| 1. |
- Ek, Weronica E., et al.
(författare)
-
Tea and coffee consumption in relation to DNA methylation in four European cohorts
- 2017
-
Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 26:16, s. 3221-3231
-
Tidskriftsartikel (refereegranskat)abstract
- Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea has been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation.To investigate if DNA methylation in blood is associated with coffee and tea consumption we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed.After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated in men or in the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption.
|
|
| 2. |
- Gustafsson, Stefan, et al.
(författare)
-
Development and validation of deep learning ECG-based prediction of myocardial infarction in emergency department patients
- 2022
-
Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Myocardial infarction diagnosis is a common challenge in the emergency department. In managed settings, deep learning-based models and especially convolutional deep models have shown promise in electrocardiogram (ECG) classification, but there is a lack of high-performing models for the diagnosis of myocardial infarction in real-world scenarios. We aimed to train and validate a deep learning model using ECGs to predict myocardial infarction in real-world emergency department patients. We studied emergency department patients in the Stockholm region between 2007 and 2016 that had an ECG obtained because of their presenting complaint. We developed a deep neural network based on convolutional layers similar to a residual network. Inputs to the model were ECG tracing, age, and sex; and outputs were the probabilities of three mutually exclusive classes: non-ST-elevation myocardial infarction (NSTEMI), ST-elevation myocardial infarction (STEMI), and control status, as registered in the SWEDEHEART and other registries. We used an ensemble of five models. Among 492,226 ECGs in 214,250 patients, 5,416 were recorded with an NSTEMI, 1,818 a STEMI, and 485,207 without a myocardial infarction. In a random test set, our model could discriminate STEMIs/NSTEMIs from controls with a C-statistic of 0.991/0.832 and had a Brier score of 0.001/0.008. The model obtained a similar performance in a temporally separated test set of the study sample, and achieved a C-statistic of 0.985 and a Brier score of 0.002 in discriminating STEMIs from controls in an external test set. We developed and validated a deep learning model with excellent performance in discriminating between control, STEMI, and NSTEMI on the presenting ECG of a real-world sample of the important population of all-comers to the emergency department. Hence, deep learning models for ECG decision support could be valuable in the emergency department.
|
|
| 3. |
- Gustafsson, Sofia, et al.
(författare)
-
Heterogeneous drug tissue binding in brain regions of rats, Alzheimer’s patients and controls : impact on translational drug development
- 2019
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- For preclinical and clinical assessment of therapeutically relevant unbound, free, brain concentrations, the pharmacokinetic parameter fraction of unbound drug in brain (fu,brain) is commonly used to compensate total drug concentrations for nonspecific brain tissue binding (BTB). As, homogenous BTB is assumed between species and in health and disease, rat BTB is routinely used. The impact of Alzheimer’s disease (AD) on drug BTB in brain regions of interest (ROI), i.e., fu,brain,ROI, is yet unclear. This study for the first time provides insight into regional drug BTB and the validity of employing rat fu,brain,ROI as a surrogate of human BTB, by investigating five marketed drugs in post-mortem tissue from AD patients (n = 6) and age-matched controls (n = 6). Heterogeneous drug BTB was observed in all within group comparisons independent of disease and species. The findings oppose the assumption of uniform BTB, highlighting the need of case-by-case evaluation of fu,brain,ROI in translational CNS research.
|
|
| 4. |
- Gustafsson, Stefan, et al.
(författare)
-
Markers of imminent myocardial infarction
- 2024
-
Ingår i: Nature Cardiovascular Research. - : Springer Nature. - 2731-0590.
-
Tidskriftsartikel (refereegranskat)abstract
- Myocardial infarction is a leading cause of death globally but is notoriously difficult to predict. We aimed to identify biomarkers of an imminent first myocardial infarction and design relevant prediction models. Here, we constructed a new case–cohort consortium of 2,018 persons without prior cardiovascular disease from six European cohorts, among whom 420 developed a first myocardial infarction within 6 months after the baseline blood draw. We analyzed 817 proteins and 1,025 metabolites in biobanked blood and 16 clinical variables. Forty-eight proteins, 43 metabolites, age, sex and systolic blood pressure were associated with the risk of an imminent first myocardial infarction. Brain natriuretic peptide was most consistently associated with the risk of imminent myocardial infarction. Using clinically readily available variables, we devised a prediction model for an imminent first myocardial infarction for clinical use in the general population, with good discriminatory performance and potential for motivating primary prevention efforts.
|
|
| 5. |
- Lind, Lars, et al.
