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| 2. |
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| 3. |
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| 4. |
- Clark, DW, et al.
(author)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Journal article (peer-reviewed)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 5. |
- Joshi, Peter K, et al.
(author)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Journal article (peer-reviewed)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 6. |
- Lee, James J, et al.
(author)
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Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.
- 2018
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 50:8, s. 1112-1121
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Journal article (peer-reviewed)abstract
- Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1million individuals and identify 1,271independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
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| 7. |
- Howe, LJ, et al.
(author)
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Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects
- 2022
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:65, s. 581-
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Journal article (peer-reviewed)abstract
- Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
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| 8. |
- Becker, Joel, et al.
(author)
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Resource profile and user guide of the Polygenic Index Repository
- 2021
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In: Nature Human Behaviour. - : Nature Research (part of Springer Nature). - 2397-3374. ; 51:6, s. 694-695
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Journal article (peer-reviewed)abstract
- Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs’ prediction accuracies, we constructed them using genome-wide association studies—some not previously published—from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the ‘additive SNP factor’. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
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| 9. |
- Frazier-Wood, Alexis C., et al.
(author)
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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
- 2016
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In: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
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Journal article (peer-reviewed)abstract
- Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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| 10. |
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| 11. |
- Smith, Jennifer A, et al.
(author)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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In: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Journal article (peer-reviewed)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 12. |
- Gretarsdottir, Solveig, et al.
(author)
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Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:8, s. 71-692
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Journal article (peer-reviewed)abstract
- We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
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| 13. |
- Iribarren, Cristina, 1993, et al.
(author)
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Human milk oligosaccharide supplementation in irritable bowel syndrome patients: A parallel, randomized, double-blind, placebo-controlled study
- 2020
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In: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 32:10
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Journal article (peer-reviewed)abstract
- Objectives Human milk oligosaccharides safely and beneficially impact bifidobacteria abundance in healthy adults, while their effects in patients with irritable bowel syndrome (IBS) are unknown. Hence, we aimed to determine the dose of 4:1 mix of 2'-O-fucosyllactose and Lacto-N-neotetraose (2'FL/LNnT) that increases fecal bifidobacteria abundance without aggravating overall gastrointestinal symptoms in IBS patients in a randomized, double-blind, controlled study. Additionally, the impact of 2'FL/LNnT on the fecal bacterial profile was assessed. Methods Irritable bowel syndrome patients diagnosed according to the Rome IV criteria received placebo (glucose), or 5 g or 10 g 2'FL/LNnT for 4 weeks followed by a four-week follow-up period. Gastrointestinal Symptom Rating Scale-IBS was used to assess gastrointestinal symptom severity; fecal microbiota composition was evaluated by GA-map (TM) Dysbiosis Test. Results Of the included 60 patients, two (one placebo and one 10 g) discontinued prematurely. Fecal bifidobacteria abundance was increased at week 4, but not at week 8, in the 10 g group compared to the other groups. Severity of overall or individual gastrointestinal symptoms did not differ between the groups at week 4 or 8, and no symptom deterioration was seen in any of the groups. The 10 g dose influenced overall fecal microbiota composition, and responders-defined as bifidobacteria increase >= 50%-could be discriminated from non-responders based on fecal microbiota modulation. Conclusions The 10 g dose of 2'FL/LNnT induced an increase in the beneficialBifidobacteriumspp. without aggravating gastrointestinal symptoms in patients with IBS. This approach may be worthwhile to modulate gut microbiota of IBS patients toward a healthier profile.
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| 14. |
- Iribarren, Cristina, 1993, et al.
(author)
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The Effects of Human Milk Oligosaccharides on Gut Microbiota, Metabolite Profiles and Host Mucosal Response in Patients with Irritable Bowel Syndrome
- 2021
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In: Nutrients. - : MDPI AG. - 2072-6643. ; 13:11
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Journal article (peer-reviewed)abstract
- Background: Human milk oligosaccharide supplementation safely modulates fecal bifidobacteria abundance and holds the potential to manage symptoms in irritable bowel syndrome (IBS). Here, we aimed to determine the role of a 4:1 mix of 2 & PRIME;-O-fucosyllactose and lacto-N-neotetraose (2 & PRIME;FL/LNnT) on the modulation of the gut microbiota composition and host mucosal response, as well as the link between the bifidobacteria abundance and metabolite modulation, in IBS patients. Methods: Biological samples were collected from IBS patients (n = 58) at baseline and week 4 post-supplementation with placebo, 5 g or 10 g doses of 2 & PRIME;FL/LNnT. The gut microbiota composition, metabolite profiles and expression of genes related to host mucosal response were determined. Results: Moderate changes in fecal, but not mucosal, microbial composition (beta-diversity) was observed during the intervention with higher dissimilarity observed within individuals receiving 10g 2 & PRIME;FL/LNnT compared to placebo. Both fecal and mucosal Bifidobacterium spp. increased after 2 & PRIME;FL/LNnT intake, with increased proportions of Bifidobacterium adolescentis and Bifidobacterium longum. Moreover, the intervention modulated the fecal and plasma metabolite profiles, but not the urine metabolite profile or the host mucosal response. Changes in the metabolite profiles were associated to changes in bifidobacteria abundance. Conclusion: Supplementation with 2 & PRIME;FL/LNnT modulated the gut microbiota, fecal and plasma metabolite profiles, but not the host mucosal response in IBS. Furthermore, the bifidogenic effect was associated with metabolite modulation. Overall, these findings support the assertion that 2 & PRIME;FL/LNnT supplementation modulate the intestinal microenvironment of patients with IBS, potentially related to health.
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| 15. |
- Leosson, K., et al.
(author)
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Comparing resonant photon tunneling via cavity modes and Tamm plasmon polariton modes in metal-coated Bragg mirrors
- 2012
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In: Optics Letters. - 0146-9592 .- 1539-4794. ; 37:19, s. 4026-4028
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Journal article (peer-reviewed)abstract
- Resonant photon tunneling was investigated experimentally in multilayer structures containing a high-contrast (TiO2/SiO2) Bragg mirror capped with a semitransparent gold film. Transmission via a fundamental cavity resonance was compared with transmission via the Tamm plasmon polariton resonance that appears at the interface between a metal film and a one-dimensional photonic bandgap structure. The Tamm-plasmon-mediated transmission exhibits a smaller dependence on the angle and polarization of the incident light for similar values of peak transmission, resonance wavelength, and finesse. Implications for transparent electrical contacts based on resonant tunneling structures are discussed.
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| 16. |
- Moraes Holst, Luiza, et al.
