| 1. |
- Aragam, KG, et al.
(författare)
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Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:12, s. 1803-1815
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
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| 2. |
- Aragam, KG, et al.
(författare)
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Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:12, s. 1803-1815
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
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| 3. |
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| 4. |
- Zulkifli, M, et al.
(författare)
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Yeast homologs of human MCUR1 regulate mitochondrial proline metabolism
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 4866-
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondria house evolutionarily conserved pathways of carbon and nitrogen metabolism that drive cellular energy production. Mitochondrial bioenergetics is regulated by calcium uptake through the mitochondrial calcium uniporter (MCU), a multi-protein complex whose assembly in the inner mitochondrial membrane is facilitated by the scaffold factor MCUR1. Intriguingly, many fungi that lack MCU contain MCUR1 homologs, suggesting alternate functions. Herein, we characterize Saccharomyces cerevisiae homologs Put6 and Put7 of MCUR1 as regulators of mitochondrial proline metabolism. Put6 and Put7 are tethered to the inner mitochondrial membrane in a large hetero-oligomeric complex, whose abundance is regulated by proline. Loss of this complex perturbs mitochondrial proline homeostasis and cellular redox balance. Yeast cells lacking either Put6 or Put7 exhibit a pronounced defect in proline utilization, which can be corrected by the heterologous expression of human MCUR1. Our work uncovers an unexpected role of MCUR1 homologs in mitochondrial proline metabolism.
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| 5. |
- Bergqvist, Joel, et al.
(författare)
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Non-infectious rhinitis is more strongly associated with early-rather than late-onset of COPD: data from the European Community Respiratory Health Survey (ECRHS)
- 2020
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Ingår i: European Archives of Oto-Rhino-Laryngology. - : Springer Science and Business Media LLC. - 0937-4477 .- 1434-4726. ; 277, s. 1353-1359
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Chronic obstructive pulmonary disease (COPD) is associated with several co-morbidities and non-infectious rhinitis (NIR) has emerged as a new possible co-morbidity. The primary aim of this study is to confirm a previously reported association between NIR and COPD in a multicentre population over time. The secondary aim is to investigate the course over time of such an association through a comparison between early- and late-onset COPD. Methods This study is part of the European Community Respiratory Health Survey (ECRHS). A random adult population from 25 centres in Europe and one in Australia was examined with spirometry and answered a respiratory questionnaire in 1998-2002 (ECRHS II) and in 2008-2013 (ECRHS III). Symptoms of non-infectious rhinitis, hay fever and asthma, and smoking habits were reported. Subjects reporting asthma were excluded. COPD was defined as a spirometry ratio of FEV1/FVC < 0.7. A total of 5901 subjects were included. Results Non-infectious rhinitis was significantly more prevalent in subjects with COPD compared with no COPD (48.9% vs 37.1%, p < 0.001) in ECRHS II (mean age 43) but not in ECHRS III (mean age 54). In the multivariable regression model adjusted for COPD, smoking, age, BMI, and gender, non-infectious rhinitis was associated with COPD in both ECRHS II and III. Conclusion Non-infectious rhinitis was significantly more common in subjects with COPD at a mean age of 43. Ten years later, the association was weaker. The findings indicate that NIR could be associated with the early onset of COPD.
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| 8. |
- Kuhnen, G, et al.
(författare)
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Genes Whose Gain or Loss of Function Changes Type 1, 2A, 2X, or 2B Muscle Fibre Proportions in Mice-A Systematic Review
- 2022
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:21
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Tidskriftsartikel (refereegranskat)abstract
- Adult skeletal muscle fibres are classified as type 1, 2A, 2X, and 2B. These classifications are based on the expression of the dominant myosin heavy chain isoform. Muscle fibre-specific gene expression and proportions of muscle fibre types change during development and in response to exercise, chronic electrical stimulation, or inactivity. To identify genes whose gain or loss-of-function alters type 1, 2A, 2X, or 2B muscle fibre proportions in mice, we conducted a systematic review of transgenic mouse studies. The systematic review was conducted in accordance with the 2009 PRISMA guidelines and the PICO framework. We identified 25 “muscle fibre genes” (Akirin1, Bdkrb2, Bdnf, Camk4, Ccnd3, Cpt1a, Epas1, Esrrg, Foxj3, Foxo1, Il15, Mapk12, Mstn, Myod1, Ncor1, Nfatc1, Nol3, Ppargc1a, Ppargc1b, Sirt1, Sirt3, Thra, Thrb, Trib3, and Vgll2) whose gain or loss-of-function significantly changes type 1, 2A, 2X or 2B muscle fibre proportions in mice. The fact that 15 of the 25 muscle fibre genes are transcriptional regulators suggests that muscle fibre-specific gene expression is primarily regulated transcriptionally. A reanalysis of existing datasets revealed that the expression of Ppargc1a and Vgll2 increases and Mstn decreases after exercise, respectively. This suggests that these genes help to regulate the muscle fibre adaptation to exercise. Finally, there are many known DNA sequence variants of muscle fibre genes. It seems likely that such DNA sequence variants contribute to the large variation of muscle fibre type proportions in the human population.
