| 1. |
- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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| 2. |
- Dolinska, Monika, et al.
(författare)
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Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option
- 2023
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
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Tidskriftsartikel (refereegranskat)abstract
- Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long -term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
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| 3. |
- Furukawa, Toshi A., et al.
(författare)
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Dismantling, optimising, and personalising internet cognitive behavioural therapy for depression : a systematic review and component network meta-analysis using individual data
- 2021
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Ingår i: Lancet psychiatry. - London, United Kingdom : Elsevier. - 2215-0374 .- 2215-0366. ; 8:6, s. 500-511
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Forskningsöversikt (refereegranskat)abstract
- Findings We identified 76 RCTs, including 48 trials contributing individual participant data (11 704 participants) and 28 trials with aggregate data (6474 participants). The participants' weighted mean age was 42.0 years and 12 406 (71%) of 17 521 reported were women. There was suggestive evidence that behavioural activation might be beneficial (iMD -1.83 [95% credible interval (CrI) -2.90 to -0.80]) and that relaxation might be harmful (1.20 [95% CrI 0.17 to 2.27]). Baseline severity emerged as the strongest prognostic factor for endpoint depression. Combining human and automated encouragement reduced dropouts from treatment (incremental odds ratio, 0.32 [95% CrI 0.13 to 0.93]). The risk of bias was low for the randomisation process, missing outcome data, or selection of reported results in most of the included studies, uncertain for deviation from intended interventions, and high for measurement of outcomes. There was moderate to high heterogeneity among the studies and their components. 511
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| 4. |
- Ji, Xuemei, et al.
(författare)
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Protein-altering germline mutations implicate novel genes related to lung cancer development
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
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| 5. |
- Johansson, Cecilia, et al.
(författare)
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Alcohol consumption and risk of incident atrial fibrillation : a population-based cohort study
- 2020
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Ingår i: European journal of internal medicine. - : Elsevier. - 0953-6205 .- 1879-0828. ; 76, s. 50-57
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Atrial fibrillation (AF) is a common tachyarrhythmia. High alcohol consumption is associated with increased AF risk. It remains unclear whether lower levels of alcohol consumption are also associated with AF risk, and whether the association differs between men and women. In this study, we investigated the association between low to moderate levels of alcohol consumption and AF risk in men and women.METHODS: We performed a population-based cohort study of 109,230 health examination participants in northern Sweden. Data regarding alcohol intake were obtained using a questionnaire administered at the health examination. Incident AF cases were identified from the Swedish National Patient Registry.RESULTS: AF was diagnosed in 5,230 individuals during a total follow-up of 1,484,547 person-years. Among men, AF risk increased over quartiles of weekly alcohol consumption (P for trend 0.001). Men with alcohol consumption in the highest quartile (≥4.83 standard drinks [each drink containing 12 gs of ethanol] per week; SDW) had a HR of 1.21 (95% CI 1.09-1.34) for AF compared to men in the lowest quartile (<0.90 SDW). In men, problem drinking was also associated with an increased AF risk (HR: 1.24; 95% CI: 1.10-1.39). Among women, AF risk was not significantly associated with alcohol consumption (P for trend 0.09 for decreasing risk of AF over quartiles of weekly alcohol consumption) or problem drinking (HR: 1.00; 95% CI 0.70-1.42).CONCLUSION: Self-reported alcohol consumption and problem drinking were associated with an increased risk of AF among men, but not in women.
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| 6. |
- Johansson, Cecilia, et al.
(författare)
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Diabetes, prediabetes, and atrial fibrillation : a population-based cohort study based on national and regional registers
- 2023
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Ingår i: Journal of Internal Medicine. - : John Wiley & Sons. - 0954-6820 .- 1365-2796. ; 294:5, s. 605-615
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies have shown an increased risk for atrial fibrillation and atrial flutter (AF) in people with type 2 diabetes and prediabetes. It is unclear whether this increase in AF risk is independent of other risk factors for AF.Objective: To investigate the association between diabetes and different prediabetic states, as independent risk factors for the onset of AF.Methods: We performed a population-based cohort study in Northern Sweden, including data on fasting plasma glucose, oral glucose tolerance test, major cardiovascular risk factors, medical history, and lifestyle factors. Participants were divided into six groups depending on glycemic status and followed through national registers for AF diagnosis. Cox proportional hazard model was used to assess the association between glycemic status and AF, using normoglycemia as reference.Results: The cohort consisted of 88,889 participants who underwent a total of 139,661 health examinations. In the model adjusted for age and sex, there was a significant association between glycemic status and development of AF in all groups except the impaired glucose tolerance group, with the strongest association for the group with known diabetes (p-value <0.001). In a model adjusted for sex, age, systolic blood pressure, body mass index, antihypertensive drugs, cholesterol, alcohol, smoking, education level, marital status, and physical activity, there was no significant association between glycemic status and AF.Conclusions/interpretation: The association between glycemic status and AF disappears upon adjustment for potential confounders. Diabetes and prediabetes do not appear to be independent risk factors for AF.