(author)
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Downregulated Mucosal Autophagy, Alpha Kinase-1 and IL-17 Signaling Pathways in Active and Quiescent Ulcerative Colitis
- 2022
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In: Clinical and Experimental Gastroenterology. - : DOVE MEDICAL PRESS LTD. - 1178-7023. ; 15, s. 129-144
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Journal article (peer-reviewed)abstract
- Background: Improved mucosal immune profiling in active and quiescent colonic inflammatory bowel disease (IBD) is needed to develop therapeutic options for treating and preventing flares. This study therefore aimed to provide a comprehensive mucosal characterization with emphasis on immunological host response of patients with active ulcerative colitis (UC active), UC during remission (UC remission) and active colonic Crohn's disease (CD active).Methods: Colonic biopsies from 47 study subjects were collected for gene expression and pathway analyses using the NanoString host-response panel, including 776 genes and 56 immune-related pathways.Results: The majority of mucosal gene expression and signaling pathway scores were increased in active IBD (n=27) compared to healthy subjects (n=10). However, both active IBD and UC remission (n=10) demonstrated decreased gene expression and signaling pathway scores related to autophagy, alpha kinase-1 and IL-17 signaling pathways compared to healthy subjects. Further, UC remission was characterized by decreased scores of several signaling pathways linked to homeostasis along with increased mononuclear cell migration pathway score as compared to healthy subjects. No major differences in the colonic mucosal gene expression between CD active (n=7) and UC (n=20) active were observed.Conclusion: This study indicates that autophagy, alpha kinase-1 and IL-17 signaling pathways are persistently downregulated in UC irrespective of disease activity. Further, UC patients in remission present a unique mucosal environment, potentially preventing patients from reaching and sustaining true homeostasis. These findings may enable better comprehension of the remitting and relapsing pattern of colonic IBD and guide future treatment and prevention of flares.
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| 17. |
- Ahluwalia, Bani, et al.
(author)
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A Distinct Faecal Microbiota and Metabolite Profile Linked to Bowel Habits in Patients with Irritable Bowel Syndrome
- 2021
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In: Cells. - : MDPI AG. - 2073-4409. ; 10:6
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Journal article (peer-reviewed)abstract
- Patients with irritable bowel syndrome (IBS) are suggested to have an altered intestinal microenvironment. We therefore aimed to determine the intestinal microenvironment profile, based on faecal microbiota and metabolites, and the potential link to symptoms in IBS patients. The faecal microbiota was evaluated by the GA-map(TM) dysbiosis test, and tandem mass spectrometry (GC-MS/MS) was used for faecal metabolomic profiling in patients with IBS and healthy subjects. Symptom severity was assessed using the IBS Severity Scoring System and anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. A principal component analysis based on faecal microbiota (n = 54) and metabolites (n = 155) showed a clear separation between IBS patients (n = 40) and healthy subjects (n = 18). Metabolites were the main driver of this separation. Additionally, the intestinal microenvironment profile differed between IBS patients with constipation (n = 15) and diarrhoea (n = 11), while no clustering was detected in subgroups of patients according to symptom severity or anxiety. Furthermore, ingenuity pathway analysis predicted amino acid metabolism and several cellular and molecular functions to be altered in IBS patients. Patients with IBS have a distinct faecal microbiota and metabolite profile linked to bowel habits. Intestinal microenvironment profiling, based on faecal microbiota and metabolites, may be considered as a future non-invasive diagnostic tool, alongside providing valuable insights into the pathophysiology of IBS.
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| 18. |
- Ahluwalia, Bani, et al.
(author)
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Aloe barbadensis Mill. extract improves symptoms in IBS patients with diarrhoea: post hoc analysis of two randomized double-blind controlled studies
- 2021
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In: Therapeutic Advances in Gastroenterology. - : SAGE Publications. - 1756-283X .- 1756-2848. ; 14
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Journal article (peer-reviewed)abstract
- Background: Aloe barbadensis Mill. (Aloe) extract was found to be well-tolerated, safe and showed beneficial effects in subsets of irritable bowel syndrome (IBS) patients in two randomized, double-blind, controlled studies. However, the individual studies were underpowered to perform subgroup analyses. We therefore determined the effect of Aloe extract in IBS subgroups in a post hoc analysis combining the results from the two studies. Methods: Data from the two controlled studies comparing Aloe and control treatment taken orally for 4 weeks, were pooled. Both studies included IBS patients fulfilling the ROME III criteria and IBS Symptom Severity Score (IBS-SSS) was assessed. We analysed the effect of Aloe extract on IBS symptom severity and the proportion of responders (IBS-SSS reduction > 50) in IBS subgroups. Results: In total, 213 IBS patients were included in the post hoc subgroup analyses. A reduction in overall symptom severity, primarily driven by effect on pain severity and frequency, comparing baseline versus end of treatment, was recorded in IBS patients with diarrhoea (IBS-D) receiving Aloe (n = 38, p < 0.001) but not control treatment (n = 33, p = 0.33), with difference between the treatment groups (p = 0.01). Moreover, the frequency of responders was higher in IBS-D patients receiving Aloe (n = 22, 58%) compared to control treatment (n = 10, 30%) (p = 0.02). The effect of Aloe extract treatment on IBS symptom severity was not superior to control treatment in the other IBS subtypes. Conclusion: Aloe extract improves symptom severity in IBS-D patients and can be regarded as a safe and effective treatment option for this patient group.
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| 19. |
- Ahluwalia, Bani, et al.
(author)
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Randomized clinical trial: Effects of Aloe barbadensis Mill. extract on symptoms, fecal microbiota and fecal metabolite profiles in patients with irritable bowel syndrome
- 2020
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In: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 32:8
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Journal article (peer-reviewed)abstract
- Background Aloe barbadensis Mill.(Aloe) with potential prebiotic effects has been suggested to reduce symptoms in patients with irritable bowel syndrome (IBS). We therefore aimed to determine the effects of an Aloe extract on symptoms of IBS, and evaluate whether effects may be mediated by fecal microbiota and metabolites in a randomized, double-blind, controlled trial. Methods Patient with IBS diagnosed according to the ROME III criteria (all subtypes), received Aloe or control treatment (inulin) for 4 weeks. IBS Symptom Severity Score (IBS-SSS) was assessed, and fecal samples collected before and at end of treatment. Fecal microbiota composition and metabolomic profile were determined. Key results In total, 160 IBS patients completed the study. The overall severity of IBS symptoms was reduced in both Aloe and control treatment groups (P < .001, both groups, comparing baseline vs end of treatment), without difference between groups (P = .62). The frequency of responders (IBS-SSS reduction >= 50) did not differ between Aloe treatment (n = 33, 39%) and control (n = 34, 45%) (P = .49). However, fecal microbiota and metabolite profiles differed between Aloe, but not control treatment responders and non-responders both before and after treatment. Conclusion In a mixed group of IBS patients, Aloe was not superior to control treatment, although it showed potential to reduce IBS symptom severity in subsets of IBS patients which could be predicted by fecal microbiota and metabolite profiles. ClinicalTrials.gov no: NCT01400048.
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| 20. |
- Algera, Joost, 1993, et al.