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| 9. |
- Saba, Luca, et al.
(författare)
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Carotid plaque-RADS : a novel stroke risk classification system
- 2024
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Ingår i: JACC Cardiovascular Imaging. - : Elsevier. - 1936-878X .- 1876-7591. ; 17:1, s. 62-75
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Tidskriftsartikel (refereegranskat)abstract
- Background: Carotid artery atherosclerosis is highly prevalent in the general population and is a well-established risk factor for acute ischemic stroke. Although the morphological characteristics of vulnerable plaques are well recognized, there is a lack of consensus in reporting and interpreting carotid plaque features.Objectives: The aim of this document is to establish a consistent and comprehensive approach for imaging and reporting carotid plaque by introducing the Plaque–Reporting and Data System (RADS) score.Methods: A panel of experts recognized the necessity to develop a classification system for carotid plaque and its defining characteristics. Using a multimodality analysis approach, the Plaque-RADS categories were established through consensus, drawing on existing published reports.Results: The authors present a universal classification that is applicable to both researchers and clinicians. The Plaque-RADS score offers a morphological assessment in addition to the prevailing quantitative parameter of “stenosis.” The Plaque-RADS score spans from grade 1 (indicating complete absence of plaque) to grade 4 (representing complicated plaque). Accompanying visual examples are included to facilitate a clear understanding of the Plaque-RADS categories.Conclusions: Plaque-RADS is a standardized and reliable system of reporting carotid plaque composition and morphology via different imaging modalities, such as ultrasound, computed tomography, and magnetic resonance imaging. This scoring system has the potential to help in the precise identification of patients who may benefit from exclusive medical intervention and those who require alternative treatments, thereby enhancing patient care. A standardized lexicon and structured reporting promise to enhance communication between radiologists, referring clinicians, and scientists.
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| 10. |
- EzEldeen, M, et al.
(författare)
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Chlorite oxidized oxyamylose differentially influences the microstructure of fibrin and self assembling peptide hydrogels as well as dental pulp stem cell behavior
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 5687-
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Tidskriftsartikel (refereegranskat)abstract
- Tailored hydrogels mimicking the native extracellular environment could help overcome the high variability in outcomes within regenerative endodontics. This study aimed to evaluate the effect of the chemokine-binding and antimicrobial polymer, chlorite-oxidized oxyamylose (COAM), on the microstructural properties of fibrin and self-assembling peptide (SAP) hydrogels. A further goal was to assess the influence of the microstructural differences between the hydrogels on the in vitro behavior of human dental pulp stem cells (hDPSCs). Structural and mechanical characterization of the hydrogels with and without COAM was performed by atomic force microscopy and scanning electron microscopy to characterize their microstructure (roughness and fiber length, diameter, straightness, and alignment) and by nanoindentation to measure their stiffness (elastic modulus). Then, hDPSCs were encapsulated in hydrogels with and without COAM. Cell viability and circularity were determined using confocal microscopy, and proliferation was determined using DNA quantification. Inclusion of COAM did not alter the microstructure of the fibrin hydrogels at the fiber level while affecting the SAP hydrogel microstructure (homogeneity), leading to fiber aggregation. The stiffness of the SAP hydrogels was sevenfold higher than the fibrin hydrogels. The viability and attachment of hDPSCs were significantly higher in fibrin hydrogels than in SAP hydrogels. The DNA content was significantly affected by the hydrogel type and the presence of COAM. The microstructural stability after COAM inclusion and the favorable hDPSCs' response observed in fibrin hydrogels suggest this system as a promising carrier for COAM and application in endodontic regeneration.
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| 11. |
- Franzke, Andreas W., et al.
