue and amino acid stable isotope techniques. Our experiment demonstrated that the amino acid technique more accurately identified the true trophic position (TP) and food chain length (FCL ¼ maximum TP) with significantly less variability around mean values for each consumer trophic level. Moreover, use of amino acids requires significantly fewer replicates to identify TP. We discuss here the relative advantages and disadvantages of both approaches for determining TP and FCL and recommend that investigators switch as soon as possible to the amino acid isotope technique for determining FCL.
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| 34. |
- Culverhouse, Robert C, et al.
(författare)
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Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression.
- 2013
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Ingår i: BMC Psychiatry. - 1471-244X. ; 13, s. 304-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Debate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions.METHODS/DESIGN: To improve understanding of the combined roles of 5-HTTLPR variation and stress in the development of depression, we are conducting a meta-analysis of multiple independent datasets. This coordinated approach utilizes new analyses performed with centrally-developed, standardized scripts. This publication documents the protocol for this collaborative, consortium-based meta-analysis of 5-HTTLPR variation, stress, and depression.STUDY ELIGIBILITY CRITERIA: Our goal is to invite all datasets, published or unpublished, with 5-HTTLPR genotype and assessments of stress and depression for at least 300 subjects. This inclusive approach is to minimize potential impact from publication bias.DATA SOURCES: This project currently includes investigators from 35 independent groups, providing data on at least N = 33,761 participants.The analytic plan was determined prior to starting data analysis. Analyses of individual study datasets will be performed by the investigators who collected the data using centrally-developed standardized analysis scripts to ensure a consistent analytical approach across sites. The consortium as a group will review and interpret the meta-analysis results.DISCUSSION: Variation in 5-HTTLPR is hypothesized to moderate the response to stress on depression. To test specific hypotheses about the role of 5-HTTLPR variation on depression, we will perform coordinated meta-analyses of de novo results obtained from all available data, using variables and analyses determined a priori. Primary analyses, based on the original 2003 report by Caspi and colleagues of a GxE interaction will be supplemented by secondary analyses to help interpret and clarify issues ranging from the mechanism of effect to heterogeneity among the contributing studies. Publication of this protocol serves to protect this project from biased reporting and to improve the ability of readers to interpret the results of this specific meta-analysis upon its completion.
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| 35. |
- Gurke, Robert, et al.
(författare)
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Omics and Multi-Omics Analysis for the Early Identification and Improved Outcome of Patients with Psoriatic Arthritis
- 2022
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:10
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Forskningsöversikt (refereegranskat)abstract
- The definitive diagnosis and early treatment of many immune-mediated inflammatory diseases (IMIDs) is hindered by variable and overlapping clinical manifestations. Psoriatic arthritis (PsA), which develops in similar to 30% of people with psoriasis, is a key example. This mixed-pattern IMID is apparent in entheseal and synovial musculoskeletal structures, but a definitive diagnosis often can only be made by clinical experts or when an extensive progressive disease state is apparent. As with other IMIDs, the detection of multimodal molecular biomarkers offers some hope for the early diagnosis of PsA and the initiation of effective management and treatment strategies. However, specific biomarkers are not yet available for PsA. The assessment of new markers by genomic and epigenomic profiling, or the analysis of blood and synovial fluid/tissue samples using proteomics, metabolomics and lipidomics, provides hope that complex molecular biomarker profiles could be developed to diagnose PsA. Importantly, the integration of these markers with high-throughput histology, imaging and standardized clinical assessment data provides an important opportunity to develop molecular profiles that could improve the diagnosis of PsA, predict its occurrence in cohorts of individuals with psoriasis, differentiate PsA from other IMIDs, and improve therapeutic responses. In this review, we consider the technologies that are currently deployed in the EU IMI2 project HIPPOCRATES to define biomarker profiles specific for PsA and discuss the advantages of combining multi-omics data to improve the outcome of PsA patients.
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| 36. |
- Han, Buhm, et al.
(författare)
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Fine Mapping Seronegative and Seropositive Rheumatoid Arthritis to Shared and Distinct HLA Alleles by Adjusting for the Effects of Heterogeneity
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 94:4, s. 522-532
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Tidskriftsartikel (refereegranskat)abstract
- Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA RA and observed independent associations for serine and leucine at position 11 in HLA-DR beta 1 (p = 1.4 x 10 (13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 x 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1*03 (encoding serine at 11) and HLA-B*08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DR beta 1 Ser11+Leu11: p = 5.8 x 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 x 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DR beta 1 position 11 were distinct (p < 2.9 x 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 x 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.
