| 1. |
- Kanai, M, et al.
(författare)
-
- 2023
-
swepub:Mat__t
|
|
| 2. |
- Aad, G, et al.
(författare)
-
- 2015
-
swepub:Mat__t
|
|
| 3. |
|
|
| 4. |
- Bravo, L, et al.
(författare)
-
- 2021
-
swepub:Mat__t
|
|
| 5. |
- Tabiri, S, et al.
(författare)
-
- 2021
-
swepub:Mat__t
|
|
| 6. |
|
|
| 7. |
- Glasbey, JC, et al.
(författare)
-
- 2021
-
swepub:Mat__t
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Sliz, E., et al.
(författare)
-
Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
|
|
| 11. |
- Tabassum, R, et al.
(författare)
-
Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
-
Tidskriftsartikel (refereegranskat)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
|
|
| 12. |
|
|
| 13. |
- Kurki, MI, et al.
(författare)
-
FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
-
Tidskriftsartikel (refereegranskat)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
|
|
| 14. |
- Abdel-Aziz, Mahmoud I., et al.
(författare)
-
A multi-omics approach to delineate sputum microbiome-associated asthma inflammatory phenotypes
- 2022
-
Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 59:1
-
Tidskriftsartikel (refereegranskat)abstract
- A multi-omics approach revealed the underlying biological pathways in the microbiome-driven severe asthma phenotypes. This may help to elucidate new leads for treatment development, particularly for the therapeutically challenging neutrophilic asthma.
|
|
| 15. |
- Danaei, Goodarz, et al.
(författare)
-
Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331288 participants
- 2015
-
Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595 .- 2213-8587. ; 3:8, s. 624-637
-
Tidskriftsartikel (refereegranskat)abstract
- Background Diabetes has been defined on the basis of different biomarkers, including fasting plasma glucose (FPG), 2-h plasma glucose in an oral glucose tolerance test (2hOGTT), and HbA(1c). We assessed the effect of different diagnostic definitions on both the population prevalence of diabetes and the classification of previously undiagnosed individuals as having diabetes versus not having diabetes in a pooled analysis of data from population-based health examination surveys in different regions. Methods We used data from 96 population-based health examination surveys that had measured at least two of the biomarkers used for defining diabetes. Diabetes was defined using HbA(1c) (HbA(1c) >= 6 . 5% or history of diabetes diagnosis or using insulin or oral hypoglycaemic drugs) compared with either FPG only or FPG-or-2hOGTT definitions (FPG >= 7 . 0 mmol/L or 2hOGTT >= 11 . 1 mmol/L or history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated diabetes prevalence, taking into account complex survey design and survey sample weights. We compared the prevalences of diabetes using different definitions graphically and by regression analyses. We calculated sensitivity and specificity of diabetes diagnosis based on HbA1c compared with diagnosis based on glucose among previously undiagnosed individuals (ie, excluding those with history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated sensitivity and specificity in each survey, and then pooled results using a random-effects model. We assessed the sources of heterogeneity of sensitivity by meta-regressions for study characteristics selected a priori. Findings Population prevalence of diabetes based on FPG- or-2hOGTT was correlated with prevalence based on FPG alone (r= 0 . 98), but was higher by 2-6 percentage points at different prevalence levels. Prevalence based on HbA(1c) was lower than prevalence based on FPG in 42 . 8% of age-sex-survey groups and higher in another 41 . 6%; in the other 15 . 6%, the two definitions provided similar prevalence estimates. The variation across studies in the relation between glucose-based and HbA(1c)-based prevalences was partly related to participants' age, followed by natural logarithm of per person gross domestic product, the year of survey, mean BMI, and whether the survey population was national, subnational, or from specific communities. Diabetes defined as HbA(1c) 6 . 5% or more had a pooled sensitivity of 52 . 8% (95% CI 51 . 3-54 . 3%) and a pooled specificity of 99 . 74% (99 . 71-99 . 78%) compared with FPG 7 . 0 mmol/L or more for diagnosing previously undiagnosed participants; sensitivity compared with diabetes defined based on FPG-or-2hOGTT was 30 . 5% (28 . 7-32 . 3%). None of the preselected study-level characteristics explained the heterogeneity in the sensitivity of HbA(1c) versus FPG. Interpretation Different biomarkers and definitions for diabetes can provide different estimates of population prevalence of diabetes, and differentially identify people without previous diagnosis as having diabetes. Using an HbA(1c)-based definition alone in health surveys will not identify a substantial proportion of previously undiagnosed people who would be considered as having diabetes using a glucose-based test.
|
|
| 16. |
- Brinkman, Paul, et al.