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| 7. |
- Johansson, Cecilia, 1988-
(författare)
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Risk markers and incidence of atrial fibrillation in northern Sweden
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Atrial fibrillation (AF) is the most common clinically significant arrythmia with a prevalence of approximately 3% in the general population. Less is known about the incidence of AF. In order to reduce the incidence of AF, it is of essence to identify modifiable risk factors for the disease.Aims: The aims of this thesis were (1) to estimate the incidence of AF and to assess the prevalence of provoking factors and risk factors for stroke and systemic embolism at the time of AF diagnosis, (2) to study the association between alcohol consumption and risk of AF, (3) to study the association between weight, height, weight change, and risk of AF, and (4) to study the association between normal or high normal blood pressure (BP), compared to optimal BP, and risk of AF.Methods: To determine the incidence of AF and the prevalence of provoking factors and risk factors for stroke and systemic embolism at AF diagnosis, an observational study was performed between January 1, 2011, and December 31, 2012, in the municipalities of Skellefteå and Norsjö, Västerbotten, Sweden. Diagnosis registries were searched for cases of incident AF. All AF diagnoses were verified by electrocardiogram. Data regarding provoking factors, type of AF and presence of risk factors for stroke and systemic embolism (as assessed by the CHA2DS2-VASc score) was obtained from medical records. Incidence was calculated by dividing the number of incident AF cases by the time at risk for the population.The association between alcohol consumption, weight, height, weight change, normal BP, high normal BP, and risk of AF was investigated in a population-based cohort study of participants of the Västerbotten Intervention Programme (VIP). Residents of Västerbotten County aged 30, 40, 50 and 60 years who had participated in the VIP health examinations between January 1, 1988, and September 5, 2014, were included. Individuals who had been diagnosed with AF before participating in the VIP were excluded. Study participants were followed until a diagnosis of AF, death, migration from the study area, or the end of the study on September 5, 2014. Incident AF cases were identified using the Swedish National Patient Registry. The health examinations included measurements of height and weight, systolic BP, diastolic BP, fasting glucose, oral glucose tolerance, and cholesterol. Participants also answered a questionnaire addressing any history of diabetes and myocardial infarction, alcohol use, education level, smoking habits, medications, and physical activity. Optimal BP was defined as BP < 120/80 mm Hg. Normal BP was defined as BP 120–129/80–84 mm Hg. High normal BP was defined as BP 130–139/85–89 mm Hg. Hypertension was defined as BP ≥ 140/90 mm Hg. Cox proportional hazards regression analysis was used to assess the associations between alcohol consumption, weight, height, weight change, normal BP, high normal BP, and risk of AF. These were performed with crude, age-adjusted, and multivariable models adjusted for other cardiovascular risk factors (age, sex, body mass index, hypertension, cholesterol, previous myocardial infarction, diabetes, problem drinking, smoking, education level, and leisure-time physical activity).Results: The incidence of AF was 4.0 cases of AF per 1000 person-years. In approximately one fifth of participants, a provoking factor was present at the first episode of AF. The CHA2DS2-VASc score was 2 or higher in 81% of participants. Permanent AF was the most common type of AF and was seen in about one third of the participants.When studying the association between alcohol consumption and risk of AF, 109,230 health examination participants were included in the study cohort and were followed for 1,484,547 person-years. During the study period, 5230 participants developed incident AF. Men with alcohol consumption in the highest quartile (≥ 4.83 standard drinks weekly) had a hazard ratio (HR) of 1.21 (95% confidence interval [CI] 1.09-1.34) for AF in a multivariable model when compared to men with an alcohol consumption in the lowest quartile (< 0.90 standard drinks weekly). In men, problem drinking was also associated with an increased risk of AF (HR 1.24, 95% CI 1.10–1.39 in a multivariable model). Among women, no significant association between alcohol consumption, problem drinking, and risk of AF was identified.In a fully adjusted model, height, weight, body mass index, and body surface area were positively associated with risk of incident AF. Among participants who underwent two health examinations 10 years apart, 1142 persons developed AF. The mean weight change from baseline was a weight gain of 4.8%. There was no significant association between either weight gain or weight loss and risk of AF.In the study of the association between normal BP, high normal BP, and risk of AF, 109,697 persons with a total of 162,982 health examinations were included. Incident AF was diagnosed in 5260 participants. There was an increased risk of incident AF in persons with normal BP (HR 1.11, 95% CI 1.01–1.27) and in persons with high normal BP (HR 1.23, 95% CI 1.10–1.38) compared to optimal BP in a multivariable model. Systolic BP and diastolic BP were associated with risk of incident AF, with HRs of 1.11 (95% CI 1.10–1.13) and 1.13 (95% CI 1.09–1.16) per 10 mmHg, respectively, in multivariable models. A restricted cubic spline analysis indicated a gradually increasing risk of AF with increasing systolic BP and diastolic BP.Conclusions: AF has an incidence of 4.0 per 1000 person-years. Alcohol consumption and problem drinking were associated with higher risk of AF in men, but not in women. Weight, height, body mass index, and body surface area were associated with increased risk of incident AF. Normal BP and high normal BP, when compared to optimal BP, were associated with increased risk of incident AF.
