| 1. |
- Pennells, Lisa, et al.
(författare)
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Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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| 2. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 3. |
- Schulz, Christina-Alexandra, et al.
(författare)
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Plasma kidney injury molecule-1 (p-KIM-1) levels and deterioration of kidney function over 16 years
- 2020
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Ingår i: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385. ; 35:2, s. 265-273
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Tidskriftsartikel (refereegranskat)abstract
- Background: The kidney injury molecule-1 (KIM-1) has previously been associated with kidney function in rodents and humans. Yet its role as a predictive marker for future decline in kidney function has remained less clear.Methods: At baseline (1991-1994), fasting plasma KIM-1 (p-KIM-1) was measured in 4739 participants of the population-based Malmö Diet and Cancer Study. Creatinine and cystatin C were used to calculate estimated glomerular filtration rate (eGFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Collaboration 2012 creatinine-cystatin C equation at baseline and follow-up examination (2007-2012). Incident CKD was defined as an eGFR <60 mL/min/1.73 m2 at follow-up.Results: During a mean follow-up time of 16.6 years, high p-KIM-1 levels were associated with a greater decline in eGFR (quartile 1 -1.36 versus quartile 4 -1.54 mL/min/1.73 m2; P < 0.001). In multivariate analyses, the risk for incident CKD at the follow-up examination was higher among participants with baseline p-KIM-1 levels in the highest quartile {odds ratio [OR] 1.45 [95% confidence interval (CI) 1.10-1.92]} compared with those within the lowest quartile. The relative impact of baseline p-KIM-1 on incidence of CKD [OR 1.20 (95% CI 1.08-1.33) per 1 standard deviation (SD) increase in p-KIM-1] was comparable to those of age and systolic blood pressure (SBP) [OR 1.55 (95% CI 1.38-1.74) and OR 1.21 (95% CI 1.09-1.35) per 1 SD increase, respectively]. Adding p-KIM-1 to a conventional risk model resulted in significantly improved C-statistics (P = 0.04) and reclassified 9% of the individuals into the correct risk direction (continuous net reclassification improvement P = 0.02). Furthermore, the risk for hospitalization due to impaired renal function increased with increasing baseline p-KIM-1 [hazard ratio per 1 SD 1.43; (95% CI 1.18-1.74)] during a mean follow-up time of 19.2 years.Conclusion: Our results show that p-KIM-1 predicts the future decline of eGFR and risk of CKD in healthy middle-aged participants. Whether p-KIM-1 can be used to prioritize preventive action that needs to be further investigated.
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| 4. |
- Svensson, Thomas, et al.
(författare)
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Plasma concentration of Caspase-8 is associated with short sleep duration and the risk of incident diabetes mellitus
- 2018
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 103:4, s. 1592-1600
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Tidskriftsartikel (refereegranskat)abstract
- Context: The biological mechanism for the association between sleep duration and incident diabetes mellitus (DM) is unclear. Sleep duration and Caspase-8, a marker of apoptotic activity, have both been implicated in beta cell function.Objective: To investigate the associations between sleep duration and plasma Caspase-8, and incident DM, respectively.Design: Prospective cohort study.Setting: The Malmö Diet and Cancer (MDC) Study is a population-based, prospective study run in the city of Malmö, Sweden.Participants: 4023 individuals from the MDC Study aged 45-68 years at baseline without a history of prevalent DM, and with information on habitual sleep duration.Main outcomes: Incident DM.Results: Mean follow-up time was 17.8 years. Sleep duration was the only behavioural variable significantly associated with plasma Caspase-8. Plasma Caspase-8 was significantly associated with incident DM per standard deviation of its transformed continuous form (hazard ratio [HR]= 1.24, 95% confidence interval [CI] 1.13-1.36), and when dichotomized into high (quartile 4) (HR=1.44, 95%CI: 1.19-1.74) compared to low (quartiles 1-3) concentrations. Caspase-8 interacted with sleep duration; compared to 7-8 hours of sleep and low plasma Caspase-8, individuals with high plasma Caspase-8 and sleep duration <6 hours (HR=3.54, 95%CI: 2.12-5.90), 6-7 hours (HR=1.81, 95%CI: 1.24-2.65), and 8-9 hours (HR=1.54, 95%CI: 1.09-2.18) were at significantly increased risks of incident DM.Conclusions: Sleep duration is associated with plasma Caspase-8. Caspase-8 independently predicts DM years before disease onset and modifies the effect of sleep duration on incident DM. Future studies should investigate if change of sleep duration modifies plasma concentrations of Caspase-8.
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| 5. |
- Wu, Chuanyan, et al.
(författare)
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Elevated circulating follistatin associates with an increased risk of type 2 diabetes
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04-1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09-1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.
