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| 2. |
- Weiner, D. J., et al.
(author)
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Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
- 2017
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:7
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Journal article (peer-reviewed)abstract
- Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
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| 3. |
- Roswall, N., et al.
(author)
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Long-Term Exposure to Transportation Noise and Risk of Incident Stroke: A Pooled Study of Nine Scandinavian Cohorts
- 2021
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In: Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 129:10
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Journal article (peer-reviewed)abstract
- BACKGROUND: Transportation noise is increasingly acknowledged as a cardiovascular risk factor, but the evidence base for an association with stroke is sparse. OBJECTIVE: We aimed to investigate the association between transportation noise and stroke incidence in a large Scandinavian population. METHODS: We harmonized and pooled data from nine Scandinavian cohorts (seven Swedish, two Danish), totaling 135,951 participants. We identified residential address history and estimated road, railway, and aircraft noise for all addresses. Information on stroke incidence was acquired through linkage to national patient and mortality registries. We analyzed data using Cox proportional hazards models, including socioeconomic and lifestyle confounders, and air pollution. RESULTS: During follow-up (median = 19.5 y), 11,056 stroke cases were identified. Road traffic noise (Lden) was associated with risk of stroke, with a hazard ratio (HR) of 1.06 [95% confidence interval (CI): 1.03, 1.08] per 10-dB higher 5-y mean time-weighted exposure in analyses adjusted for individual- and area-level socioeconomic covariates. The association was approximately linear and persisted after adjustment for air pollution [particulate matter (PM) with an aerodynamic diameter of <= 2.5 mu m (PM2.5) and NO2]. Stroke was associated with moderate levels of 5-y aircraft noise exposure (40-50 vs. <= 40 dB) (HR = 1.12; 95% CI: 0.99, 1.27), but not with higher exposure (>= 50 dB, HR = 0.94; 95% CI: 0.79, 1.11). Railway noise was not associated with stroke. DISCUSSION: In this pooled study, road traffic noise was associated with a higher risk of stroke. This finding supports road traffic noise as an important cardiovascular risk factor that should be included when estimating the burden of disease due to traffic noise.
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| 4. |
- Barregård, Lars, 1948, et al.
(author)
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Human and Methodological Sources of Variability in the Measurement of Urinary 8-Oxo-7,8-dihydro-2 '-deoxyguanosine
- 2013
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In: Antioxidants and Redox Signaling. - : Mary Ann Liebert Inc. - 1523-0864 .- 1557-7716. ; 18:18, s. 2377-2391
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Journal article (peer-reviewed)abstract
- Aims: Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is a widely used biomarker of oxidative stress. However, variability between chromatographic and ELISA methods hampers interpretation of data, and this variability may increase should urine composition differ between individuals, leading to assay interference. Furthermore, optimal urine sampling conditions are not well defined. We performed inter-laboratory comparisons of 8-oxodG measurement between mass spectrometric-, electrochemical- and ELISA-based methods, using common within-technique calibrants to analyze 8-oxodG-spiked phosphate-buffered saline and urine samples. We also investigated human subject- and sample collection-related variables, as potential sources of variability. Results: Chromatographic assays showed high agreement across urines from different subjects, whereas ELISAs showed far more inter-laboratory variation and generally overestimated levels, compared to the chromatographic assays. Excretion rates in timed 'spot' samples showed strong correlations with 24 h excretion (the 'gold' standard) of urinary 8-oxodG (r(p) 0.67-0.90), although the associations were weaker for 8-oxodG adjusted for creatinine or specific gravity (SG). The within-individual excretion of 8-oxodG varied only moderately between days (CV 17% for 24 h excretion and 20% for first void, creatinine-corrected samples). Innovation: This is the first comprehensive study of both human and methodological factors influencing 8-oxodG measurement, providing key information for future studies with this important biomarker. Conclusion: ELISA variability is greater than chromatographic assay variability, and cannot determine absolute levels of 8-oxodG. Use of standardized calibrants greatly improves intra-technique agreement and, for the chromatographic assays, importantly allows integration of results for pooled analyses. If 24 h samples are not feasible, creatinine- or SG-adjusted first morning samples are recommended.