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| 8. |
- Johansson, Cecilia, et al.
(författare)
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Weight, height, weight change, and risk of incident atrial fibrillation in middle-aged men and women
- 2020
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Ingår i: Journal of Arrhythmia. - : John Wiley & Sons. - 1880-4276 .- 1883-2148. ; 36:6, s. 974-981
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Tidskriftsartikel (refereegranskat)abstract
- Background: Anthropometric factors are reported to be risk factors for atrial fibrillation (AF), but it is unclear whether weight change in mid‐life is associated with AF. We aimed to study the possible associations of weight, height, and weight change with the risk of incident AF in men and women.Methods: Our study cohort included 108 417 persons (51% women) who participated in a population‐based health examination in northern Sweden at 30, 40, 50, or 60 years of age. The health examination included weight and height measurement and collection of data regarding cardiovascular risk factors. Within this cohort, 40 275 participants underwent two health examinations with a 10‐year interval. We identified cases with a first‐ever diagnosis of AF through the Swedish National Patient Registry.Results: During a total follow‐up of 1 469 820 person‐years, 5154 participants developed incident AF. The mean age at inclusion was 46.3 years, and mean age at AF diagnosis was 66.6 years. After adjustment for potential confounders, height, weight, body mass index (BMI), and body surface area (BSA) were positively associated with risk of incident AF in both men and women. Among participants who underwent two health examinations 10 years apart, 1142 persons developed AF. The mean weight change from baseline was a gain of 4.8%. Weight gain or weight loss was not significantly associated with risk of incident AF.Conclusions: Height, weight, BMI, and BSA showed positive associations with risk of incident AF in both men and women. Midlife weight change was not significantly associated with AF risk.
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| 9. |
- Johansson, Kristina, 1986-
(författare)
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Biomarkers and risk of intracerebral hemorrhage : population-based studies in northern Sweden
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundIntracerebral hemorrhage (ICH) is a disease associated with a high morbidity and mortality and treatment options for the condition are limited. Even though an ICH event usually comes as a surprise to the affected individual, pathogenetic processes often have occurred before the sudden ICH event and may have preceded disease onset by years. It is possible that individuals at increased risk of ICH could be identified using biomarkers, for example markers of hemostasis and fibrinolysis. Even if these biomarkers are not part of the causal chain, they could be used as risk indicators to better define high-risk groups. Another approach could be to measure already established risk markers for ICH, such as self-reported alcohol consumption, using a blood biomarker. That could increase measurement reliability and consequently the accuracy of the estimates of ICH risk.AimsThe aim of this thesis was to investigate potential biomarkers and risk of ICH. Specific aims were to evaluate the associations between factor XII, D-dimer, von Willebrand factor (VWF), ABO blood groups with focus on blood group O, phosphatidylethanol (PEth), and risk of ICH.MethodsIn our first study, aiming to investigate the association between factor XII and risk of hemorrhagic stroke, we followed participants of the health examination northern Sweden MONItoring trends and determinants in CArdiovascular disease (MONICA) performed in 1994 as a cohort until 2011. Factor XII concentrations were measured in blood samples drawn at the baseline health examination where the participants also answered a questionnaire regarding lifestyle factors and medical history. Diagnosis codes from the National Patient Register and the Swedish Cause of Death Register were used to find cases of hemorrhagic stroke, defined as ICH or subarachnoid hemorrhage. In the subsequent studies, the associations between biomarkers (factor XII, D-dimer, VWF, ABO blood groups, and PEth) and risk of ICH were investigated using a matched, nested case-referent design including individuals that had participated in the Västerbotten Intervention Programme, the MONICA and the Mammography Screening Project in 1985–2007. The participants donated blood samples at baseline for