(författare)
-
Identification and prospective stability of electronic nose (eNose)-derived inflammatory phenotypes in patients with severe asthma
- 2019
-
Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 143:5, s. 1811-1820.e7
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using “omics” technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes.Objectives: We aimed (1) to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses) and (2) to assess the stability of eNose-derived phenotypes in relation to withinpatient clinical and inflammatory changes.Methods: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability.Results: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNosedriven clusters (n = 26/33/19) were revealed, showing differences in circulating eosinophil (P = .045) and neutrophil (P = .017) percentages and ratios of patients using oral corticosteroids (P = .035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P = .045).Conclusions: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma.
|
|
| 17. |
- Dulvy, Nicholas K., et al.
(författare)
-
Overfishing drives over one-third of all sharks and rays toward a global extinction crisis
- 2021
-
Ingår i: Current Biology. - : Cell Press. - 0960-9822 .- 1879-0445. ; 31:21, s. 4773-4787
-
Tidskriftsartikel (refereegranskat)abstract
- The scale and drivers of marine biodiversity loss are being revealed by the International Union for Conservation of Nature (IUCN) Red List assessment process. We present the first global reassessment of 1,199 species in Class Chondrichthyes-sharks, rays, and chimeras. The first global assessment (in 2014) concluded that one-quarter (24%) of species were threatened. Now, 391 (32.6%) species are threatened with extinction. When this percentage of threat is applied to Data Deficient species, more than one-third (37.5%) of chondrichthyans are estimated to be threatened, with much of this change resulting from new information. Three species are Critically Endangered (Possibly Extinct), representing possibly the first globalmarine fish extinctions due to overfishing. Consequently, the chondrichthyan extinction rate is potentially 25 extinctions per million species years, comparable to that of terrestrial vertebrates. Overfishing is the universal threat affecting all 391 threatened species and is the sole threat for 67.3% of species and interacts with three other threats for the remaining third: loss and degradation of habitat (31.2% of threatened species), climate change (10.2%), and pollution (6.9%). Species are disproportionately threatened in tropical and subtropical coastal waters. Science-based limits on fishing, effective marine protected areas, and approaches that reduce or eliminate fishing mortality are urgently needed to minimize mortality of threatened species and ensure sustainable catch and trade of others. Immediate action is essential to prevent further extinctions and protect the potential for food security and ecosystem functions provided by this iconic lineage of predators.
|
|
| 18. |
- Sherman, C. Samantha, et al.
(författare)
-
Half a century of rising extinction risk of coral reef sharks and rays
- 2023
-
Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Sharks and rays are key functional components of coral reef ecosystems, yet many populations of a few species exhibit signs of depletion and local extinctions. The question is whether these declines forewarn of a global extinction crisis. We use IUCN Red List to quantify the status, trajectory, and threats to all coral reef sharks and rays worldwide. Here, we show that nearly two-thirds (59%) of the 134 coral-reef associated shark and ray species are threatened with extinction. Alongside marine mammals, sharks and rays are among the most threatened groups found on coral reefs. Overfishing is the main cause of elevated extinction risk, compounded by climate change and habitat degradation. Risk is greatest for species that are larger-bodied (less resilient and higher trophic level), widely distributed across several national jurisdictions (subject to a patchwork of management), and in nations with greater fishing pressure and weaker governance. Population declines have occurred over more than half a century, with greatest declines prior to 2005. Immediate action through local protections, combined with broad-scale fisheries management and Marine Protected Areas, is required to avoid extinctions and the loss of critical ecosystem function condemning reefs to a loss of shark and ray biodiversity and ecosystem services, limiting livelihoods and food security. © 2023, The Author(s).
|
|
| 19. |
- Badi, Yusef Eamon, et al.
(författare)
-
Mapping atopic dermatitis and anti–IL-22 response signatures to type 2–low severe neutrophilic asthma
- 2022
-
Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 149:1, s. 89-101
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti–IL-22 (fezakinumab [FZ]) is enriched in severe asthma.Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort.Results: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, TH2, and TH17/TH22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P <.05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P <.05) and particularly in neutrophilic and mixed granulocytic sputum (P <.05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with TH22/IL-22 pathways.Conclusions: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.
|
|
| 20. |
- Kolmert, Johan, et al.