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| 37. |
- Hüffmeier, Ulrike, et al.
(författare)
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Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 996-999
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Tidskriftsartikel (refereegranskat)abstract
- Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10⁻¹⁷). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10⁻³). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10⁻²⁰, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.
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| 38. |
- Lawen, Tarek, et al.
(författare)
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Six-month prostate cancer empowerment program (PC-PEP) improves urinary function : a randomized trial
- 2024
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 16:5
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This is a secondary analysis examining a six-month home-based Prostate Cancer-Patient Empowerment Program (PC-PEP) on patient-reported urinary, bowel, sexual, and hormonal function in men with curative prostate cancer (PC) against standard of care.Methods: In a crossover clinical trial, 128 men scheduled for PC surgery (n = 62) or radiotherapy with/without hormones (n = 66) were randomized to PC-PEP (n = 66) or waitlist-control and received the standard of care for 6 months, and then PC-PEP to the end of the year. PC-PEP included daily emails with video instructions, aerobic and strength training, dietary guidance, stress management, and social support, with an initial PFMT nurse consultation. Over 6 months, participants in the PC-PEP received optional text alerts (up to three times daily) reminding them to follow the PFMT video program, encompassing relaxation, quick-twitch, and endurance exercises; compliance was assessed weekly. Participants completed baseline, 6, and 12-month International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC) questionnaires.Results: At 6 months, men in the PC-PEP reported improved urinary bother (IPSS, p = 0.004), continence (EPIC, p < 0.001), and irritation/obstruction function (p = 0.008) compared to controls, with sustained urinary continence benefits at 12 months (p = 0.002). Surgery patients in the waitlist-control group had 3.5 (95% CI: 1.2, 10, p = 0.024) times and 2.3 (95% CI: 0.82, 6.7, p = 0.11) times higher odds of moderate to severe urinary problems compared to PC-PEP at 6 and 12 months, respectively.Conclusions: PC-PEP significantly improves lower urinary tract symptoms, affirming its suitability for clinical integration alongside established mental health benefits in men with curative prostate cancer.
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| 39. |
- Näslund, J., et al.
(författare)
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Fish biodiversity in different types of tributary mouths located within impounded sections of Swedish boreal rivers
- 2023
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Ingår i: International Journal of Ecohydrology and Hydrobiology. - : Elsevier. - 1642-3593 .- 2080-3397. ; 23:1, s. 48-65
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Tidskriftsartikel (refereegranskat)abstract
- Large boreal rivers in Sweden are generally impounded by hydropower dams and a large proportion of main stem shallow flowing habitats have been lost. Tributaries often contain the last undisturbed habitats and could be important for the conservation of species diversity. In particular, tributary mouth areas could be biodiversity hot-spots, due to their vicinity to the main stem and favorable environmental conditions. In this study, we investigate whether tributary mouth areas in two impounded boreal rivers (Ume River and Lule River) could be regarded as biodiversity hot-spots for fish. Based on standardized electrofishing in 20 tributary mouths, we find that overall fish diversity is generally low. The highest species richness and diversity was found in mouth areas dominated by intermediate substrate sizes (gravel – cobble). Few, if any, species were found in areas where fine sediments (smaller than sand) dominated. The tributary mouth areas had similar species richness and diversity as areas in the tributaries located 1-km upstream of the mouth, but the fish community composition often differed between these two types of sites. Management action favoring fish diversity in the tributary mouth areas could include protection or rehabilitation of areas dominated by medium sized substrate and reduction of erosion and transport of fine sediments in the tributaries. Overall, we find no support for tributary mouths being hot-spots for fish biodiversity and while some patterns in diversity gives hints on suitable management action, it is important to further understand impacts in tributaries and their mouths and the temporal dynamics of the fish community.
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| 40. |
- Okada, Yukinori, et al.
(författare)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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| 41. |
- Singer, Andrew C., et al.