(author)
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Randomised controlled trial: effects of gluten-free diet on symptoms and the gut microenvironment in irritable bowel syndrome
- 2022
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In: Alimentary Pharmacology and Therapeutics. - : Wiley. - 0269-2813 .- 1365-2036. ; 56:9, s. 1318-1327
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Journal article (peer-reviewed)abstract
- Background A gluten-free diet reduces symptoms in some patients with irritable bowel syndrome (IBS) through unclear mechanisms. Aims To assess the effects of gluten-free versus gluten-containing diet on symptoms and the gut microenvironment, and to identify predictors of response to the gluten-free diet in IBS. Methods Twenty patients with IBS and 18 healthy controls (HC) followed a gluten-free diet during two 14-day intervention periods where they sprinkled either gluten (14 g/day) or rice flour powder over their meals. Primary outcomes included effects of the interventions on IBS symptoms (IBS-SSS) and bowel habits. Secondary outcomes included effects of gluten-free diet on faecal microbiota and metabolite profile. Results IBS symptoms improved during the gluten-free (p = 0.02), but not the gluten-containing period, with no difference between the interventions. IBS patients reported fewer loose stools during the gluten-free intervention (p = 0.01). Patients with IBS and HC presented distinct metabolite profiles based on the effects of the gluten-free diet (p < 0.001). True responders (reduced IBS-SSS by >= 50 solely after gluten-free period) and non-responders were discriminated based on the effects of the gluten-free diet on the microbiota (p < 0.01) and metabolite profiles (p < 0.001). The response to the gluten-free diet could be predicted by the metabolite profile before the intervention (p < 0.001). Conclusions A gluten-free diet may influence symptoms in a subset of patients with IBS, with a particular effect on bowel habits. A gluten-free diet seems to impact the gut microenvironment. Responsiveness to the gluten-free diet may be predicted by the metabolite profile. : NCT03869359.
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| 21. |
- Bennet, Sean, et al.
(author)
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Altered intestinal antibacterial gene expression response profile in irritable bowel syndrome is linked to bacterial composition and immune activation
- 2018
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In: Neurogastroenterology and Motility. - : Wiley. - 1350-1925. ; 30:12
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Journal article (peer-reviewed)abstract
- Background Immune activity and gut microbiota may impact the pathophysiology of irritable bowel syndrome (IBS). We aimed to determine whether antibacterial gene expression of immune activity-defined IBS patients differed compared to healthy subjects (HS) and ulcerative colitis (UC) patients and whether antibacterial profiles reflected gut microbiota composition and IBS symptoms. Methods Key Results Expression of 84 antibacterial genes in biopsies from HS, IBS patients (clustered according to immune activity (systemic and intestinal cytokines): immunonormal or immunoactive), and UC patients was assessed by Human Antibacterial Response RT2 Profiler PCR Array. In IBS patients, 16S rRNA gene sequencing of fecal and mucosal bacteria was performed and symptom pattern and severity were assessed. Intestinal antibacterial gene expression profiles differed between IBS patients (n = 31) and HS (n = 16), but did not differ between IBS subgroups based on bowel habit predominance or symptom severity. Based on previously identified IBS clusters, IBS patients with normal (n = 15) and enhanced immune activity (n = 16) had clearly separate antibacterial gene expression profiles from active UC patients (n = 12) and differed compared to each other and to HS. The differences in antibacterial gene expression profiles between immunonormal and immunoactive IBS patients were also reflected in distinct fecal and mucosal microbiota composition profiles, but not in symptom pattern or severity. Conclusions & Inferences This study demonstrates an altered antibacterial gene expression profile in IBS patients compared to HS and UC patients. While not linked to symptoms, immune activity-defined IBS clusters showed different intestinal antibacterial gene expression and distinct fecal and mucosal bacterial profiles.
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| 22. |
- Cesarini, David, et al.
(author)
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Genotype-covariate interaction effects and the heritability of adult body mass index
- 2017
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In: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 49:8, s. 1174-1181
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Journal article (peer-reviewed)abstract
- Obesity is a worldwide epidemic, with major health and economic costs. Here we estimate heritability for body mass index (BMI) in 172,000 sibling pairs and 150,832 unrelated individuals and explore the contribution of genotype-covariate interaction effects at common SNP loci. We find evidence for genotype-age interaction (likelihood ratio test (LRT) = 73.58, degrees of freedom (df) = 1, P = 4.83 × 10-18), which contributed 8.1% (1.4% s.e.) to BMI variation. Across eight self-reported lifestyle factors, including diet and exercise, we find genotype-environment interaction only for smoking behavior (LRT = 19.70, P = 5.03 × 10-5 and LRT = 30.80, P = 1.42 × 10-8), which contributed 4.0% (0.8% s.e.) to BMI variation. Bayesian association analysis suggests that BMI is highly polygenic, with 75% of the SNP heritability attributable to loci that each explain <0.01% of the phenotypic variance. Our findings imply that substantially larger sample sizes across ages and lifestyles are required to understand the full genetic architecture of BMI.
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| 23. |
- Cesarini, David, et al.
(author)
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The behavioral genetics of behavioral anomalies
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Other publication (other academic/artistic)abstract
- A number of recent papers have examined the environmental and genetic sources of individual differences in economic and financial decision making. Here we contribute to this burgeoning literature by extending it to a number of key behavioral anomalies that are thought to be of importance for consumption, savings, and portfolio selection decisions. Using survey-based evidence from more than 11,000 Swedish twins, we demonstrate that a number of anomalies such as, for instance, the conjunction fallacy, default bias, and loss aversion are moderately heritable. In contrast, our estimates imply that variation in common environment explains only a small share of individual differences. We also report suggestive evidence in favor of a shared genetic architecture between cognitive reflection and a subset of the studied anomalies. These results offer some support for the proposition that the heritable variation in behavioral anomalies is partly mediated by genetic variance in cognitive ability. Taken together with previous findings, our results underline the importance of genetic differences as a source of heterogeneity in economic and financial decision making.
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| 24. |
- Cöster, Maria C., et al.
