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2.
J Ren Nutr ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31668939

RESUMO

OBJECTIVES: This study aims to investigate the separate contributions of liver fat and visceral fat on microalbuminuria and impaired renal function, and second, to examine whether non-alcoholic fatty liver disease is causally related to microalbuminuria and/or impaired renal function. METHODS: Associations between visceral adipose tissue (VAT), hepatic triglyceride content (HTGC), and risk of microalbuminuria and renal function were studied cross-sectionally in the Netherlands Epidemiology of Obesity study. Mendelian randomization using GWAS meta-analysis data was performed to estimate the causal effect of non-alcoholic fatty liver disease (PNPLA3, LYPLAL1, NCAN, GCKR) on eGFR (Nmax 118,460), microalbuminuria (Nmax 54,116), and impaired renal function (Nmax 118,147). RESULTS: In total, 2,023 participants (mean age 55.5 ± 6.0 years, 53% women) were included of which 29% had fatty liver and 2.0% chronic kidney disease stage ≥3. In joint models, VAT was associated with a 2-fold increased risk of microalbuminuria which was mainly driven by the association in women (total population: per standard deviation [SD] = 55.4 cm2, odds ratio [OR] 2.02, 95% confidence interval [CI] 1.18-3.47; women: OR 2.83, 95% CI 1.44, 5.56), but HTGC was not (total population: per SD = 7.9%, OR 1.20, 95% CI 0.85, 1.70). No associations were found for VAT and HTGC with eGFR (VAT: per SD = 55.4 cm2, OR 1.25, 95% CI 0.83, 1.87; HTGC: per SD = 7.9%, OR 0.65, 95% CI 0.42, 0.99). No causal effect of NAFLD on microalbuminuria or impaired renal function was found. CONCLUSIONS: In observational analyses, visceral fat was associated with microalbuminuria in women. Liver fat was not associated with microalbuminuria or renal function, which was supported by Mendelian randomization. Visceral fat might be more important than liver fat in the etiology of microalbuminuria.

3.
Lancet ; 394(10213): 1993-2001, 2019 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-31727410

RESUMO

BACKGROUND: Hand osteoarthritis is a prevalent joint condition that has a high burden of disease and an unmet medical need for effective therapeutic options. Since local inflammation is recognised as contributing to osteoarthritic complaints, the Hand Osteoarthritis Prednisolone Efficacy (HOPE) study aimed to investigate the efficacy and safety of short-term prednisolone in patients with painful hand osteoarthritis and synovial inflammation. METHODS: The HOPE study is a double-blind, randomised, placebo-controlled trial. We recruited eligible adults from rheumatology outpatient clinics at two sites in the Netherlands. Patients were considered eligible if they had symptomatic hand osteoarthritis and signs of inflammation in their distal and proximal interphalangeal (DIP/PIP) joints. For inclusion, patients were required to have four or more DIP/PIP joints with osteoarthritic nodes; at least one DIP/PIP joint with soft swelling or erythema; at least one DIP/PIP joint with a positive power Doppler signal or synovial thickening of at least grade 2 on ultrasound; and finger pain of at least 30 mm on a 100-mm visual analogue scale (VAS) that flared up during a 48-h non-steroidal anti-inflammatory drug (NSAID) washout (defined as worsening of finger pain by at least 20 mm on the VAS). Eligible patients were randomly assigned (1:1) to receive 10 mg prednisolone or placebo orally once daily for 6 weeks, followed by a 2-week tapering scheme, and a 6-week follow-up without study medication. The patients and study team were masked to treatment assignment. The primary endpoint was finger pain, assessed on a VAS, at 6 weeks in participants who had been randomly assigned to groups and attended the baseline visit. This study is registered with the Netherlands Trial Registry, number NTR5263. FINDINGS: We screened patients for enrolment between Dec 3, 2015, and May 31, 2018. Patients completed baseline visits and started treatment between Dec 14, 2015, and July 2, 2018, and the last study visit of the last patient was Oct 4, 2018. Of 149 patients assessed for eligibility, 57 (38%) patients were excluded (predominantly because they did not meet one or several inclusion criteria, most often because of an absence of synovial inflammation or of flare-ups after NSAID washout) and 92 (62%) patients were eligible for inclusion. We randomly assigned 46 (50%) patients to receive prednisolone and 46 (50%) patients to receive placebo, all of whom were included in the modified intention-to-treat analysis of the primary endpoint. 42 (91%) patients in the prednisolone group and 42 (91%) in the placebo group completed the 14-week study. The mean change between baseline and week 6 on VAS-reported finger pain was -21·5 (SD 21·7) in the prednisolone group and -5·2 (24·3) in the placebo group, with a mean between-group difference (of prednisolone vs placebo) of -16·5 (95% CI -26·1 to -6·9; p=0·0007). The number of non-serious adverse events was similar between the groups. Five serious adverse events were reported during our study: one serious adverse event in the prednisolone group (a myocardial infarction) and four serious adverse events in the placebo group (an infected traumatic leg haematoma that required surgery, bowel surgery, atrial fibrillation that required a pacemaker implantation, and symptomatic uterine myomas that required a hysterectomy). Four (4%) patients discontinued the study because of an adverse event: one (2%) patient receiving prednisolone (for a myocardial infarction) and three (7%) patients receiving placebo (for surgery of the bowel and for an infected leg haematoma and for Lyme disease arthritis of the knee). INTERPRETATION: Treatment with 10 mg prednisolone for 6 weeks is efficacious and safe for the treatment of patients with painful hand osteoarthritis and signs of inflammation. The results of our study provide clinicians with a new short-term treatment option for patients with hand osteoarthritis who report a flare-up of their disease. FUNDING: Dutch Arthritis Society.