future research which were stored at -80 degrees C until biomarker analyses. The majority of the participants also underwent a baseline health examination including a questionnaire. First-ever ICH diagnoses during the study period 1985–2007 were validated using medical records and autopsy reports. To each case, two referents were matched for age, sex, geographical region, health examination date and health examination setting. ResultsIn the cohort study of the association between factor XII concentrations and risk of hemorrhagic stroke, 1,852 participants were included among which 30 experienced a hemorrhagic stroke event. There was an association between high factor XII and risk of hemorrhagic stroke in a multivariable model (hazard ratio 1.51; 95% confidence interval [CI] 1.03–2.21 per standard deviation [SD] of factor XII). In the case-referent study of the association between factor XII and risk of ICH, 70 cases with ICH and 137 matched referents were included. We found no association between factor XII and risk of ICH in a multivariable model (odds ratio [OR] 1.06; 95% CI 0.57–1.97 per SD of factor XII). The study of the association between D-dimer and risk of ICH included 141 cases and 255 matched referents. We found an association between D-dimer and risk of ICH in a multivariable model (OR 1.36; 95% CI 1.05–1.77 per SD of D-dimer). When stratifying the analysis for time between blood sampling and ICH event in tertiles, the association remained significant in the cases with the shortest time between blood sampling and ICH event in a multivariable model (OR 1.78; 95% CI 1.05–3.05 per SD of D-dimer). The study investigating the association between VWF and risk of ICH included 139 cases and 276 referents. We found no association between VWF and risk of ICH in a multivariable model (OR 0.85; 95% CI 0.54–1.34 per SD of VWF). In the analysis investigating the associations between ABO blood groups and risk of ICH, 162 cases and 317 referents were included. We found no association between blood group O compared to non-O blood groups and risk of ICH (OR 0.96; 95% CI 0.65–1.42). In the study of the association between PEth concentrations and risk of ICH, 97 cases and 180 referents were included. There was an association between PEth concentrations > 0.30 µmol/L compared to < 0.01 µmol/L and risk of ICH in a multivariable model (OR 4.64; 95% CI 1.49–14.40).ConclusionsHigh concentrations of D-dimer and PEth are associated with an increased risk of ICH. Our conclusion of the two studies investigating the association between factor XII and risk of hemorrhagic stroke and ICH respectively is that there is no association between factor XII and risk of ICH. We found no association between VWF or blood group O and risk of ICH.
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| 10. |
- Johansson, Kristina, et al.
(författare)
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Factor XII Concentrations and Risk of Intracerebral Haemorrhage : A Prospective Case-Referent Study
- 2021
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Ingår i: Journal of Stroke & Cerebrovascular Diseases. - : Elsevier. - 1052-3057 .- 1532-8511. ; 30:3
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: In a previous pilot study, we found an association between high factorXII levels and risk of haemorrhagic stroke suggesting that factor XII is a risk markerfor intracerebral haemorrhage (ICH). The aim of this study was to further investigate the association between factor XII and risk of ICH in a larger population.Materials and Methods:This study was conducted as a prospective nested case-referent study. All participants underwent a health examination and blood sampling for factor XII analysis at baseline. Cases were defined as participants who were diagnosed with a first-ever ICH between 1985 and 2000. Two referents were matched to eachcase.Results:We identified 70 individuals withfirst-ever ICH and 137 matchedreferents who had undergone a health examination and donated blood samples Factor XII Concentrations and Risk of Intracerebral Haemorrhage. A Prospective Case-Referent Studybefore the ICH event. The mean age was 54 years, and 33% were women. The median time-to-event was 3.5 years (range 0.04 to 10.2 years). Conditional logistic regression showed no association between factor XII and risk of ICH, (odds ratio1.06 per SD; [95% confidence interval: 0.57–1.97] in a multivariable model).Conclusions: A previous finding of an association between high concentration of factor XII and risk of ICH could not be replicated in this larger study
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