(author)
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Validation of Two Foot and Ankle Scores – SEFAS (Self-reported Foot And Ankle Score) and AOFAS
- 2014
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Conference paper (peer-reviewed)abstract
- INTRODUCTION: The American Orthopedic Foot and Ankle Score (AOFAS) is for many foot and ankle surgeons the gold standard for evaluation of foot and ankle disorders. The score comprises of four different questionnaires depending on which region is evaluated, and covers three different constructs; pain, function and range of motion and alignment. AOFAS however, requires clinical examination, and can therefore not be used as a patient-reported outcome measure (PROM). In contrast, the Self-Reported Foot and Ankle Score (SEFAS) is a PROM that recently has been validated with good results in patients with foot and ankle disorders. The SEFAS contains 12 questions and covers different constructs such as pain, function and limitation of function. The aim of this study was to compare the SEFAS and AOFAS in patients with disorders in the great toe, the hindfoot and ankle, taking psychometric properties for scores into account.PATIENTS AND METHODS: The SEFAS and AOFAS scores were completed by 73 patients with disorders in the great toe and by 89 patients with disorders in the hindfoot or ankle. The time it took to complete the questionnaire was measured in 17 patients. In all patients, construct validity for SEFAS versus AOFAS was estimated by Spearman´s correlation coefficient and we also evaluated if there were any floor and ceiling effects. Test-retest reliability (intra-observer reliability) was measured for SEFAS in 68 patients and for AOFAS in 33 patients with intra-class correlation coefficient (ICC). Inter-observer reliability was calculated in nine patients for AOFAS using ICC. Responsiveness, i.e. the ability of a score to detect changes after a surgical intervention, was estimated by effect size (ES) and standardized response mean (SRM) in 120 patients for SEFAS and in 112 patients for AOFAS.RESULTS: The SEFAS was completed more than three times faster than AOFAS (165 seconds versus 515 seconds). SEFAS had good convergent validity (strong correlation) with AOFAS with a Spearman´s correlation coefficient of 0.64 in patients with great toe disorders and 0.65 in patients with hind foot/ankle disorders. There were no floor or ceiling effects in either of the scores. ICC was in patients with great toe disorders 0.94 (95% CI: 0.87-0.97) for SEFAS and 0.77 (95% CI: 0.39-0.93) for AOFAS, and in patients with hindfoot/ankle disorders 0.92 (95%CI: 0.85-0.95) for SEFAS and 0.52 (95%CI: 0.13-0.77) for AOFAS. ES was 1.4 for SEFAS and 1.8 for AOFAS and SRM 1.4 for SEFAS and 1.6 for AOFAS in patients with great toe disorders. ES was 1.2 for SEFAS and 1.1 for AOFAS and SRM 1.1 for SEFAS and 0.9 for AOFAS in patients with hindfoot/ ankle disorders. Inter-observer reliability was 0.43 (95% CI: 0.0-0.84) for AOFAS.DISCUSSION AND CONCLUSION: In this study there was a strong correlation between SEFAS and AOFAS indicating good construct validity for SEFAS. Both scores had good responsiveness and no floor or ceiling effects. The test-retest reliability was better for SEFAS than AOFAS while the inter-observer reliability was low for AOFAS. Finally, SEFAS was completed three times faster than AOFAS. In conclusion we consider SEFAS at least equal to AOFAS for evaluation of patients with foot and ankle disorders, and as no clinical examination is demanded in SEFAS, it is an ideal instrument for evaluation of clinical patient outcome in national registers.
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| 25. |
- Dahlén, Rahil, et al.
(author)
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Infliximab Inhibits Activation and Effector Functions of Peripheral Blood T Cells in vitro from Patients with Clinically Active Ulcerative Colitis
- 2013
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In: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475. ; 78:3, s. 275-284
-
Journal article (peer-reviewed)abstract
- Many patients with inflammatory bowel disease (IBD) are undergoing therapy with infliximab, an antibody specific for TNF. However, the exact mechanisms of action of infliximab are not completely understood. The aim of this study was to determine the in vitro effects of infliximab on blood T cells derived from anti-TNF therapy-naive ulcerative colitis (UC) patients with clinically active disease. Peripheral blood mononuclear cells were stimulated polyclonally or by antigen in the presence or absence of infliximab. The T cell phenotype was investigated by flow cytometry, cytokine secretion was determined by ELISA, and cell proliferation was determined by thymidine assay or CFSE dye. Presence of infliximab resulted in reduced expression of CD25 in CD4(+) and CD8(+) T cell populations and inhibited secretion of IFN-, IL-13, IL-17A, TNF as well as granzyme A. Infliximab also suppressed CD4(+) and CD8(+) T cell proliferation. These effects of infliximab were recorded both in T cells activated by polyclonal and antigen-specific stimulation. The effects of infliximab on T cell apoptosis and induction of FOXP3(+)CD4(+) T regulatory cells were ambiguous and depended on the originating cellular source and/or the stimulation mode and strength. In conclusion, infliximab is able to reduce T cell activation as measured by CD25, proliferation and cytokine secretion in vitro from UC patients with clinically active disease. These data suggest that suppression of T cell activity may be important for infliximab-mediated disease remission in patients with UC.
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| 26. |
- Dawes, Christopher T., et al.
(author)
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Linking Genes and Political Orientations: Testing the Cognitive Ability as Mediator Hypothesis
- 2015
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In: Political Psychology. - : Wiley: 24 months. - 1467-9221 .- 0162-895X. ; 36:6, s. 649-665
-
Journal article (peer-reviewed)abstract
- Recent research has demonstrated that genetic differences explain a sizeable fraction of the variance in political orientations, but little is known about the pathways through which genes might affect political preferences. In this article, we use a uniquely assembled dataset of almost 1,000 Swedish male twin pairs containing detailed information on cognitive ability and political attitudes in order to further examine the genetic and environmental causes of political orientations. Our study makes three distinct contributions to our understanding of the etiology of political orientations: (1) we report heritability estimates across different dimensions of political ideology; (2) we show that cognitive ability and political orientations are related; and (3) we provide evidence consistent with the hypothesis that cognitive ability mediates part of the genetic influence on political orientations. These findings provide important clues about the nature of the complex pathways from molecular genetic variation to political orientations.
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| 27. |
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| 28. |
- Dumanski, Jan P., et al.
(author)
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Smoking is associated with mosaic loss of chromosome Y
- 2015
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 347:6217, s. 81-83
-
Journal article (peer-reviewed)abstract
- Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared to females. This observation, together with the fact that males have a higher incidence of and mortality from most non-sex-specific cancers, remains unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of nonhematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts [TwinGene: odds ratio (OR) = 4.3, 95% CI = 2.8-6.7; ULSAM: OR = 2.4, 95% CI = 1.6-3.6; and PIVUS: OR = 3.5, 95% CI = 1.4-8.4] encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.
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| 29. |
- Helgadottir, Anna, et al.
(author)
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Apolipoprotein(a) Genetic Sequence Variants Associated With Systemic Atherosclerosis and Coronary Atherosclerotic Burden But Not With Venous Thromboembolism
- 2012
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 60:8, s. 722-729
-
Journal article (peer-reviewed)abstract
- Objectives The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. Background It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. Methods The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (ne = 4,572); venous thromboembolism (ne = 4,607); intracranial aneurysm (ne = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). Results LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 X 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 x 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 x 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 x 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 x 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). Conclusions LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes. (J Am Coll Cardiol 2012; 60: 722-9) (C) 2012 by the American College of Cardiology Foundation
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| 30. |
- Iribarren, Cristina, 1993, et al.