(författare)
-
Longitudinal effects of aging on plasma proteins levels in older adults : associations with kidney function and hemoglobin levels
- 2019
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:2
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A targeted proteomics chip has been shown to be useful to discover novel associations of proteins with cardiovascular disease. We investigated how these proteins change with aging, and whether this change is related to a decline in kidney function, or to a change in hemoglobin levels.MATERIAL AND METHODS: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, including 1,016 participants from the general population aged 70 at baseline, 84 proteins were measured at ages 70, 75, 80. At these occasions, glomerular filtration rate (eGFR) was estimated and the hemoglobin levels were measured.RESULTS: Sixty-one of the 84 evaluated proteins changed significantly during the 10-year follow-up (multiple testing-adjusted alpha = 0.00059), most showing an increase. The change in eGFR was inversely related to changes of protein levels for the vast majority of proteins (74%). The change in hemoglobin was significantly related to the change in 40% of the evaluated proteins, with no obvious preference of the direction of these relationships.CONCLUSION: The majority of evaluated proteins increased with aging in adults. Therefore, normal ranges for proteins might be given in age-strata. The increase in protein levels was associated with the degree of reduction in eGFR for the majority of proteins, while no clear pattern was seen for the relationships between the proteins and the change in hemoglobin levels. Studies on changes in urinary proteins are warranted to understand the association between the reduction in eGFR and increase in plasma protein levels.
|
|
| 6. |
- Lind, Lars, et al.
(författare)
-
Methylation-based estimated biological age and cardiovascular disease
- 2018
-
Ingår i: European Journal of Clinical Investigation. - : John Wiley & Sons. - 0014-2972 .- 1365-2362. ; 48:2
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: DNA methylation changes over life at specific sites in the genome, which can be used to estimate "biological age." The aim of this population-based longitudinal cohort study was to investigate the association between estimated biological age and incident cardiovascular disease (CVD).MATERIALS AND METHODS: Based on formulas published by Hannum et al and Horvath et al, "biological age" was calculated using data from the Illumina 450k Bead Methylation chip in 832 participants free from cardiovascular disease in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70 years at the examination). The difference between estimated biological and chronological age was calculated (DiffAge).RESULTS: During 10 years of follow-up, 153 incident cases of cardiovascular disease occurred. In the sex-adjusted analyses, the Horvath estimation of DiffAge was significantly related to incident cardiovascular disease (HR 1.040, 95% CI 1.010-1.071, P = .0079). Thus, for each year of increased biological age, a 4% increased risk of future cardiovascular disease was observed. This relationship was still significant following adjustment for the traditional risk factors sex, BMI, diabetes, HDL and LDL-cholesterol, systolic blood pressure and smoking (HR 1.033, 95% CI 1.004-1.063, P = .024). No such significant association was found using the Hannum formula.CONCLUSIONS: DNA methylation-based estimation of "biological age" per Horvath was associated with incident cardiovascular disease.
|
|
| 7. |
|
|
| 8. |
- Wang, Yunzhang, et al.
(författare)
-
Epigenetic influences on aging : a longitudinal genome-wide methylation study in old Swedish twins
- 2018
-
Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 13:9, s. 975-987
-
Tidskriftsartikel (refereegranskat)abstract
- Age-related changes in DNA methylation were observed in cross-sectional studies, but longitudinal evidence is still limited. Here, we aimed to characterize longitudinal age-related methylation patterns using 1011 blood samples collected from 385 Swedish twins (age at entry: mean 69 and standard deviation 9.7, 73 monozygotic and 96 dizygotic pairs) up to five times (mean 2.6) over 20 years (mean 8.7). We identified 1316 age-associated methylation sites (P<1.3x10(-7)) using a longitudinal epigenome-wide association study design. We measured how estimated cellular compositions changed with age and how much they confounded the age effect. We validated the results in two independent longitudinal cohorts, where 118 CpGs were replicated in Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, 390 samples) (P<3.9x10(-5)), 594 in Lothian Birth Cohort (LBC, 3018 samples) (P<5.1x10(-5)) and 63 in both. Functional annotation of age-associated CpGs showed enrichment in CCCTC-binding factor (CTCF) and other transcription factor binding sites. We further investigated genetic influences on methylation and found no interaction between age and genetic effects in the 1316 age-associated CpGs. Moreover, in the same CpGs, methylation differences within twin pairs increased with 6.4% over 10 years, where monozygotic twins had smaller intra-pair differences than dizygotic twins. In conclusion, we show that age-related methylation changes persist in a longitudinal perspective, and are fairly stable across cohorts. The changes are under genetic influence, although this effect is independent of age. Moreover, methylation variability increase over time, especially in age-associated CpGs, indicating the increase of environmental contributions on DNA methylation with age.
