A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.

ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Normal range CAG repeat size variations in the HTT gene are associated with an adverse lipoprotein profile partially mediated by body mass index.

Tandem cytosine-adenine-guanine (CAG) repeat sizes of 36 or more in the huntingtin gene (HTT) cause Huntington's disease (HD). Apart from neuropsychiatric complications, the disease is also accompanied by metabolic dysregulation and weight loss, which contribute to a progressive functional decline. Recent studies also reported an association between repeats below the pathogenic threshold (<36) for HD and body mass index (BMI), suggesting that HTT repeat sizes in the non-pathogenic range are associated with metabolic dysregulation. In this study, we hypothesized that HTT repeat sizes < 36 are associated with metabolite levels, possibly mediated through reduced BMI. We pooled data from three European cohorts (n = 10 228) with genotyped HTT CAG repeat size and metabolomic measurements. All 145 metabolites were measured on the same targeted platform in all studies. Multilevel mixed-effects analysis using the CAG repeat size in HTT identified 67 repeat size metabolite associations. Overall, the metabolomic profile associated with larger CAG repeat sizes in HTT were unfavorable-similar to those of higher risk of coronary artery disease and type 2 diabetes-and included elevated levels of amino acids, fatty acids, low-density lipoprotein (LDL)-, very low-density lipoprotein- and intermediate density lipoprotein (IDL)-related metabolites while with decreased levels of very large high-density lipoprotein (HDL)-related metabolites. Furthermore, the associations of 50 metabolites, in particular, specific very large HDL-related metabolites, were mediated by lower BMI. However, no mediation effect was found for 17 metabolites related to LDL and IDL. In conclusion, our findings indicate that large non-pathogenic CAG repeat sizes in HTT are associated with an unfavorable metabolomic profile despite their association with a lower BMI.

Circulating metabolites modulated by diet are associated with depression.

Metabolome reflects the interplay of genome and exposome at molecular level and thus can provide deep insights into the pathogenesis of a complex disease like major depression. To identify metabolites associated with depression we performed a metabolome-wide association analysis in 13,596 participants from five European population-based cohorts characterized for depression, and circulating metabolites using ultra high-performance liquid chromatography/tandem accurate mass spectrometry (UHPLC/MS/MS) based Metabolon platform. We tested 806 metabolites covering a wide range of biochemical processes including those involved in lipid, amino-acid, energy, carbohydrate, xenobiotic and vitamin metabolism for their association with depression. In a conservative model adjusting for life style factors and cardiovascular and antidepressant medication use we identified 8 metabolites, including 6 novel, significantly associated with depression. In individuals with depression, increased levels of retinol (vitamin A), 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1) (lecithin) and mannitol/sorbitol and lower levels of hippurate, 4-hydroxycoumarin, 2-aminooctanoate (alpha-aminocaprylic acid), 10-undecenoate (11:1n1) (undecylenic acid), 1-linoleoyl-GPA (18:2) (lysophosphatidic acid; LPA 18:2) are observed. These metabolites are either directly food derived or are products of host and gut microbial metabolism of food-derived products. Our Mendelian randomization analysis suggests that low hippurate levels may be in the causal pathway leading towards depression. Our findings highlight putative actionable targets for depression prevention that are easily modifiable through diet interventions.

Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels.

BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.

Challenges in conducting efficacy trials for new COVID-19 vaccines in developed countries.

The protection from COVID-19 vaccination wanes a few months post-administration of the primary vaccination series or booster doses. New COVID-19 vaccine candidates aiming to help control COVID-19 should show long-term efficacy, allowing a possible annual administration. Until correlates of protection are strongly associated with long-term protection, it has been suggested that any new COVID-19 vaccine candidate must demonstrate at least 75% efficacy (although a 40%-60% efficacy would be sufficient) at 12 months in preventing illness in all age groups within a large randomized controlled efficacy trial. This article discusses four of the many scientific, ethical, and operational challenges that these trials will face in developed countries, focusing on a pivotal trial in adults. These challenges are (1) the comparator and trial population; (2) how to enroll sufficient numbers of adult participants of all age groups considering that countries will recommend COVID-19 booster doses to different populations; (3) whether having access to a comparator booster for the trial is actually feasible; and (4) the changing epidemiology of severe acute respiratory syndrome coronavirus 2 across countries involved in the trial. It is desirable that regulatory agencies publish guidance on the requirements that a trial like the one discussed should comply with to be acceptable from a regulatory standpoint. Ideally, this should happen even before there is a vaccine candidate that could fulfill the requirements mentioned above, as it would allow an open discussion among all stakeholders on its appropriateness and feasibility.

Timing of physical activity in relation to liver fat content and insulin resistance.