4.
PLoS Med ; 16(10): e1002883, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31603898

RESUMO

BACKGROUND: Recurrent venous thromboembolism (VTE) is common. Current guidelines suggest that patients with unprovoked VTE should continue anticoagulants unless they have a high bleeding risk, whereas all others can stop. Prediction models may refine this dichotomous distinction, but existing models apply only to patients with unprovoked first thrombosis. We aimed to develop a prediction model for all patients with first VTE, either provoked or unprovoked. METHODS AND FINDINGS: Data were used from two population-based cohorts of patients with first VTE from the Netherlands (Multiple Environment and Genetic Assessment of Risk Factors for Venous Thrombosis [MEGA] follow-up study, performed from 1994 to 2009; model derivation; n = 3,750) and from Norway (Tromsø study, performed from 1999 to 2016; model validation; n = 663). Four versions of a VTE prediction model were developed: model A (clinical, laboratory, and genetic variables), model B (clinical variables and fewer laboratory markers), model C (clinical and genetic factors), and model D (clinical variables only). The outcome measure was recurrent VTE. To determine the discriminatory power, Harrell's C-statistic was calculated. A prognostic score was assessed for each patient. Kaplan-Meier plots for the observed recurrence risks were created in quintiles of the prognostic scores. For each patient, the 2-year predicted recurrence risk was calculated. Models C and D were validated in the Tromsø study. During 19,201 person-years of follow-up (median duration 5.7 years) in the MEGA study, 507 recurrences occurred. Model A had the highest predictive capability, with a C-statistic of 0.73 (95% CI 0.71-0.76). The discriminative performance was somewhat lower in the other models, with C-statistics of 0.72 for model B, 0.70 for model C, and 0.69 for model D. Internal validation showed a minimal degree of optimism bias. Models C and D were externally validated, with C-statistics of 0.64 (95% CI 0.62-0.66) and 0.65 (95% CI 0.63-0.66), respectively. According to model C, in 2,592 patients with provoked first events, 367 (15%) patients had a predicted 2-year risk of >10%, whereas in 1,082 patients whose first event was unprovoked, 484 (45%) had a predicted 2-year risk of <10%. A limitation of both cohorts is that laboratory measurements were missing in a substantial proportion of patients, which therefore were imputed. CONCLUSIONS: The prediction model we propose applies to patients with provoked or unprovoked first VTE-except for patients with (a history of) cancer-allows refined risk stratification, and is easily usable. For optimal individualized treatment, a management study in which bleeding risks are also taken into account is necessary.