(author)
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Fecal luminal factors from patients with irritable bowel syndrome induce distinct gene expression of colonoids
- 2022
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In: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 34:10
-
Journal article (peer-reviewed)abstract
- Background: Alteration of the host-microbiota cross talk at the intestinal barrier may participate in the pathophysiology of irritable bowel syndrome (IBS). Therefore, we aimed to determine effects of fecal luminal factors from IBS patients on the colonic epithelium using colonoids. Methods: Colon-derived organoid monolayers, colonoids, generated from a healthy subject, underwent stimulation with fecal supernatants from healthy subjects and IBS patients with predominant diarrhea, phosphate-buffered saline (PBS), or lipopolysaccharide (LPS). Cytokines in cell cultures and fecal LPS were measured by ELISA and mRNA gene expression of monolayers was analyzed using Qiagen RT2 Profiler PCR Arrays. The fecal microbiota profile was determined by the GA-map (TM) dysbiosis test and the fecal metabolite profile was analyzed by untargeted liquid chromatography/mass spectrometry. Key results: Colonoid monolayers stimulated with fecal supernatants from healthy subjects (n = 7), PBS (n = 4) or LPS (n = 3) presented distinct gene expression profiles, with some overlap ((RY)-Y-2 = 0.70, Q(2) = 0.43). Addition of fecal supernatants from healthy subjects and IBS patients (n = 9) gave rise to different gene expression profiles of the colonoid monolayers ((RY)-Y-2 = 0.79, Q(2) = 0.64). Genes (n = 22) related to immune response (CD1D, TLR5) and barrier integrity (CLDN15, DSC2) contributed to the separation. Levels of proinflammatory cytokines in colonoid monolayer cultures were comparable when stimulated with fecal supernatants from either donor types. Fecal microbiota and metabolite profiles, but not LPS content, differed between the study groups. Conclusions: Fecal luminal factors from IBS patients induce a distinct colonic epithelial gene expression, potentially reflecting the disease pathophysiology. The culture of colonoids from healthy subjects with fecal supernatants from IBS patients may facilitate the exploration of IBS related intestinal micro-environmental and barrier interactions.
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| 31. |
- Iribarren, Cristina, 1993, et al.
(author)
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Temporal stability of fecal metabolomic profiles in irritable bowel syndrome
- 2024
-
In: Neurogastroenterology and Motility. - 1350-1925 .- 1365-2982. ; 36:3
-
Journal article (peer-reviewed)abstract
- Background: The potential of the fecal metabolome to serve as a biomarker for irritable bowel syndrome (IBS) depends on its stability over time. Therefore, this study aimed to determine the temporal dynamics of the fecal metabolome, and the potential relationship with stool consistency, in patients with IBS and healthy subjects. Methods: Fecal samples were collected in two cohorts comprising patients with IBS and healthy subjects. For Cohort A, fecal samples collected during 5 consecutive days were analyzed by gas chromatography-tandem mass spectrometry (GC–MS/MS). For Cohort B, liquid chromatography-MS (LC–MS) was used to analyze fecal samples collected at week 0 (healthy and IBS) and at week 4 (patients only). Stool consistency was determined by the Bristol Stool Form scale. Key Results: Fecal samples were collected from Cohort A (seven healthy subjects and eight IBS patients), and Cohort B (seven healthy subjects and 11 IBS patients). The fecal metabolome of IBS patients was stable short-term (Cohort A, 5 days and within the same day) and long-term (Cohort B, 4 weeks). A similar trend was observed over 5 days in the healthy subjects of Cohort A. The metabolome dissimilarity was larger between than within participants over time in both healthy subjects and IBS patients. Further analyses showed that patients had greater range of stool forms (types) than healthy subjects, with no apparent influence on metabolomic dynamics. Conclusion & Inferences: The fecal metabolome is stable over time within IBS patients as well as healthy subjects. This supports the concept of a stable fecal metabolome in IBS despite fluctuations in stool consistency, and the use of single timepoint sampling to further explore how the fecal metabolome is related to IBS pathogenesis.
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| 32. |
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| 33. |
- Johannesson, Magnus, et al.
(author)
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Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence
- 2017
-
In: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718.
-
Journal article (peer-reviewed)abstract
- Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P −8) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P −6), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10−6). Despite the well-known difference in twin-based heritability2 for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg = 0.89, LD score regression P = 5.4 × 10−29). These findings provide new insight into the genetic architecture of intelligence.
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| 34. |
- Johannesson, Magnus, et al.
(author)
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Meta-GWAS Accuracy and Power (MetaGAP) Calculator Shows that Hiding Heritability Is Partially Due to Imperfect Genetic Correlations across Studies
- 2017
-
In: PLoS Genetics. - : Public Library of Science. - 1553-7404 .- 1553-7390. ; 13:1, s. 1-23
-
Journal article (peer-reviewed)abstract
- Large-scale genome-wide association results are typically obtained from a fixed-effects meta-analysis of GWAS summary statistics from multiple studies spanning different regions and/or time periods. This approach averages the estimated effects of genetic variants across studies. In case genetic effects are heterogeneous across studies, the statistical power of a GWAS and the predictive accuracy of polygenic scores are attenuated, contributing to the so-called ‘missing heritability’. Here, we describe the online Meta-GWAS Accuracy and Power (MetaGAP) calculator (available at www.devlaming.eu) which quantifies this attenuation based on a novel multi-study framework. By means of simulation studies, we show that under a wide range of genetic architectures, the statistical power and predictive accuracy provided by this calculator are accurate. We compare the predictions from the MetaGAP calculator with actual results obtained in the GWAS literature. Specifically, we use genomic-relatedness-matrix restricted maximum likelihood to estimate the SNP heritability and cross-study genetic correlation of height, BMI, years of education, and self-rated health in three large samples. These estimates are used as input parameters for the MetaGAP calculator. Results from the calculator suggest that cross-study heterogeneity has led to attenuation of statistical power and predictive accuracy in recent large-scale GWAS efforts on these traits (e.g., for years of education, we estimate a relative loss of 51–62% in the number of genome-wide significant loci and a relative loss in polygenic score R2of 36–38%). Hence, cross-study heterogeneity contributes to the missing heritability.
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| 35. |
- Johannesson, Magnus, et al.
(author)
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Polygenic risk scores for schizophrenia and bipolar disorder predict creativity
- 2015
-
In: Nature Neuroscience. - : Nature Publishing Group. - 1097-6256 .- 1546-1726. ; 18:7, s. 953-
-
Journal article (peer-reviewed)abstract
- We tested whether polygenic risk scores for schizophrenia and bipolar disorder would predict creativity. Higher scores were associated with artistic society membership or creative profession in both Icelandic (P = 5.2 x 10(-6) and 3.8 x 10(-6) for schizophrenia and bipolar disorder scores, respectively) and replication cohorts (P = 0.0021 and 0.00086). This could not be accounted for by increased relatedness between creative individuals and those with psychoses, indicating that creativity and psychosis share genetic roots.
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| 36. |
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| 37. |
- Karlsson, Magnus K., et al.