AIMS/HYPOTHESIS: We hypothesised that the insulin-sensitising effect of physical activity depends on the timing of the activity. Here, we examined cross-sectional associations of breaks in sedentary time and timing of physical activity with liver fat content and insulin resistance in a Dutch cohort. METHODS: In 775 participants of the Netherlands Epidemiology of Obesity (NEO) study, we assessed sedentary time, breaks in sedentary time and different intensities of physical activity using activity sensors, and liver fat content by magnetic resonance spectroscopy (n=256). Participants were categorised as being most active in the morning (06:00-12:00 hours), afternoon (12:00-18:00 hours) or evening (18:00-00:00 hours) or as engaging in moderate-to-vigorous-physical activity (MVPA) evenly distributed throughout the day. Most active in a certain time block was defined as spending the majority (%) of total daily MVPA in that block. We examined associations between sedentary time, breaks and timing of MVPA with liver fat content and HOMA-IR using linear regression analyses, adjusted for demographic and lifestyle factors including total body fat. Associations of timing of MVPA were additionally adjusted for total MVPA. RESULTS: The participants (42% men) had a mean (SD) age of 56 (4) years and a mean (SD) BMI of 26.2 (4.1) kg/m2. Total sedentary time was not associated with liver fat content or insulin resistance, whereas the amount of breaks in sedentary time was associated with higher liver fat content. Total MVPA (-5%/h [95% CI -10%/h, 0%/h]) and timing of MVPA were associated with reduced insulin resistance but not with liver fat content. Compared with participants who had an even distribution of MVPA throughout the day, insulin resistance was similar (-3% [95% CI -25%, 16%]) in those most active in morning, whereas it was reduced in participants who were most active in the afternoon (-18% [95% CI -33%, -2%]) or evening (-25% [95% CI -49%, -4%]). CONCLUSIONS/INTERPRETATION: The number of daily breaks in sedentary time was not associated with lower liver fat content or reduced insulin resistance. Moderate-to-vigorous activity in the afternoon or evening was associated with a reduction of up to 25% in insulin resistance. Further studies should assess whether timing of physical activity is also important for the occurrence of type 2 diabetes.

Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors.

BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Determination and characterization of patient subgroups based on pain trajectories in hand osteoarthritis.

OBJECTIVES: To investigate pain, pain trajectories and their determinants in hand osteoarthritis (OA). METHODS: Data from the HOSTAS (Hand OSTeoArthritis in Secondary care) consisting of consecutive hand OA patients were used. Australian Canadian Osteoarthritis Hand Index (AUSCAN) pain was measured yearly for four years. Patients with complete AUSCAN at ≥2 time points were eligible for longitudinal analysis. Associations between variables of interest and baseline AUSCAN pain were investigated with linear regression. Development of pain over time was modelled using latent class growth analysis (LCGA). Associations of LCGA classes with variables of interest were analysed using multinomial logistic regression adjusted for baseline pain. RESULTS: A total of 484/538 patients [mean (s.d.) age 60.8 (8.5) years, 86% women, mean (s.d.) AUSCAN pain 9.3 (4.3)] were eligible for longitudinal analysis. Sex, marital and working status, education, disease duration and severity, anxiety and depression scores, lower health-related quality of life (HR-QoL), specific illness perceptions and coping styles were associated with baseline pain. LCGA yielded three classes, characterized by average pain levels at baseline; average pain remained stable over time within classes. Classes with more pain were positively associated with BMI, tender joint count, symptom duration, hand function scores and depression scores, negatively with physical HR-QoL, and education level. CONCLUSION: Baseline pain was associated with patient and disease characteristics, and psychosocial factors. LCGA showed three pain trajectories in hand OA patients, with different baseline pain levels and stable pain over time. Classes were distinguished by BMI, education level, disease severity, depression and HR-QoL.

Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation.

Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, âˆ¼1.2), the A1 and B haplotypes are associated with an âˆ¼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, âˆ¼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.

Metabolomics dissection of depression heterogeneity and related cardiometabolic risk.