5.
Cardiol Ther ; 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31621037

RESUMO

INTRODUCTION: We investigated improvement of electrocardiographic LVH detection by adding measures of adiposity and/or novel electrocardiographic measures. Left ventricular hypertrophy (LVH) is an important risk factor for adverse cardiovascular outcomes. Improvement of electrocardiographic criteria for LVH is desirable, since electrocardiography is widely used. METHODS: We included 1091 participants of the Netherlands Epidemiology of Obesity Study (NEO) who underwent cardiac magnetic resonance imaging (MRI). Performance of Sokolow-Lyon and Cornell voltage and product criteria was assessed. Stepwise regression analysis was performed with each conventional electrocardiographic criterion and age, sex, body mass index (BMI), waist circumference, and waist:hip ratio (p-entry < 0.05, p-removal > 0.10). T-wave abnormalities or the spatial QRS-T angle (SA) were added to the improved models. RESULTS: The study population had a mean (SD) age of 56 (6) years, BMI of 26.1 (4.0) kg/m2 and 46% were men. MRI-LVH was present in 10% of participants. The c-statistic for Sokolow-Lyon voltage was 0.58, R2 was 0.02 and sensitivity at 90% specificity was 16%, for Sokolow-Lyon product this was 0.62, 0.02, and 21%, for Cornell voltage 0.65, 0.04, and 28% and for Cornell product 0.67, 0.04, and 25%. Best performing models were obtained by addition of both BMI and SA (Sokolow-Lyon voltage: c-statistic 0.74, R2 0.11, sensitivity of 41% at 90% specificity; Sokolow-Lyon product: 0.75, 0.12, 42%; Cornell voltage: c-statistic 0.70, R2 0.08, sensitivity of 38% at 90% specificity; Cornell product: c-statistic 0.72, R2 0.08, sensitivity of 44% at 90% specificity). CONCLUSIONS: Electrocardiographic detection of LVH improved by adding BMI and SA to a model with conventional electrocardiographic criteria. This approach would require little extra effort and application in clinical practice is feasible. However, results should first be replicated in high-risk populations.

6.
Haematologica ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582554

RESUMO

Venous thromboembolism is a frequent complication in patients with cancer. Homozygous carriers of the fibrinogen gamma gene (FGG) rs2066865 have a moderately increased risk of venous thromboembolism, but the effect of the FGG variant in cancer is unknown. We aimed to investigate the effect of the FGG variant and active cancer on the risk of venous thromboembolism. Cases with incident venous thromboembolism (n= 640) and a randomly selected age-weighted sub-cohort (n=3734) were derived from a population-based cohort (the Tromso study). Cox-regression was used to estimate hazard ratios with 95% confidence intervals for VTE according to categories of cancer and FGG. In those without cancer, homozygosity at the FGG variant was associated with a 70% (HR 1.7 95% CI 1.2-2.3) increased risk of venous thromboembolism compared to non-carriers. Cancer patients homozygous for the FGG variant had a 2-fold (HR 2.0 95% CI 1.1-3.6) higher risk of venous thromboembolism than cancer patients without the variant. Moreover, the 6-month cumulative incidence of venous thromboembolism among cancer patients was 6.4% (95% CI, 3.5%-11.6%) in homozygous carriers of FGG and 3.1% (95% CI, 2.3%-4.7%) in those without risk alleles. A synergistic effect was observed between rs2066865 and active cancer on the risk of VTE (Synergy index: 1.81, 95% CI: 1.02-3.21, Attributable proportion: 0.43, 95% CI: 0.11-0.74). In conclusion, homozygosity at the FGG variant and active cancer yielded synergistic effect on the risk of venous thromboembolism.