(författare)
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Compliance to Oseltamivir among Two Populations in Oxfordshire, United Kingdom Affected by Influenza A(H1N1)pdm09, November 2009 : A Waste Water Epidemiology Study
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- Antiviral provision remains the focus of many pandemic preparedness plans, however, there is considerable uncertainty regarding antiviral compliance rates. Here we employ a waste water epidemiology approach to estimate oseltamivir (Tamiflu (R)) compliance. Oseltamivir carboxylate (oseltamivir's active metabolite) was recovered from two waste water treatment plant (WWTP) catchments within the United Kingdom at the peak of the autumnal wave of the 2009 Influenza A (H1N1)pdm09 pandemic. Predictions of oseltamivir consumption from detected levels were compared with two sources of national government statistics to derive compliance rates. Scenario and sensitivity analysis indicated between 3-4 and 120-154 people were using oseltamivir during the study period in the two WWTP catchments and a compliance rate between 45-60%. With approximately half the collected antivirals going unused, there is a clear need to alter public health messages to improve compliance. We argue that a near real-time understanding of drug compliance at the scale of the waste water treatment plant (hundreds to millions of people) can potentially help public health messages become more timely, targeted, and demographically sensitive, while potentially leading to less mis- and un-used antiviral, less wastage and ultimately a more robust and efficacious pandemic preparedness plan.
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| 42. |
- Singer, Andrew C., et al.
(författare)
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Intra- and inter-pandemic variations of antiviral, antibiotics and decongestants in wastewater treatment plants and receiving rivers
- 2014
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Ingår i: PLOS ONE. - : Public library of science. - 1932-6203. ; 9:9
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Tidskriftsartikel (refereegranskat)abstract
- The concentration of eleven antibiotics (trimethoprim, oxytetracycline, ciprofloxacin, azithromycin, cefotaxime, doxycycline, sulfamethoxazole, erythromycin, clarithromycin, ofloxacin, norfloxacin), three decongestants (naphazoline, oxymetazoline, xylometazoline) and the antiviral drug oseltamivir's active metabolite, oseltamivir carboxylate (OC), were measured weekly at 21 locations within the River Thames catchment in England during the month of November 2009, the autumnal peak of the influenza A[H1N1]pdm09 pandemic. The aim was to quantify the pharmaceutical response to the pandemic and compare this to drug use during the late pandemic (March 2010) and the inter-pandemic periods (May 2011). A large and small wastewater treatment plant (WWTP) were sampled in November 2009 to understand the differential fate of the analytes in the two WWTPs prior to their entry in the receiving river and to estimate drug users using a wastewater epidemiology approach. Mean hourly OC concentrations in the small and large WWTP's influent were 208 and 350 ng/L (max, 2070 and 550 ng/L, respectively). Erythromycin was the most concentrated antibiotic measured in Benson and Oxford WWTPs influent (max = 6,870 and 2,930 ng/L, respectively). Napthazoline and oxymetazoline were the most frequently detected and concentrated decongestant in the Benson WWTP influent (1650 and 67 ng/L) and effluent (696 and 307 ng/L), respectively, but were below detection in the Oxford WWTP. OC was found in 73% of November 2009's weekly river samples (max = 193 ng/L), but only in 5% and 0% of the late-and inter-pandemic river samples, respectively. The mean river concentration of each antibiotic during the pandemic largely fell between 17-74 ng/L, with clarithromycin (max = 292 ng/L) and erythromycin (max = 448 ng/L) yielding the highest single measure. In general, the concentration and frequency of detecting antibiotics in the river increased during the pandemic. OC was uniquely well-suited for the wastewater epidemiology approach owing to its nature as a prodrug, recalcitrance and temporally-and spatially-resolved prescription statistics.
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| 43. |
- Singer, Andrew C., et al.
(författare)
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Intra- and inter-pandemic variations of antiviral, antibiotics and decongestants in wastewater treatment plants and receiving rivers
- 2015. - 1
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Ingår i: Water treatment in developed and developing nations. - Oakville, ON : Apple Academic Press. - 9781771882453 - 9781771882415 - 9780429154713 ; , s. 155-186
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Bokkapitel (refereegranskat)abstract
- Pandemics are unique public health emergencies that can result in a large sudden increase in the use of a restricted set of pharmaceuticals within a short time period. In the case of an influenza pandemic, antiviral use will greatly exceed inter-pandemic use in most countries by several orders of magnitude, as few countries maintain significant inter-pandemic usage-Japan being a notable exception [1]. Depending on the severity of the pandemic, antibiotics have the potential to significantly exceed inter-pandemic usage for the treatment of secondary bacterial respiratory infections [2]. Decongestant usage is also predicted to increase with an increase in upper-and lower-respiratory tract infections [3].
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