BACKGROUND: A recent hypothesis postulates the existence of an 'immune-metabolic depression' (IMD) dimension characterized by metabolic dysregulations. Combining data on metabolomics and depressive symptoms, we aimed to identify depressions associated with an increased risk of adverse metabolic alterations. METHOD: Clustering data were from 1094 individuals with major depressive disorder in the last 6 months and measures of 149 metabolites from a 1H-NMR platform and 30 depressive symptoms (IDS-SR30). Canonical correlation analyses (CCA) were used to identify main independent metabolite-symptom axes of variance. Then, for the replication, we examined the association of the identified dimensions with metabolites from the same platform and cardiometabolic diseases in an independent population-based cohort (n = 6572). RESULTS: CCA identified an overall depression dimension and a dimension resembling IMD, in which symptoms such as sleeping too much, increased appetite, and low energy level had higher relative loading. In the independent sample, the overall depression dimension was associated with lower cardiometabolic risk, such as (i.e. per s.d.) HOMA-1B -0.06 (95% CI -0.09 - -0.04), and visceral adipose tissue -0.10 cm2 (95% CI -0.14 - -0.07). In contrast, the IMD dimension was associated with well-known cardiometabolic diseases such as higher visceral adipose tissue 0.08 cm2 (95% CI 0.04-0.12), HOMA-1B 0.06 (95% CI 0.04-0.09), and lower HDL-cholesterol levels -0.03 mmol/L (95% CI -0.05 - -0.01). CONCLUSIONS: Combining metabolomics and clinical symptoms we identified a replicable depression dimension associated with adverse metabolic alterations, in line with the IMD hypothesis. Patients with IMD may be at higher cardiometabolic risk and may benefit from specific treatment targeting underlying metabolic dysregulations.

The association between adiposity and atypical energy-related symptoms of depression: A role for metabolic dysregulations.

BACKGROUND: Adiposity has been shown to be linked with atypical energy-related symptoms (AES) of depression. We used genomics to separate the effect of adiposity from that of metabolic dysregulations to examine whether the link between obesity and AES is dependent on the presence of metabolic dysregulations. METHOD: Data were from NEO (n = 5734 individuals) and NESDA (n = 2238 individuals) cohorts, in which the Inventory of Depressive Symptomatology (IDS-SR30) was assessed. AES profile was based on four symptoms: increased appetite, increased weight, low energy level, and leaden paralysis. We estimated associations between AES and two genetic risk scores (GRS) indexing increasing total body fat with (metabolically unhealthy adiposity, GRS-MUA) and without (metabolically healthy adiposity, GRS-MHA) metabolic dysregulations. RESULTS: We validated that both GRS-MUA and GRS-MHA were associated with higher total body fat in NEO study, but divergently associated with biomarkers of metabolic health (e.g., fasting glucose and HDL-cholesterol) in both cohorts. In the pooled results, per standard deviation, GRS-MUA was specifically associated with a higher AES score (ß = 0.03, 95%CI: 0.01; 0.05), while there was no association between GRS-MHA and AES (ß = -0.01, 95%CI: -0.03; 0.01). CONCLUSION: These results suggest that the established link between adiposity and AES profile emerges in the presence of metabolic dysregulations, which may represent the connecting substrate between the two conditions.

Transition readiness among adolescents and young adults with haemophilia in the Netherlands: Nationwide questionnaire study.

INTRODUCTION: Care for adolescents with haemophilia is transferred from paediatric to adult care around the age of 18 years. Transition programs help to prepare adolescents for this transfer and prevent declining treatment adherence. Evaluating transition readiness may identify areas for improvement. OBJECTIVE: Assess transition readiness among Dutch adolescents and young adults with haemophilia, determine factors associated with transition readiness, and identify areas of improvement in transition programs. METHODS: All Dutch adolescents and young adults aged 12-25 years with haemophilia were invited to participate in a nationwide questionnaire study. Transition readiness was assessed using multiple-choice questions and was defined as being ready or almost ready for transition. Potential factors associated with transition readiness were investigated, including: socio-demographic and disease-related factors, treatment adherence, health-related quality of life, and self-efficacy. RESULTS: Data of 45 adolescents and 84 young adults with haemophilia (47% with severe haemophilia) were analyzed. Transition readiness increased with age, from 39% in 12-14 year-olds to 63% in 15-17 year-olds. Nearly all post-transition young adults (92%, 77/84) reported they were ready for transition. Transition readiness was associated with treatment adherence, as median VERITAS-Pro treatment adherence scores were worse in patients who were not ready (17, IQR 9-29), compared to those ready for transition (11, IQR 9-16). Potential improvements were identified: getting better acquainted with the adult treatment team prior to transition and information on managing healthcare costs. CONCLUSIONS: Nearly all post-transition young adults reported they were ready for transition. Improvements were identified regarding team acquaintance and preparation for managing healthcare costs.