7.
JAMA Netw Open ; 2(9): e1910915, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31539074

RESUMO

Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures: Type 2 diabetes and glycemic traits. Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (ß = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

8.
Diabetes ; 68(12): 2327-2336, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31537524

RESUMO

Early-phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early-phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early-phase insulin response was defined as the difference between the natural logarithm-transformed insulin concentrations of the postprandial state at 30 min after a meal challenge and the fasting state (Δinsulin). After Bonferroni correction, rs505922 (ß: -6.5% [minor allele frequency (MAF) 0.32, P = 3.3 × 10-8]) located in the ABO gene reached genome-wide significant level (P < 5 × 10-8) and was also replicated successfully (ß: -7.8% [MAF 0.32, P = 7.2 × 10-5]). The function of the ABO gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic ß-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic ß-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early-phase insulin secretion.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31535691

RESUMO

OBJECTIVES: To evaluate self-reported and assessor-reported joint counts for pain and their value in measuring pain and joint activity in hand OA patients. METHODS: A total of 524 patients marked painful joints on hand diagrams. Nurses assessed tenderness upon palpation. Pain was measured with a visual analogue scale pain and the Australian/Canadian hand OA index subscale pain. Synovitis and bone marrow lesions in right hand distal/proximal interphalangeal joints on MRI served as measure of joint activity. Agreement was assessed on the patient (intraclass correlation coefficient, Bland-Altman plot) and joint level (percentage absolute agreement). Correlations with measures of pain and joint activity were analysed, and joint level associations with synovitis/bone marrow lesions were calculated. RESULTS: Self-reported painful joint count (median 8, interquartile range 4-13) was consistently higher than assessor-reported tender joint count (3, 1-7). Agreement between patients and nurses on overall scores was low. Percentage absolute agreement on the joint level was 61-89%. Joint counts correlated similarly but weakly with measures of pain and joint activity (r = 0.14-0.38). On the joint level, assessor-reported tenderness was more strongly associated with synovitis/bone marrow lesions than self-reported pain. CONCLUSION: In hand OA, self- and assessor-reported joint counts cannot be used interchangeably, and measure other pain aspects than questionnaires. Assessor-reported tenderness was most closely related to MRI-defined joint activity.

10.
JAMA Netw Open ; 2(8): e1910223, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31461149

RESUMO

Importance: An increase in opioid prescription has been observed in the Netherlands. It is vital to understand this increase and to identify risk factors for opioid prescription to ensure that health interventions remain appropriately targeted. Objectives: To determine the prevalence of opioid prescriptions and adverse events associated with opioids, and to identify risk factors associated with opioid prescription in the Dutch population. Design, Setting, and Participants: This cohort study used national statistics from the Netherlands from January 1, 2013, to December 31, 2017, including the full Dutch population of 16 779 575 people in 2013 and 17 081 507 people in 2017. Data from the Dutch Health Monitor surveys of 2012 and 2016 were also included. Databases were anonymized prior to analysis. All analyses were performed between December 2018 and February 2019. Exposure: Opioid prescription. Main Outcomes and Measures: The main outcomes were the dynamics of opioid prescriptions, hospital admissions for opioid overdose, and opioid overdose mortalities. The secondary outcome was risk factors associated with opioid prescription. Results: In 2013, 814 211 individuals (4.9% of the total population) received an opioid prescription. In 2017, 1 027 019 individuals (6.0% of the total population) received at least 1 opioid prescription (mean [SD] age, 59.3 [18.5] years; 613 203 [59.7%] women). The rate of hospital admissions for opioid overdose was 9.2 per 100 000 inhabitants in 2013 and 13.1 per 100 000 inhabitants in 2017 (relative risk, 1.43 [95% CI, 1.34-1.52]). Similarly, an increased risk of opioid overdose death was observed, from 0.83 per 100 000 inhabitants in 2013 to 1.2 per 100 000 inhabitants in 2017 (relative risk, 1.49 [95% CI, 1.20-1.85]). Based on data from the 2012 Dutch Health Monitor survey, risk factors associated with opioid prescription included being older than 65 years (odds ratio [OR], 4.20 [95% CI, 3.98-4.43]), having only a primary school education (OR, 3.62 [95% CI, 3.46-3.77]), being widowed (OR, 3.30 [95% CI, 3.13-3.49]), reporting always feeling symptoms of depression (OR, 3.77 [95% CI, 3.41-4.18]), and reporting poor or very poor physical health (OR, 10.40 [95% CI, 10.01-10.81]). Self-reported back pain (OR, 4.34 [95% CI, 4.23-4.46]) and rheumatoid arthritis or fibromyalgia (OR, 3.77 [95% CI, 3.65-3.90]) were also associated with opioid prescription. However, unemployment (OR, 1.05 [95% CI, 0.96-1.13]) was not associated with opioid prescription, and alcohol use disorder (OR, 0.76 [95% CI, 0.73-0.80]) was negatively associated with opioid prescription. Conclusions and Relevance: This study found that opioid prescriptions have increased in the Netherlands. Although the risk of adverse events is still relatively low, there is an urgent need to review pain management to prevent a further increase in opioid prescription.