|
|
| 9. |
- Wikman, Anna, et al.
(författare)
-
Factors associated with re-initiation of antidepressant treatment following discontinuation during pregnancy : a register-based cohort study.
- 2020
-
Ingår i: Archives of Women's Mental Health. - : Springer Science and Business Media LLC. - 1434-1816 .- 1435-1102. ; 23:5, s. 709-717
-
Tidskriftsartikel (refereegranskat)abstract
- Antidepressant treatment when facing a pregnancy is an important issue for many women and their physicians. We hypothesized that women with a greater burden of pre-pregnancy psychiatric illness would be more likely to re-initiate antidepressants following discontinuation of treatment during pregnancy. A register-based cohort study was carried out including 38,595 women who gave birth between the 1st of January 2007 and the 31st of December 2014, who had filled a prescription for an antidepressant medication in the year prior to conception. Logistic regressions were used to explore associations between maternal characteristics and antidepressant treatment discontinuation or re-initiation during pregnancy. Most women discontinued antidepressant treatment during pregnancy (n = 29,095, 75.4%), of whom nearly 12% (n = 3434, 11.8%) re-initiated treatment during pregnancy. In adjusted analyses, parous women (aOR 1.22, 95% CI 1.12-1.33), with high educational level (aOR 1.21, 95% CI 1.08-1.36); born within the EU (excluding Nordic countries, aOR 1.41, 95% CI 1.03-1.92) or a Nordic country (aOR 1.42, 95% CI 1.22-1.65); who more often reported prior hospitalizations due to psychiatric disorders (aOR 1.50, 95% CI 1.10-2.03, for three or more episodes); and had longer duration of pre-pregnancy antidepressant use (aOR 6.10, 95% CI 5.48-6.77, for >2 years antidepressant use), were more likely to re-initiate antidepressants than were women who remained off treatment. Women with a greater burden of pre-pregnancy psychiatric illness were more likely to re-initiate antidepressants. Thus, pre-pregnancy psychiatric history may be particularly important for weighing the risks and benefits of discontinuing antidepressants during pregnancy.
|
|
| 10. |
- Aarnio, Mikko, et al.
(författare)
-
Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl positron emission tomography and computed tomography
- 2022
-
Ingår i: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 163:3, s. 489-495
-
Tidskriftsartikel (refereegranskat)abstract
- Knowledge of etiological mechanisms underlying whiplash-associated disorders is incomplete. Localisation and quantification of peripheral musculoskeletal injury and inflammation in whiplash-associated disorders would facilitate diagnosis, strengthen patients' subjective pain reports, and aid clinical decisions, all of which could lead to improved treatment. In this longitudinal observational study, we evaluated combined [11C]-D-deprenyl positron emission tomography and computed tomography after acute whiplash injury and at 6-month follow-up. Sixteen adult patients (mean age 33 years) with whiplash injury grade II were recruited at the emergency department. [11C]-D-deprenyl positron emission tomography and computed tomography, subjective pain levels, self-rated neck disability, and active cervical range of motion were recorded within 7 days after injury and again at 6-month follow-up. Imaging results showed possible tissue injuries after acute whiplash with an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints, associated with subjective pain locale and levels, as well as self-rated disability. At follow-up, some patients had recovered and some showed persistent symptoms and reductions in [11C]-D-deprenyl uptake correlated to reductions in pain levels. These findings help identify affected peripheral structures in whiplash injury and strengthen the idea that positron emission tomography and computed tomography detectable organic lesions in peripheral tissue are relevant for the development of persistent pain and disability in whiplash injury.
|
|