(författare)
-
Urinary Leukotriene E-4 and Prostaglandin D-2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation A Clinical Observational Study
- 2021
-
Ingår i: American Journal of Respiratory and Critical Care Medicine. - NEW YORK, USA : AMER THORACIC SOC. - 1073-449X .- 1535-4970. ; 203:1, s. 37-53
-
Tidskriftsartikel (refereegranskat)abstract
- Rationale: New approaches are needed to guide personalized treatment of asthma. Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping. Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma. Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE(2) pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE(2) metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD(2) metabolite 2,3-dinor-11 beta-PGF(2 alpha). High concentrations of LTE4 and PGD(2) metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOARED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.
|
|
| 21. |
- Yasinska, Valentyna, et al.
(författare)
-
Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids
- 2023
-
Ingår i: ERJ Open Research. - : European Respiratory Society. - 2312-0541. ; 9:5
-
Tidskriftsartikel (refereegranskat)abstract
- Rationale: Patients with severe asthma are dependent upon treatment with high doses of inhaled corticosteroids (ICS) and often also oral corticosteroids (OCS). The extent of endogenous androgenic anabolic steroid (EAAS) suppression in asthma has not previously been described in detail. The objective of the present study was to measure urinary concentrations of EAAS in relation to exogenous corticosteroid exposure.Methods: Urine collected at baseline in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcomes) study of severe adult asthmatics (SA, n=408) was analysed by quantitative mass spectrometry. Data were compared to that of mild-to-moderate asthmatics (MMA, n=70) and healthy subjects (HC, n=98) from the same study.Measurements and main results: The concentrations of urinary endogenous steroid metabolites were substantially lower in SA than in MMA or HC. These differences were more pronounced in SA patients with detectable urinary OCS metabolites. Their dehydroepiandrosterone sulfate (DHEA-S) concentrations were <5% of those in HC, and cortisol concentrations were below the detection limit in 75% of females and 82% of males. The concentrations of EAAS in OCS-positive patients, as well as patients on high-dose ICS only, were more suppressed in females than males (p<0.05). Low levels of DHEA were associated with features of more severe disease and were more prevalent in females (p<0.05). The association between low EAAS and corticosteroid treatment was replicated in 289 of the SA patients at follow-up after 12–18 months.Conclusion: The pronounced suppression of endogenous anabolic androgens in females might contribute to sex differences regarding the prevalence of severe asthma.
|
|
| 22. |
- George, Leena, et al.
(författare)
-
Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma
- 2020
-
Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : WILEY. - 0105-4538 .- 1398-9995. ; 75:2, s. 370-380
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Whether the clinical or pathophysiologic significance of the "treatable trait" high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma.Methods: Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U-BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U-BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/mu L as a cut-off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values).Results: There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U-BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts.Conclusion: Despite shared "treatable traits" between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.
|
|
| 23. |
- Schofield, James P. R., et al.
(författare)
-
Topological data analysis (TDA) of U-BIOPRED paediatric peripheral blood gene expression identified asthma phenotypes characterised by alternative splicing of glucocorticoid receptor (GR) mRNA
- 2018
-
Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 52
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Molecular stratification of childhood asthma could enable targeted therapy.Aims: Unbiased analysis of gene expression in paediatric severe (SA) and moderate/mild asthma (MA) blood samples to identify sub-phenotypes.Methods: Transcriptomic profiling by microarray analysis of blood from the U-BIOPRED paediatric cohort (Fleming ERJ 2015), pre- and school-age children, (SApre, n=62; MApre, n=42; SAsc, n=75 and MAsc, n=37). Topological data analysis (TDA) was used for unbiased clustering.Results: Sub-phenotypes, P1, P2, P3 and P4 were identified and are highlighted in the TDA network in the figure and a heatmap of selected variables. P1 (38% of the cohort, median 11 yrs) was characterised by low expression of glucocorticoid receptor (GR) mRNA splice variant with a long 3’ UTR (q = 2.43E-17), but no significant difference in the expression of glucocorticoid receptor (GR) mRNA splice variant with a short 3’ UTR. In P1, COX2 expression was up (q = 1.89E-06) and IFN-γ was down (q = 5.61E-06), characteristics of a decreased steroid response.Conclusion: Unbiased analysis of U-BIOPRED paediatric peripheral blood gene expression identified a sub-phenotype, P1, with an inhibited steroid response. P1 is associated with low expression of a splice variant of GR with a long 3’ UTR.
|
|