11.
Int J Obes (Lond) ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462693

RESUMO

BACKGROUND: It is unclear to what extent adherence to dietary guidelines may specifically affect visceral fat and liver fat. We aimed to study the association between the Dutch Healthy Diet Index (DHD-index) and total body fat, visceral adipose tissue (VAT) and hepatic triglyceride content (HTGC) in middle-aged men and women. DESIGN: In this cross-sectional study, VAT was assessed by magnetic resonance imaging (MRI) in 2580 participants, and HTGC by proton-MR spectroscopy in 2083 participants. Habitual dietary intake and physical activity were estimated by questionnaire. Adherence to the current Dutch dietary guidelines was estimated by the 2015 DHD-index score based on the thirteen components (vegetables, fruit, wholegrain products, legumes, nuts, dairy, fish, tea, liquid fats, red meat, processed meat, sweetened beverages, and alcohol). The DHD-index ranges between 0 and 130 with a higher score indicating a healthier diet. We used linear regression to examine associations of the DHD-index with VAT and HTGC, adjusted for age, smoking, education, ethnicity, basal metabolic rate, energy restricted diet, menopausal state, physical activity, total energy intake, and total body fat. We additionally excluded the components one by one to examine individual contributions to the associations. RESULTS: Included participants (43% men) had a mean (SD) age of 56 (6) years and DHD-index score of 71 (15). A 10-point higher DHD-index score was associated with 2.3 cm2 less visceral fat (95% CI; -3.5; -1.0 cm2) and less liver fat (0.94 times, 95% CI; 0.90; 0.98). Of all components, exclusion of dairy attenuated the associations with TBF and VAT. CONCLUSIONS: Adherence to the dietary guidelines as estimated by the DHD-index was associated with less total body fat, and with less visceral and liver fat after adjustment for total body fat. These findings might contribute to better understanding of the mechanisms underlying associations between dietary habits and cardiometabolic diseases.

12.
Blood ; 134(19): 1645-1657, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31420334

RESUMO

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

13.
Br J Haematol ; 187(2): 219-226, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31257573

RESUMO

The measurement of homocysteine is still part of routine thrombosis or thrombophilia work-up in many thrombosis centres in the world. Previous observational studies have shown that hyperhomocysteinaemia is associated with an increased risk of first and recurrent venous thrombosis (VT). Randomised trials, however, showed no benefit of homocysteine-lowering therapy on the risk of first or recurrent VT. This discrepancy could be explained by incomplete adjustment for confounders in the observational studies. We investigated in a large population-based follow-up study whether if the levels of homocysteine and its metabolites, methionine and cysteine, were associated with recurrent VT. Approximately three months after discontinuation of anticoagulant treatment, homocysteine, methionine and cysteine concentrations were measured in 2210 patients with VT. During a median follow-up of 6·9 years, 340 patients developed a recurrence (incidence rate, 2·8/100 patient-years). We found that elevated homocysteine concentrations were not associated with an increased risk of recurrent VT, neither as a continuous variable per 5 µmol/l increase (hazard ratio [HR] 0·98 (95% confidence interval [CI], 0·90-1·04)) nor when levels were >95th (>23·0 µmol/l) percentile (HR 1·03 (95% CI, 0·65-1·64)). Similar results were obtained for cysteine and methionine values. We conclude that hyperhomocysteinaemia is not associated with an increased risk of recurrent VT.