(author)
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Geschlechtsspezifische unterschiede von leistenschmerzen im fußball
- 2014
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In: Deutsche Zeitschrift fur Sportmedizin. - : Deutsche Zeitschrift Fur Sportmedizin/German Journal of Sports Medicine. - 0344-5925. ; 65:2, s. 38-42
-
Journal article (peer-reviewed)abstract
- Problem: Groin pain is common in soccer players but the prevalence has only been examined in uncontrolled studies. Methods: 479 male soccer players aged 25 years (17 - 43) (mean with range), 144 female soccer players aged 23 years (16 - 47), 74 men with no history of soccer training aged 26 years (16 - 42) and 94 women with no history of soccer training aged 23 years (range 15 - 43) answered a mailed questionnaire that included specific questions on groin pain and training history. Data are presented as proportions (%) or as mean with 95 % confidence intervals (95% CI). Results: 55% male soccer players and 26% male controls had experienced groin pain, resulting in an odds ratio (OR) of 3.7 (95% CI 2.1, 6.6). The corresponding proportions were in female soccer players 28 % and in female controls 13 % giving an OR of 2.8 (95% CI 1.4, 5.8). When comparing the genders the higher proportion of males than females that had experienced groin pain resulted in an OR of 2.9 (95% CI 1.9, 4.5) for male versus female soccer players and an OR of 2.6 (95% CI 1.1, 5.3) for male versus female controls. Discussion: Playing soccer and being of the male gender are factors associated with a higher risk of experiencing groin pain.
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| 38. |
- Karlsson, Magnus K., et al.
(author)
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Prevention of falls in old people-a review
- 2013
-
In: Reviews in Clinical Gerontology. - 0959-2598. ; 23:3, s. 206-222
-
Research review (peer-reviewed)abstract
- Physical training, if including specific different training modalities, reduces the fall risk in healthy community-dwelling older people, as does a home hazards modification programme. Vitamin D supplementation in older individuals with low levels of vitamin D, adjustment of psychotropic medication, and structured modification of multi-pharmacy are all drug-focused programmes that reduce the number of falls. Anti-slip shoe devices during icy conditions for older people who walk outdoors and multifaceted podiatry in patients with specific foot disability reduce the fall risk. First eye cataract surgery and pacemakers in patients with cardio-inhibitory carotid sinus hypersensitivity are surgical interventions that reduce the fall risk. Multi-factorial preventive programmes that include training, both individually designed and generally prescribed, also reduce the fall frequency. With this in mind, we ought to initiate fall preventive programmes in older people, especially in high-risk groups, to reduce the number of falls and fallers in society.
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| 39. |
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| 40. |
- Klingberg, Eva, et al.
(author)
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A distinct gut microbiota composition in patients with ankylosing spondylitis is associated with increased levels of fecal calprotectin
- 2019
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In: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 21:1
-
Journal article (peer-reviewed)abstract
- Background Ankylosing spondylitis (AS) shares many characteristics with inflammatory bowel disease (IBD). Intestinal microbiota most likely plays an important role in the development of IBDs and may also be involved in the pathogenesis of AS. We aimed to define and compare the fecal microbiota composition in patients with AS, ulcerative colitis (UC), and healthy controls (HC) and to determine relationships between fecal microbiota, fecal calprotectin, and disease-related variables in AS. Methods Fecal microbiota composition was assessed with GA-map (TM) Dysbiosis Test (Genetic Analysis, Oslo, Norway), which also reports the degree of deviation of the microbiota composition compared with a healthy control population, a Dysbiosis Index (DI) score 1-5. The AS patients were assessed with questionnaires, back mobility tests, fecal calprotectin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Results Totally, 150 patients with AS (55% men, median age 55.5 years, median BASDAI 3.2), 18 patients with UC (56% men, median age 30.5 years), and 17 HC (65% men, median age 22 years) were included. Principal component analysis showed highly separate clustering of fecal microbiota from the patients with AS, UC, and HC. Compared with HC, fecal microbiota in AS was characterized by a higher abundance of Proteobacteria, Enterobacteriaceae, Bacilli, Streptococcus species, and Actinobacteria, but lower abundance of Bacteroides and Lachnospiraceae. Further, fecal microbiota composition differed between patients with normal (<= 50 mg/kg, n = 57) and increased (>= 200 mg/kg, n = 36) fecal calprotectin. Patients with increased fecal calprotectin had lower abundance of bacteria with anti-inflammatory properties such as Faecalibacterium prausnitzii and Clostridium and higher abundance of the genus Streptococcus. No association was found between the fecal microbiota composition and HLAB27 status, disease activity, function, or medication. Dysbiosis (defined as DI >= 3) was found in 87% of AS patients. Conclusions Patients with AS have a distinct fecal microbiota signature, which is linked to fecal calprotectin levels, a marker of intestinal inflammation, but not to other clinical parameters. These findings suggest a local interplay between intestinal microbiota and gut inflammation in AS.
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| 41. |
- Loewen, Peter John, et al.
(author)
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The heritability of moral standards for everyday dishonesty
- 2013
-
In: Journal of Economic Behavior and Organization. - : Elsevier. - 0167-2681. ; 93, s. 363-366
-
Journal article (peer-reviewed)abstract
- Previous research on the acceptability of dishonest actions has focused on the role of social norms and internal reward mechanisms. Using a sample of over 2000 Swedish adult twins, this manuscript examines whether there exists another source that is driving differences in perceptions of the acceptability of dishonest actions: genetic variation. We find that much of the variation in perceptions of the acceptability of dishonest actions is attributable to genetic variation between individuals.
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| 42. |
- Magnusson, Carl, 1976, et al.
(author)
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Suboptimal prehospital decision- making for referral to alternative levels of care - frequency, measurement, acceptance rate and room for improvement
- 2022
-
In: Bmc Emergency Medicine. - : Springer Science and Business Media LLC. - 1471-227X. ; 22:1
-
Journal article (peer-reviewed)abstract
- Background The emergency medical services (EMS) have undergone dramatic changes during the past few decades. Increased utilisation, changes in care-seeking behaviour and competence among EMS clinicians have given rise to a shift in EMS strategies in many countries. From transport to the emergency department to at the scene deciding on the most appropriate level of care and mode of transport. Among the non-conveyed patients some may suffer from "time-sensitive conditions" delaying diagnosis and treatment. Thus, four questions arise: How often are time-sensitive cases referred to primary care or self-care advice? How can we measure and define the level of inappropriate clinical decision-making? What is acceptable? How to increase patient safety? Main text To what extent time-sensitive cases are non-conveyed varies. About 5-25% of referred patients visit the emergency department within 72 hours, 5% are hospitalised, 1-3% are reported to have a time-sensitive condition and seven-day mortality rates range from 0.3 to 6%. The level of inappropriate clinical decision-making can be measured using surrogate measures such as emergency department attendances, hospitalisation and short-term mortality. These measures do not reveal time-sensitive conditions. Defining a scoring system may be one alternative, where misclassifications of time-sensitive cases are rated based on how severely they affected patient outcome. In terms of what is acceptable there is no general agreement. Although a zero-vision approach does not seem to be realistic unless under-triage is split into different levels of severity with zero-vision in the most severe categories. There are several ways to reduce the risk of misclassifications. Implementation of support systems for decision-making using machine learning to improve the initial assessment is one approach. Using a trigger tool to identify adverse events is another. Conclusion A substantial number of patients are non-conveyed, including a small portion with time-sensitive conditions. This poses a threat to patient safety. No general agreement on how to define and measure the extent of such EMS referrals and no agreement of what is acceptable exists, but we conclude an overall zero-vision is not realistic. Developing specific tools supporting decision making regarding EMS referral may be one way to reduce misclassification rates.