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| 5. |
- Murphy, M. P., et al.
(author)
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Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo
- 2022
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In: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 4:6, s. 651-662
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Journal article (peer-reviewed)abstract
- Multiple roles of reactive oxygen species (ROS) and their consequences for health and disease are emerging throughout biological sciences. This development has led researchers unfamiliar with the complexities of ROS and their reactions to employ commercial kits and probes to measure ROS and oxidative damage inappropriately, treating ROS (a generic abbreviation) as if it were a discrete molecular entity. Unfortunately, the application and interpretation of these measurements are fraught with challenges and limitations. This can lead to misleading claims entering the literature and impeding progress, despite a well-established body of knowledge on how best to assess individual ROS, their reactions, role as signalling molecules and the oxidative damage that they can cause. In this consensus statement we illuminate problems that can arise with many commonly used approaches for measurement of ROS and oxidative damage, and propose guidelines for best practice. We hope that these strategies will be useful to those who find their research requiring assessment of ROS, oxidative damage and redox signalling in cells and in vivo. Reactive oxygen species (ROS) have important roles in health and disease, but are chemically complex and difficult to measure accurately. This consensus statement proposes guidelines and best practices on the nomenclature and assessment of ROS, oxidative reactions and oxidative damage in cells, tissues and in vivo.
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| 6. |
- Thacher, Jesse D., et al.
(author)
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Occupational noise exposure and risk of incident stroke: a pooled study of five Scandinavian cohorts
- 2022
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In: OCCUPATIONAL AND ENVIRONMENTAL MEDICINE. - : BMJ. - 1351-0711 .- 1470-7926. ; 79:9, s. 594-601
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Journal article (peer-reviewed)abstract
- Objectives To investigate the association between occupational noise exposure and stroke incidence in a pooled study of five Scandinavian cohorts (NordSOUND). Methods We pooled and harmonised data from five Scandinavian cohorts resulting in 78 389 participants. We obtained job data from national registries or questionnaires and recoded these to match a job-exposure matrix developed in Sweden, which specified the annual average daily noise exposure in five exposure classes (L-Aeq8h): <70, 70-74, 75-79, 80-84, >= 85 dB(A). We identified residential address history and estimated 1-year average road traffic noise at baseline. Using national patient and mortality registers, we identified 7777 stroke cases with a median follow-up of 20.2 years. Analyses were conducted using Cox proportional hazards models adjusting for individual and area-level potential confounders. Results Exposure to occupational noise at baseline was not associated with overall stroke in the fully adjusted models. For ischaemic stroke, occupational noise was associated with HRs (95% CI) of 1.08 (0.98 to 1.20), 1.09 (0.97 to 1.24) and 1.06 (0.92 to 1.21) in the 75-79, 80-84 and >= 85 dB(A) exposure groups, compared with <70 dB(A), respectively. In subanalyses using time-varying occupational noise exposure, we observed an indication of higher stroke risk among the most exposed (>= 85 dB(A)), particularly when restricting analyses to people exposed to occupational noise within the last year (HR: 1.27; 95% CI: 0.99 to 1.63). Conclusions We found no association between occupational noise and risk of overall stroke after adjustment for confounders. However, the non-significantly increased risk of ischaemic stroke warrants further investigation.
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| 7. |
- Casares, L., et al.
(author)
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The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity
- 2022
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In: Redox Biology. - : Elsevier BV. - 2213-2317. ; 51
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Journal article (peer-reviewed)abstract
- The transcription factor BACH1 is a potential therapeutic target for a variety of chronic conditions linked to oxidative stress and inflammation, as well as cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these compounds have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of two CDDO-derivatives (CDDO-Me and CDDO-TFEA), but not of CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-Me and CDDO-TFEA inhibit BACH1, which explains the much higher potency of these CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-Me and CDDO-TFEA inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. In an in vitro model, both CDDO-derivatives impaired lung cancer cell invasion in a BACH1-dependent and NRF2-independent manner, while CDDO was inactive. Altogether, our study identifies CDDO-Me and CDDO-TFEA as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs.