14.
J Thromb Haemost ; 17(11): 1886-1897, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31325222

RESUMO

BACKGROUND: It is insufficiently understood if there is an association between diabetes and VT, and what the underlying mechanism would be. OBJECTIVES: We aimed to study the association between glucose concentrations with several coagulation factors in the general population. METHODS: This is a cross-sectional analysis of baseline measurements within 5778 participants of the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort study of individuals 45 to 65 years. Associations between fasting glucose and HbA1c concentrations, and postprandial glucose response and factor (F) VIII, FIX, FXI, and fibrinogen levels were examined using linear regression analyses and by calculating mean levels per category of glucose concentrations while adjusting for confounding factors. RESULTS: Per each mmol/L higher fasting glucose concentration we observed higher levels of fasting FVIII (5.33%, 95% CI: 4.00-6.65), FIX (6.19%, 95% CI: 5.15-7.23), and FXI (2.11%, 95% CI: 1.20-3.02). Results for fasting HbA1c and postprandial glucose response were similar. Participants with an impaired fasting glucose, high fasting glucose, and diabetes mellitus had higher mean levels of FVIII, FIX, and FXI than those with a normal glucose metabolism, with the highest differences in the levels of FVIII, FIX, and FXI between a high fasting glucose and a normal glucose metabolism. All associations attenuated after adjustment for total body fat, yet all of the above associations remained after adjustment for the confounding factors, except for fibrinogen when contrasted to glucose. CONCLUSION: Concentrations of fasting glucose and HbA1c and postprandial glucose response were positively associated with FVIII, FIX, and FXI, and to some extent also with fibrinogen.

15.
Stroke ; 50(8): 2181-2186, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31284847

RESUMO

Background and Purpose- Hypercoagulable states in migraine patients may play a role in the pathophysiology underlying the association between migraine and ischemic stroke. This study aims to provide more insight into the potential association of headache, ischemic stroke, and the intrinsic coagulation pathway. Methods- We included patients from the RATIO study (Risk of Arterial Thrombosis in Relation to Oral Contraceptives), a Dutch population-based case-control study including young women (age <50) with ischemic stroke and healthy controls. We defined a headache group based on a questionnaire on headache history. Intrinsic coagulation proteins were measured through both antigen levels (FXII, FXI, prekallikrein, HK [high molecular weight kininogen]) and protein activation, determined by measuring activated protein complex with C1esterase-inhibitor (FXIIa-C1-INH, FXIa-C1-INH, Kallikrein-C1-INH) or antitrypsin-inhibitor (FXIa-AT-INH). We calculated adjusted odds ratios and performed an interaction analysis assessing the increase in stroke risk associated with high levels of intrinsic coagulation and history of headache. Results- We included 113 ischemic stroke cases and 598 healthy controls. In total, 134 (19%) patients had a history of headache, of whom 38 were cases and 96 controls. The combination of headache and high intrinsic coagulation protein levels (all but FXII antigen level and both FXIa-inhibitors) was associated with an increase in ischemic stroke risk higher than was expected based on their individual effects (adjusted odds ratio FXI antigen level alone: 1.7, 95% CI, 1.0-2.9; adjusted odds ratio headache alone: 2.0, 95% CI, 1.1-3.7; combination: 5.2, 95% CI, 2.3-11.6) Conclusions- Headache and high intrinsic coagulation protein levels may biologically interact, increasing risk for ischemic stroke.