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| 43. |
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| 44. |
- Magnusson Hanson, Linda, et al.
(author)
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Treatment with antidepressants in the Swedish population in relation to major workplace downsizing
- 2014
-
In: 17th EPA Section Meeting 2014. ; , s. 75-75
-
Conference paper (peer-reviewed)abstract
- Background/Objectives: Previous research has indicated that downsizing may be a risk factor for morbidity and mortality both among those who are made redundant and those remaining in the workplace. However, there are contradictory results and little evidence on clinically relevant mental health effects. Our objective was to investigate change in antidepressants treatment across 5 years in relation to workplace downsizing.Methods: This study is based on all individuals in Sweden 22-54 years of age in 2006, registered as living in Sweden Dec 31 2004 to Dec 31 2010, gainfully employed and with a stable labour market position in 2004-2006. Organisational changes were assessed from national statistics on workplaces and purchases of prescribed psychotropic drugs from the Prescribed Drug Register. People with their primary employment at an establishment with ≥ 18 % personnel reduction were considered exposed to major downsizing between the end of 2006 to the end of 2007, 2007-2008 or 2008- 2009. We applied a repeated-measures regression analysis by the generalised estimating equations (GEE) method, calculating yearly prevalence of any antidepressant treatment two years before, during the year of major downsizing and two years after workplace downsizing and tested for trends.Results: There was a significant increase in prevalence of antidepressant treatment during the years preceding a major downsizing, although small, for all exposed (632500 persons). In separate analyses, however, only those who remained at the same establishment at the end of the downsizing period (stayers) had a significant upward trend before and a downward trend in the years after, and this was most obvious among survivors with no long period of sickness absence or disability pension the past two year before downsizing. The prevalence ratio (PR) comparing year -1 to -2 was 1.11 with 95 % confidence interval (CI) of 1.10-1.13 and the PR comparing year 2 to 1 after was 0.98 (CI 0.96-1.00, P<0.05). Among those becoming unemployed, the prevalence of antidepressant treatment tended to increase before but then stayed virtually the same during and after downsizing. The patterns were slightly different for people with longer periods of sickness absence or disability pension before, especially for those changing jobs, but a significant decrease in prevalence was only found when analysing stayers, job changers and unemployed collectively (PR 0.83, CI 0.77-0.88).Discussion/Conclusions: This large scale study indicates that downsizing is associated with increased risk of treatment with antidepressants among those seemingly healthy before and remaining in work after major personnel reduction. Moreover, the increased prevalence for those remaining at the same workplace seems to be explained by workplace characteristics or anticipation some time before downsizing was carried out.Funding: The study was supported by the Swedish Research Council for Health, Working Life and Welfare (FORTE) [grant numbers 2009-1758, 2008-1103], partly through the Stockholm Stress Centre of excellence.
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| 45. |
- Magnusson, Maria K, 1972, et al.
(author)
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CD25 and TNF receptor II reflect early primary response to infliximab therapy in patients with ulcerative colitis
- 2013
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In: United European Gastroenterology Journal. - : Wiley. - 2050-6406 .- 2050-6414. ; 1:6, s. 467-476
-
Journal article (peer-reviewed)abstract
- Background Although infliximab treatment is an option for patients with ulcerative colitis (UC), not all patients do respond to therapy, and cellular mechanisms leading to therapy response are incompletely known. Objective The objective of this article is to determine early effects of infliximab therapy on T cells in the blood of UC patients and if effects differed in therapy responders and nonresponders. Methods: Blood samples were obtained before and two weeks post-treatment start from 34 anti-tumor necrosis factor (TNF) therapy-naïve UC patients undergoing infliximab therapy. Response to therapy was evaluated prior to the fourth treatment dose. Expression of T cell surface markers and levels of soluble receptors and cytokines in serum were determined. Results At baseline, there were no differences in cellular, biochemical or clinical parameters between therapy responders and nonresponders. Infliximab therapy reduced frequencies of CD25+ T cells and increased frequencies of annexin V+ T cells in patients responding to infliximab, but not in nonresponding patients, two weeks after therapy start. Only therapy responders had decreased serum levels of sCD25 and sTNFRII two weeks after treatment start. In contrast, clinical parameters did not reflect therapy outcome already two weeks after therapy start. Conclusion Soluble and membrane-bound T cell receptors may be early indicators of infliximab therapy response in UC, which can be of clinical importance for the decision when to continue or to stop the treatment.
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| 46. |
- Magnusson, Maria K., et al.
(author)
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The Mucosal Antibacterial Response Profile and Fecal Microbiota Composition Are Linked to the Disease Course in Patients with Newly Diagnosed Ulcerative Colitis
- 2017
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In: Inflammatory Bowel Diseases. - : Oxford University Press. - 1078-0998 .- 1536-4844. ; 23:6, s. 956-966
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Journal article (peer-reviewed)abstract
- Background: The clinical disease course of ulcerative colitis (UC) varies substantially between individuals and can currently not be reliably predicted. The gut microbiota and the host's immune defense are key players for gut homeostasis and may be linked to disease outcome. The aim of this study was to determine fecal microbiota composition and mucosal antibacterial response profile in untreated patients with newly diagnosed UC and the impact of these factors on disease course. Methods: Stool samples and intestinal biopsies were obtained from therapy-naive newly diagnosed patients with UC. Patients were defined to have mild or moderate/severe disease course assessed by disease activity during the 3 years follow-up. Fecal microbiota was analyzed by the GA-map Dysbiosis test (n = 18), and gene expression in intestinal biopsies was analyzed by RT2 Profiler polymerase chain reaction array (n = 13) and real-time polymerase chain reaction (n = 44). Results: At the time of diagnosis of UC, the fecal microbiota composition discriminated between patients with mild versus moderate/severe disease course. Also, the mucosal antibacterial gene expression response profile differed between patients with mild versus moderate/severe disease course with bactericidal/permeability-increasing protein (BPI) being most important for the discrimination. Mucosal bactericidal/permeability-increasing protein gene expression at diagnosis was higher in patients with mild versus moderate/severe disease course when confirmed in a larger patient cohort (P = 0.0004, n = 44) and was a good predictor for the number of flares during the 3 years follow-up (R-2 = 0.395, P < 0.0001). Conclusions: In patients with newly diagnosed UC, fecal microbiota composition and mucosal antibacterial response profile, especially bactericidal/permeability-increasing protein, are linked to disease course.