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| 8. |
- Hjaeresen, S., et al.
(author)
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MIF in the cerebrospinal fluid is decreased during relapsing-remitting while increased in secondary progressive multiple sclerosis
- 2022
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In: Journal of the Neurological Sciences. - : Elsevier BV. - 0022-510X. ; 439
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Journal article (peer-reviewed)abstract
- Background: Macrophage migration inhibitory factor (MIF) is involved in the function of both the innate and adaptive immune systems and in neuroprotection and has recently been implicated in multiple sclerosis (MS). Objectives: Determination of MIF levels in the cerebrospinal fluid (CSF) of patients with distinct subtypes of MS and the cellular localization of MIF in human brain tissue. Methods: The levels of MIF were investigated in CSF from patients with clinically isolated syndrome (CIS) (n = 26), relapsing-remitting MS (RRMS) (n = 22), secondary progressive MS (SPMS) (n = 19), and healthy controls (HCs) (n = 24), using ELISA. The effect of disease-modifying therapies in the RRMS and SPMS cohorts were examined. Cellular distribution of MIF in the human brain was studied using immunochemistry and the newly available OligoInternode database. Results: MIF was significantly decreased in treatmentnaive CIS and RRMS patients compared to HCs but was elevated in SPMS. Interestingly, MIF levels were sex-dependent and significantly higher in women with CIS and RRMS. MIF expression in the human brain was localized to neurons, astrocytes, pericytes, and oligo5 oligodendrocytes but not in microglia. Conclusion: The finding that MIF was decreased in newly diagnosed CIS and RRMS patients but was high in patients with SPMS may suggest that MIF levels in CSF are regulated by local MIF receptor expression that affects the overall MIF signaling in the brain and may represent a protective mechanism that eventually fails.
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| 9. |
- Hjaeresen, S., et al.
(author)
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The levels of the serine protease HTRA1 in cerebrospinal fluid correlate with progression and disability in multiple sclerosis
- 2021
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In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 268, s. 3316-3324
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Journal article (peer-reviewed)abstract
- Background High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease. Objective Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue. Methods Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map. Results HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons. Conclusion HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.
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| 10. |
- Khilji, M. S., et al.
(author)
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The inducible β5i proteasome subunit contributes to proinsulin degradation in GRP94-deficient β-cells and is overexpressed in type 2 diabetes pancreatic islets
- 2020
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In: American Journal of Physiology - Endocrinology and Metabolism. - 0193-1849. ; 318:6
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Journal article (peer-reviewed)abstract
- Proinsulin is a misfolding-prone protein, and its efficient breakdown is critical when β-cells are confronted with high-insulin biosynthetic demands, to prevent endoplasmic reticulum stress, a key trigger of secretory dysfunction and, if uncompensated, apoptosis. Proinsulin degradation is thought to be performed by the constitutively expressed standard proteasome, while the roles of other proteasomes are unknown. We recently demonstrated that deficiency of the proinsulin chaperone glucoseregulated protein 94 (GRP94) causes impaired proinsulin handling and defective insulin secretion associated with a compensated endoplasmic reticulum stress response. Taking advantage of this model of restricted folding capacity, we investigated the role of different proteasomes in proinsulin degradation, reasoning that insulin secretory dynamics require an inducible protein degradation system. We show that the expression of only one enzymatically active proteasome subunit, namely, the inducible β5i-subunit, was increased in GRP94 CRISPR/Cas9 knockout (KO) cells. Additionally, the level of β5i-containing intermediate proteasomes was significantly increased in these cells, as was β5i-related chymotrypsin-like activity. Moreover, proinsulin levels were restored in GRP94 KO upon β5i small interfering RNA-mediated knockdown. Finally, the fraction of β-cells expressing the β5i subunit is increased in human islets from type 2 diabetes patients. We conclude that β5i is an inducible proteasome subunit dedicated to the degradation of mishandled proinsulin. Copyright © 2020 the American Physiological Society.
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