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| 6. |
- Bao, Xue, et al.
(författare)
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Plasma prostasin : a novel risk marker for incidence of diabetes and cancer mortality
- 2022
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 65:10, s. 1642-1651
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Diabetes is associated with an increased risk of cancer. Prostasin is an epithelial sodium channel stimulator that has been associated with suppression of tumours, glucose metabolism and hyperglycaemia-associated tumour pathology. However, the association between prostasin, diabetes and cancer mortality has not been well investigated in humans. We aim to investigate the associations between plasma prostasin and diabetes, and to explore whether prostasin has an effect on cancer mortality risk in individuals with hyperglycaemia. Methods: Plasma prostasin was measured using samples from the Malmö Diet and Cancer Study Cardiovascular Cohort, and statistical analysis was performed from both sex-specific quartiles and per 1 SD. The cross-sectional association between plasma prostasin and diabetes was first studied in 4658 participants (age 57.5 ± 5.9 years, 39.9% men). After excluding 361 with prevalent diabetes, the associations of prostasin with incident diabetes and cancer mortality risk were assessed using Cox regression analysis. The interactions between prostasin and blood glucose levels as well as other covariates were tested. Results: The adjusted OR for prevalent diabetes in the 4th vs 1st quartile of prostasin concentrations was 1.95 (95% CI 1.39, 2.76) (p for trend <0.0001). During mean follow-up periods of 21.9 ± 7.0 and 23.5 ± 6.1 years, respectively, 702 participants developed diabetes and 651 died from cancer. Prostasin was significantly associated with the incidence of diabetes. The adjusted HR for diabetes in the 4th vs 1st quartile of prostasin concentrations was 1.76 (95% CI 1.41, 2.19) (p for trend <0.0001). Prostasin was also associated with cancer mortality There was a significant interaction between prostasin and fasting blood glucose for cancer mortality risk (p for interaction =0.022), with a stronger association observed in individuals with impaired fasting blood glucose levels at baseline (HR per 1 SD change 1.52; 95% CI 1.07, 2.16; p=0.019). Conclusions/interpretation: Plasma prostasin levels are positively associated with diabetes risk and with cancer mortality risk, especially in individuals with high blood glucose levels, which may shed new light on the relationship between diabetes and cancer. Graphical abstract: [Figure not available: see fulltext.]
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| 7. |
- Bao, Xue, et al.
(författare)
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Proteomic Profiles of Body Mass Index and Waist-to-Hip Ratio and Their Role in Incidence of Diabetes
- 2022
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 107:7, s. 2982-2990
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Tidskriftsartikel (refereegranskat)abstract
- Context: It is unclear to what extent the plasma proteome of abdominal fat distribution differs from that of body mass index, and whether the differences have clinical implications. Objective: To evaluate the difference between the plasma proteomic profiles of body mass index (BMI) and waist-to-hip ratio (WHR), and then examine the identified BMI- or WHR-specific proteins in relation to incidence of diabetes. Methods: Data were obtained from the Malmö Diet and Cancer-Cardiovascular Cohort study in the general community. Participants (n = 4203) with no previous diabetes (aged 57.2 ± 6.0 years, 37.8% men) were included. Plasma proteins (n = 136) were measured by the Proseek proximity extension method. BMI- and WHR-specific proteins were identified at baseline using a 2-step iterative resampling approach to optimize internal replicability followed by β coefficient comparisons. The identified proteins were considered internally replicated and were then studied in relation to incident diabetes by Cox proportional hazards regression analysis. The main outcome measure was incident diabetes over a mean follow-up of 20.3 ± 5.9 years. Results: After excluding 21 overlapping proteins and proteins that did not show significantly different associations with BMI vs WHR, 10 internally replicated proteins were found to be specific to BMI, and 22 were found to be specific to WHR (false discovery rate-adjusted P < .05). Of the WHR-specific proteins, 18 remained associated with diabetes risk after multivariate adjustments, whereas none of the BMI-specific proteins showed associations with diabetes risk. Conclusion: Abdominal fat distribution was associated with some unique characteristics of the plasma proteome that potentially could be related to its additional risk of diabetes beyond general obesity.
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| 8. |
- Brunkwall, Louise, et al.
(författare)
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The Malmö Offspring Study (MOS) : design, methods and first results.