16.
Am J Kidney Dis ; 74(6): 751-760, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31358312

RESUMO

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD), defined as estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2, is a risk factor for cardiovascular morbidity and mortality. Little is known about low birth weight and risk for CKD in middle-aged adults in the general population. We estimated the causal association between birth weight and eGFR in a Dutch cohort of middle-aged men and women. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 6,671 participants in the Netherlands Epidemiology of Obesity (NEO) Study. Replication study using data for 133,814 participants studied by the CKDGen consortium. EXPOSURE: Birth weight was self-reported and also based on an instrumental variable, 59 birth weight-associated genetic variants, derived from an independent data source. OUTCOME: eGFR at the age of 45 to 65 years. ANALYTICAL APPROACH: We assessed the association between self-reported birth weight and eGFR in the NEO Study using multivariable linear regression, adjusted for age, sex, education, smoking, and alcohol use. The effect of the instrument on eGFR was estimated using separate 2-sample Mendelian randomization analyses: one using individual data from the NEO cohort and one using summary data from the CKDGen consortium. RESULTS: At baseline, mean eGFR was 86±12.4 (SD) mL/min/1.73m2. After multivariable adjustment, self-reported birth weight was not associated with kidney function in middle age. Two-sample Mendelian randomization analysis showed that in the NEO cohort, for each 500-g lower birth weight defined using genetic variants, there was a 3.7 (95% CI, 0.5-6.9)-mL/min/1.73m2 lower eGFR at the age of 45 to 65 years. However, using CKDGen summary-level data, there was a smaller nonsignificant relationship between birth weight and eGFR. LIMITATIONS: Birth weight was self-reported. CONCLUSIONS: Lower birth weight defined using genetic variants was associated with lower eGFRs in Dutch middle-aged adults. However, this finding was not replicated within the CKDGen consortium.

17.
PLoS One ; 14(6): e0218549, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220183

RESUMO

INTRODUCTION: It is crucial to understand the factors that introduce variability before applying metabolomics to clinical and biomarker research. OBJECTIVES: We quantified technical and biological variability of both fasting and postprandial metabolite concentrations measured using 1H NMR spectroscopy in plasma samples. METHODS: In the Netherlands Epidemiology of Obesity study (n = 6,671), 148 metabolite concentrations (101 metabolites belonging to lipoprotein subclasses) were measured under fasting and postprandial states (150 minutes after a mixed liquid meal). Technical variability was evaluated among 265 fasting and 851 postprandial samples, with the identical blood plasma sample being measured twice by the same laboratory protocol. Biological reproducibility was assessed by measuring 165 individuals twice across time for evaluation of short- (<6 months) and long-term (>3 years) biological variability. Intra-class coefficients (ICCs) were used to assess variability. The ICCs of the fasting metabolites were compared with the postprandial metabolites using two-sided paired Wilcoxon test separately for short- and long-term measurements. RESULTS: Both fasting and postprandial metabolite concentrations showed high technical reproducibility using 1H NMR spectroscopy (median ICC = 0.99). Postprandial metabolite concentrations revealed slightly higher ICC scores than fasting ones in short-term repeat measures (median ICC in postprandial and fasting metabolite concentrations 0.72 versus 0.67, Wilcoxon p-value = 8.0×10-14). Variability did not increase further in a long-term repeat measure, with median ICC in postprandial of 0.64 and in fasting metabolite concentrations 0.66. CONCLUSION: Technical reproducibility is excellent. Biological reproducibility of postprandial metabolite concentrations showed a less or equal variability than fasting metabolite concentrations over time.