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| 47. |
- Magnusson, Maria K, 1972, et al.
(author)
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The Mucosal Antibacterial Response Profile and Fecal Microbiota Composition Are Linked to the Disease Course in Patients with Newly Diagnosed Ulcerative Colitis
- 2017
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In: Inflammatory Bowel Diseases. - : Oxford University Press (OUP). - 1078-0998. ; 23:6, s. 956-966
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Journal article (peer-reviewed)abstract
- Background: The clinical disease course of ulcerative colitis (UC) varies substantially between individuals and can currently not be reliably predicted. The gut microbiota and the host's immune defense are key players for gut homeostasis and may be linked to disease outcome. The aim of this study was to determine fecal microbiota composition and mucosal antibacterial response profile in untreated patients with newly diagnosed UC and the impact of these factors on disease course. Methods: Stool samples and intestinal biopsies were obtained from therapy-naive newly diagnosed patients with UC. Patients were defined to have mild or moderate/severe disease course assessed by disease activity during the 3 years follow-up. Fecal microbiota was analyzed by the GA-map Dysbiosis test (n = 18), and gene expression in intestinal biopsies was analyzed by RT2 Profiler polymerase chain reaction array (n = 13) and real-time polymerase chain reaction (n = 44). Results: At the time of diagnosis of UC, the fecal microbiota composition discriminated between patients with mild versus moderate/severe disease course. Also, the mucosal antibacterial gene expression response profile differed between patients with mild versus moderate/severe disease course with bactericidal/permeability-increasing protein (BPI) being most important for the discrimination. Mucosal bactericidal/permeability-increasing protein gene expression at diagnosis was higher in patients with mild versus moderate/severe disease course when confirmed in a larger patient cohort (P = 0.0004, n = 44) and was a good predictor for the number of flares during the 3 years follow-up (R-2 = 0.395, P < 0.0001). Conclusions: In patients with newly diagnosed UC, fecal microbiota composition and mucosal antibacterial response profile, especially bactericidal/permeability-increasing protein, are linked to disease course.
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| 48. |
- Magnusson, Patrik K. E., et al.
(author)
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The Swedish Twin Registry : establishment of a biobank and other recent developments
- 2013
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In: Twin Research and Human Genetics. - Cambridge, United Kingdom : Cambridge University Press. - 1832-4274 .- 1839-2628. ; 16:1, s. 317-329
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Journal article (peer-reviewed)abstract
- The Swedish Twin Registry (STR) today contains more than 194,000 twins and more than 75,000 pairs have zygosity determined by an intra-pair similarity algorithm, DNA, or by being of opposite sex. Of these, approximately 20,000, 25,000, and 30,000 pairs are monozygotic, same-sex dizygotic, and opposite-sex dizygotic pairs, respectively. Since its establishment in the late 1950s, the STR has been an important epidemiological resource for the study of genetic and environmental influences on a multitude of traits, behaviors, and diseases. Following large investments in the collection of biological specimens in the past 10 years we have now established a Swedish twin biobank with DNA from 45,000 twins and blood serum from 15,000 twins, which effectively has also transformed the registry into a powerful resource for molecular studies. We here describe the main projects within which the new collections of both biological samples as well as phenotypic measures have been collected. Coverage by year of birth, zygosity determination, ethnic heterogeneity, and influences of in vitro fertilization are also described.
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| 49. |
- Mavroudis, Georgios, et al.
(author)
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Mucosal and Systemic Immune Profiles Differ During Early and Late Phases of the Disease in Patients With Active Ulcerative Colitis
- 2019
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In: Journal of Crohns & Colitis. - : Oxford University Press (OUP). - 1873-9946. ; 13:11, s. 1450-1458
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Journal article (peer-reviewed)abstract
- Background and Aims: Alterations in the immunopathogenesis in ulcerative colitis [UC] during the disease course have been proposed. We therefore aimed to determine mucosal and systemic immune profiles in individual patients at the time of diagnosis [early disease] and after 10 years [late disease]. Methods: Patients with UC provided serum and mucosal biopsies during a flare in early and in late disease. Serum samples were analysed using the Olink Proseek Inflammation panel. mRNA gene expression of biopsies was analysed using the Qiagen RT2 Profiler PCR Arrays Antibacterial response and T Helper Cell Differentiation. Results: Orthogonal projections to latent structures discriminant analyses [OPLS-DA] demonstrated that the profile of 15 serum proteins discriminated in early and late disease [R2 = 0.84, Q2 = 0.65] in 15 UC patients. Eight of these proteins were differently expressed between the groups [Q <0.05]. Further, OPLS-DA of the mRNA profiles in biopsies strongly discriminated early and late disease with high predictability [R2 = 0.96, Q2 = 0.89]; 42 genes were differently expressed at the two time points [Q <0.05]. Finally, principal component analysis showed that T helper [Th] 1- and Th2-related genes were associated with early disease and late disease, respectively, and hierarchical cluster analysis was able to cluster patients with early from late disease with only minor overlap. Conclusions: Mucosal and systemic immune profiles differ between early and late disease in patients with active UC, with a transition from a Th1- to a Th2-driven disease in the intestine. Improved understanding of the variation in immunopathogenesis during the disease course in UC is important to guide individualised treatment decision making.
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| 50. |
- Moraes Holst, Luiza, et al.
(author)
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Fecal Luminal Factors from Patients with Gastrointestinal Diseases Alter Gene Expression Profiles in Caco-2 Cells and Colonoids
- 2022
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067 .- 1661-6596. ; 23:24
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Journal article (peer-reviewed)abstract
- Previous in vitro studies have shown that the intestinal luminal content, including metabolites, possibly regulates epithelial layer responses to harmful stimuli and promotes disease. Therefore, we aimed to test the hypothesis that fecal supernatants from patients with colon cancer (CC), ulcerative colitis (UC) and irritable bowel syndrome (IBS) contain distinct metabolite profiles and establish their effects on Caco-2 cells and human-derived colon organoids (colonoids). The metabolite profiles of fecal supernatants were analyzed by liquid chromatography-mass spectrometry and distinguished patients with CC (n = 6), UC (n = 6), IBS (n = 6) and healthy subjects (n = 6). Caco-2 monolayers and human apical-out colonoids underwent stimulation with fecal supernatants from different patient groups and healthy subjects. Their addition did not impair monolayer integrity, as measured by transepithelial electrical resistance; however, fecal supernatants from different patient groups and healthy subjects altered the gene expression of Caco-2 monolayers, as well as colonoid cultures. In conclusion, the stimulation of Caco-2 cells and colonoids with fecal supernatants derived from CC, UC and IBS patients altered gene expression profiles, potentially reflecting the luminal microenvironment of the fecal sample donor. This experimental approach allows for investigating the crosstalk at the gut barrier and the effects of the gut microenvironment in the pathogenesis of intestinal diseases.
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