- 2021
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Ingår i: European Journal of Epidemiology. - : Springer Nature. - 0393-2990 .- 1573-7284. ; 36, s. 103-116
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Tidskriftsartikel (refereegranskat)abstract
- As cardio metabolic disease manifestations tend to cluster in families there is a need to better understand the underlying mechanisms in order to further develop preventive strategies. In fact, genetic markers used in genetic risk scores, important as they are, will not be able alone to explain these family clusters. Therefore, the search goes on for the so called missing heritability to better explain these associations. Shared lifestyle and social conditions in families, but also early life influences may be of importance. Gene-environmental interactions should be explored. In recent years interest has grown for the role of diet-microbiota associations, as microbiota patterns may be shared by family members. In the Malmö Offspring Study that started in 2013, we have so far been able to examine about 4700 subjects (18-71 years) representing children and grandchildren of index subjects from the first generation, examined in the Malmö Diet Cancer Study during 1991 to 1996. This will provide rich data and opportunities to analyse family traits of chronic disease across three generations. We will provide extensive genotyping and phenotyping including cardiovascular and respiratory function, as well as markers of glucose metabolism. In addition, also cognitive function will be assessed. A 4-day online dietary recall will be conducted and gut as well as oral microbiota analysed. The ambition is to provide one of the first large-scale European family studies with individual data across three generations, which could deepen our knowledge about the role of family traits for chronic disease and its underlying mechanisms.
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| 9. |
- Bruno, Rosa Maria, et al.
(författare)
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Early and supernormal vascular aging : Clinical characteristics and association with incident cardiovascular events
- 2020
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Ingår i: Hypertension. - 0194-911X. ; , s. 1616-1624
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Tidskriftsartikel (refereegranskat)abstract
- Pulse wave velocity is an established marker of early vascular aging but may also help identifying individuals with supernormal vascular aging. We tested the hypothesis that individuals with the largest difference (Δ-age) between chronological and vascular age show the lowest rate of cardiovascular events and may thus be defined as supernormal vascular aging. Vascular age was defined as the predicted age in the best fitting multivariable regression model including classical risk factors and treatment and pulse wave velocity, in a subset of the Reference Values for Arterial Stiffness Collaboration Database (n=3347). Δ-age was then calculated as chronological age minus vascular age, and the 10th and 90th percentiles were used to define early (Δ-age<-5.7 years), normal (Δ-age -5.7 to 6.8 years) and supernormal vascular aging (Δ-age>6.8 years). The risk for fatal and nonfatal cardiovascular events associated with vascular aging categories was investigated in the Malmö Diet and Cancer Study cohort (n=2642). In the Malmö Diet and Cancer Study Cohort (6.6-year follow-up, 286 events), Δ-age was significantly (P<0.01) and inversely associated with cardiovascular events. Compared with normal vascular aging, supernormal vascular aging had lower risk (hazard ratio, 0.59 [95% CI, 0.41-0.85]), whereas early vascular aging had higher risk (hazard ratio, 2.70 [95% CI, 1.55-4.70]) of cardiovascular events, in particular coronary events. There was no significant association with all-cause mortality. This study represents the first validation of the clinical significance of the supernormal vascular aging concept, based on prospective data. Its further characterization may help discovering novel protective molecular pathways and providing preventive strategies for successful vascular aging.
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| 10. |
- Dybjer, Elin, et al.
(författare)
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Type 1 diabetes, cognitive ability and incidence of cardiovascular disease and death over 60 years of follow-up time in men
- 2022
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 39:8
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Tidskriftsartikel (refereegranskat)abstract
- Aims There are few cohorts of type 1 diabetes that follow individuals over more than half a century in terms of health outcomes. The aim of this study was to examine associations between type 1 diabetes, diagnosed before age 18, and long-term morbidity and mortality, and to investigate whether cognitive ability plays a role in long-term morbidity and mortality risk. Methods In a Swedish cohort, 120 men with type 1 diabetes and 469 without type 1 diabetes were followed between 18 and 77 years of age as regards morbidity and mortality outcomes, and impact of cognitive ability at military conscription for the outcomes. In Cox regression analyses and Kaplan-Meier analyses with log-rank tests, associations between diabetes and cognitive ability respectively, and outcomes (mortality, cardiovascular morbidity and diabetes complications) were investigated. Results Men with type 1 diabetes suffered from dramatically higher mortality (HR 4.62, 95% CI: 3.56-5.60), cardiovascular mortality (HR 5.60, 95% CI: 3.27-9.57), and cardiovascular events (HR 3.97, 95% CI: 2.79-5.64) compared to men without diabetes. Higher cognitive ability at military conscription was associated with lower mortality in men without diabetes, but was not associated with any outcome in men with diabetes. Conclusions In this historical cohort study with 60 years of follow-up time and a less effective treatment of diabetes than today, mortality rates and cardiovascular outcomes were high for men with type 1 diabetes. Morbidity or mortality did not differ between those that had low to normal or high cognitive ability among men with type 1 diabetes.
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