(författare)
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Testing the Use of Advanced Upper Limb Prostheses: Towards Quantifying the Movement Quality with Inertial-Magnetic Measurement Units
- 2023
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Ingår i: Prosthesis. - : MDPI AG. - 2673-1592. ; 5:1, s. 264-281
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Tidskriftsartikel (refereegranskat)abstract
- Background: A thorough assessment of upper limb prostheses could help facilitate their transfer from scientific developments into the daily lives of users. Ideally, routine clinical testing would include assessments of upper limb function using motion-capturing technology. This is particularly relevant for the state-of-the-art upper limb prostheses. Methods: We designed a test based on an activity of daily life (“tray-task”) which could be completed outside the laboratory, and developed a set of outcome measures aimed at characterizing the movement quality. For this purpose, kinematics of the thorax and the humerus were captured with an inertial–magnetic measurement unit (IMMU) motion-capture system. Six prosthesis users and ten able-bodied participants were recruited to test the feasibility of the proposed assessment procedure and to evaluate the outcome variables. Results: All participants completed the test either at home or in our lab. The prosthesis users needed more time to complete the task and showed a larger range of motion in the thoracic flexion and a smaller range of motion in the humeral elevation, compared to the able-bodied participants. Furthermore, the prosthesis users’ movements were less smooth and characterized by less stable coordination patterns between the humerus and thorax. Conclusion: A new test method and associated outcome variables have been proposed.
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| 12. |
- Kilbo Edlund, Karl, et al.
(författare)
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Occupational particle exposure and chronic kidney disease: a cohort study in Swedish construction workers.
- 2024
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Ingår i: Journal of Occupational and Environmental Medicine. - : BMJ Publishing Group Ltd. - 1351-0711 .- 1470-7926. ; 81:5, s. 238-243
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Tidskriftsartikel (refereegranskat)abstract
- Increasing epidemiological and experimental evidence suggests that particle exposure is an environmental risk factor for chronic kidney disease (CKD). However, only a few case-control studies have investigated this association in an occupational setting. Hence, our objective was to investigate associations between particle exposure and CKD in a large cohort of Swedish construction workers.We performed a retrospective cohort study in the Swedish Construction Workers' Cohort, recruited 1971-1993 (n=286089). A job-exposure matrix was used to identify workers exposed to nine different particulate exposures, which were combined into three main categories (inorganic dust and fumes, wood dust and fibres). Incident CKD and start of renal replacement therapy (RRT) were obtained from validated national registries until 2021 and analysed using adjusted Cox proportional hazards models.Exposure to inorganic dust and fumes was associated with an increased risk of CKD and RRT during working age (adjusted HR for CKD at age <65 years 1.15, 95%CI 1.05 to 1.26). The elevated risk did not persist after retirement age. Exposure to cement dust, concrete dust and diesel exhaust was associated with CKD. Elevated HRs were also found for quartz dust and welding fumes.Workers exposed to inorganic particles seem to be at elevated risk of CKD and RRT. Our results are in line with previous evidence of renal effects of ambient air pollution and warrant further efforts to reduce occupational and ambient particle exposure.
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| 13. |
- Torén, Kjell, 1952, et al.
(författare)
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Occupational risks associated with severe COVID-19 disease and SARS-CoV-2 infection-a Swedish national case-control study conducted from October 2020 to December 2021
- 2023
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Ingår i: Scandinavian Journal of Work Environment & Health. - 0355-3140. ; 49:6, s. 386-394
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Tidskriftsartikel (refereegranskat)abstract
- Objective This study aimed to investigate whether workplace factors and occupations are associated with SARSCoV-2 infection or severe COVID-19 in the later waves of the pandemic.Methods We studied 552 562 cases with a positive test for SARS-CoV-2 in the Swedish registry of communicable diseases, and 5985 cases with severe COVID-19 based on hospital admissions from October 2020 to December 2021. Four population controls were assigned the index dates of their corresponding cases. We linked job histories to job-exposure matrices to assess the odds for different transmission dimensions and different occupations. We used adjusted conditional logistic analyses to estimate odds ratios (OR) for severe COVID-19 and SARS-CoV-2 with 95% confidence intervals (CI).Results The highest OR for severe COVID-19 were for: regular contact with infected patients, (OR 1.37, 95% CI 1.23-1.54), close physical proximity (OR 1.47, 95% CI 1.34-1.61), and high exposure to diseases or infections (OR 1.72, 95% CI 1.52-1.96). Mostly working outside had lower OR (OR 0.77, 95% CI 0.57-1.06). The odds for SARS-CoV-2 when mostly working outside were similar (OR 0.83, 95% CI 0.80-0.86). The occupation with the highest OR for severe COVID-19 (compared with low-exposure occupations) was certified specialist physician (OR 2.05, 95% CI 1.31-3.21) among women and bus and tram drivers (OR 2.04, 95% CI 1.49-2.79) among men.Conclusions Contact with infected patients, close proximity and crowded workplaces increase the risks for severe COVID-19 and SARS-CoV-2 infection. Outdoor work is associated with decreased odds for SARS-CoV-2 infection and severe COVID-19.
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