18.
J Clin Epidemiol ; 114: 60-71, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31212001

RESUMO

OBJECTIVES: European regulations do not allow modification or waiver of informed consent for medicines randomized controlled trials (RCTs) where the three 2016 Council for International Organizations of Medical Sciences (CIOMS) provisions are met (consent would be impractical or unfeasible, yet the trial would have high social value and pose no or minimal risk to participants). We aimed to identify whether any such trials of medicines were being conducted in Europe. STUDY DESIGN AND SETTING: This is a survey of all phase 4 "ongoing" RCTs on the EU clinical trial register between July 1, 2016 and June 30, 2018, to identify those with potentially high levels of pragmatism. Trials that were excluded were as follows: those conducted on rare diseases; conducted on healthy volunteers (except those assessing vaccines); masked (single-, double-blind) trials; single-center trials; those where one could expect to lead patients to prefer one intervention over the other; and miscellaneous reasons. The degree of pragmatism of the RCTs was self-assessed by trials' investigators by means of the PRECIS-2 tool. Investigators of those trials considered to be highly pragmatic assessed the fulfillment of the three CIOMS provisions. Seven patients assessed the social value of the RCTs. Finally, 33 members of 11 research ethics committees (RECs) assessed the social value of the trials and whether they posed no more than minimal risk to participants. Investigators, patients, and REC members assessed the fulfillment of the CIOMS provisions as "yes," "not sure" or "no." RESULTS: Of the 638 phase 4 trials, 420 were RCTs, and 21 of these (5%) were candidates to be pragmatic. Investigators of 15 of these 21 RCTs self-assessed their trial's degree of pragmatism: 14 were highly pragmatic. Of these 14, eight fulfilled the three CIOMS provisions. Assessments by patients and RECs were inconsistent for several trials. CONCLUSIONS: We found few low-risk participant-level pragmatic RCTs that could be suitable for modified or waived participants' informed consent. European regulators should consider amending the current regulation and encouraging the conduct of such trials.

19.
J Thromb Haemost ; 17(9): 1535-1543, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31148376

RESUMO

BACKGROUND: Cholesteryl ester transfer protein (CETP) plays an important role in lipoprotein metabolism. Previous studies have suggested that the CETP TaqI B1/B2 allele is associated with the risk of venous thrombosis (VT). AIM: To investigate the associations between genetically determined CETP concentrations and 22 hemostatic factors in healthy individuals, and the risk of a first VT event, in a large VT case-control study. METHODS: Analyses were performed in the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) case-control study. CETP unweighted/weighted genetic risk scores (GRSs) were derived from three single-nucleotide polymorphisms that were identified from a recent genome-wide association study on serum CETP concentrations. The associations between CETP GRSs and 22 hemostatic factors (procoagulant/anticoagulant and fibrinolytic factors) were assessed by linear regression from an additive model in controls (n = 2813). The associations between CETP GRSs and the risk of a first VT were assessed by logistic regression analyses in 3950 VT cases and 4765 controls. RESULTS: In the controls (median age, 49 years; 53% women), both unweighted and weighted GRSs showed that factor VII activity was negatively associated with the genetically determined CETP concentration (weighted GRS ß -3.08 IU/dL per µg/mL genetically determined CETP, 95% confidence interval -5.73 to -0.42). No association was observed with the risk of a first VT. CONCLUSIONS: Genetically determined CETP concentrations only showed a weak negative association with factor VII activity. However, this did not lead to an association with the risk of a first VT.

20.
J Thromb Haemost ; 17(9): 1527-1534, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31188515

RESUMO

BACKGROUND: Several models are available to predict recurrent venous thrombosis (VT) in patients with unprovoked first events. OBJECTIVES: To validate these prediction models externally. METHODS: Within the MEGA follow-up study (n = 3750), we externally validated the Vienna and DASH score. These models were validated (a) by using the original study's criteria for patients with unprovoked VT and (b) by using our own criteria for unprovoked VT. In addition, absolute recurrence risks based on individual VT risk factors were calculated. RESULTS: The recurrence rate was 5.2 (95% CI, 4.6-5.9) per 100 patient-years in those who had a first unprovoked VT according to our definition. For the Vienna model it was 3.4 per 100 patient-years and for DASH 3.8 per 100 patient-years. The C-statistic was 0.62 for Vienna and 0.65 for DASH. The C-statistic declined to 0.58 for both Vienna and DASH when we used our own definition of "unprovoked VT." Within the provoked group a strong gradient in risk was found dependent on the presence of traditional risk factors or biomarkers in a patient. CONCLUSIONS: The ability to distinguish patients' recurrence risks is lower than proposed in the original prediction model studies and dependent on the definition that is used for an unprovoked first event. Furthermore, our results suggest that a more-refined risk estimation is possible, also in patients with a provoked first event, who are currently all classified as low risk.

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