Hepatic triglyceride content is intricately associated with numerous metabolites and biochemical pathways.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of triglycerides in hepatocytes and is associated with insulin resistance, atherogenic dyslipidaemia and cardiometabolic diseases. Thus far, the extent of metabolic dysregulation associated with hepatic triglyceride accumulation has not been fully addressed. In this study, we aimed to identify metabolites associated with hepatic triglyceride content (HTGC) and map these associations using network analysis. METHODS: To gain insight in the spectrum of metabolites associated with hepatic triglyceride accumulation, we performed a comprehensive plasma metabolomics screening of 1363 metabolites in apparently healthy middle aged (age 45-65) individuals (N = 496) in whom HTGC was measured by proton magnetic resonance spectroscopy. An atlas of metabolite-HTGC associations, based on univariate results, was created using correlation-based Gaussian graphical model (GGM) and genome scale metabolic model network analyses. Pathways associated with the clinical prognosis marker fibrosis 4 (FIB-4) index were tested using a closed global test. RESULTS: Our analyses revealed that 118 metabolites were univariately associated with HTGC (p-value <6.59 × 10-5 ), including 106 endogenous, 1 xenobiotic and 11 partially characterized/uncharacterized metabolites. These associations were mapped to several biological pathways including branched amino acids (BCAA), diglycerols, sphingomyelin, glucosyl-ceramide and lactosyl-ceramide. We also identified a novel possible HTGC-related pathway connecting glutamate, metabolonic lactone sulphate and X-15245 using the GGM network. These pathways were confirmed to be associated with the FIB-4 index as well. The full interactive metabolite-HTGC atlas is provided online: https://tofaquih.github.io/AtlasLiver/. CONCLUSIONS: The combined network and pathway analyses indicated extensive associations between BCAA and the lipids pathways with HTGC and the FIB-4 index. Moreover, we report a novel pathway glutamate-metabolonic lactone sulphate-X-15245 with a potential strong association with HTGC. These findings can aid elucidating HTGC metabolomic profiles and provide insight into novel drug targets for fibrosis-related outcomes.

Association of ABO blood groups with venous thrombosis recurrence in middle-aged patients: insights from a weighted Cox analysis dedicated to ambispective design.

BACKGROUND: In studies of time-to-events, it is common to collect information about events that occurred before the inclusion in a prospective cohort. When the studied risk factors are independent of time, including both pre- and post-inclusion events in the analyses, generally referred to as relying on an ambispective design, increases the statistical power but may lead to a selection bias. In the field of venous thromboembolism (VT), ABO blood groups have been the subject of extensive research due to their substantial effect on VT risk. However, few studies have investigated their effect on the risk of VT recurrence. Motivated by the study of the association of genetically determined ABO blood groups with VT recurrence, we propose a methodology to include pre-inclusion events in the analysis of ambispective studies while avoiding the selection bias due to mortality. METHODS: This work relies on two independent cohorts of VT patients, the French MARTHA study built on an ambispective design and the Dutch MEGA study built on a standard prospective design. For the analysis of the MARTHA study, a weighted Cox model was developed where weights were defined by the inverse of the survival probability at the time of data collection about the events. Thanks to the collection of information on the vital status of patients, we could estimate the survival probabilities using a delayed-entry Cox model on the death risk. Finally, results obtained in both studies were then meta-analysed. RESULTS: In the combined sample totalling 2,752 patients including 993 recurrences, the A1 blood group has an increased risk (Hazard Ratio (HR) of 1.18, p = 4.2 × 10-3) compared with the O1 group, homogeneously in MARTHA and in MEGA. The same trend (HR = 1.19, p = 0.06) was observed for the less frequent A2 group. CONCLUSION: The proposed methodology increases the power of studies relying on an ambispective design which is frequent in epidemiologic studies about recurrent events. This approach allowed to clarify the association of ABO blood groups with the risk of VT recurrence. Besides, this methodology has an immediate field of application in the context of genome wide association studies.

Out-of-hospital opioid prescriptions after knee and hip arthroplasty: prescribers and the first prescribed opioid.

BACKGROUND: We determined the first prescribed opioid and the prescribers of opioids after knee and hip arthroplasty (KA/HA) between 2013 and 2018 in the Netherlands. We also evaluated whether the first prescribed opioid dose was associated with the total dispensed dose and long-term opioid use in the first postoperative year. METHODS: The Dutch Foundation for Pharmaceutical Statistics was linked to the Dutch Arthroplasty Register. Stratified for KA/HA, the first out-of-hospital opioid within 30 days of operation was quantified as median morphine milligram equivalent (MME). Opioid prescribers were orthopaedic surgeons, general practitioners, rheumatologists, anaesthesiologists, and other physicians. Long-term use was defined as ≥1 opioid prescription for >90 postoperative days. We used linear and logistic regression analyses adjusted for confounders. RESULTS: Seventy percent of 46 106 KAs and 51% of the 42 893 HAs were prescribed ≥1 opioid. Oxycodone increased as first prescribed opioid (from 44% to 85%) whereas tramadol decreased (64-11%), but their dosage remained stable (stronger opioids were preferred by prescribers). An increase in the first prescription of 1% MME resulted in a 0.43%/0.37% increase in total MME (KA/HA, respectively). A 100 MME increase in dose of the first dispensed opioid had a small effect on long-term use (prevalence: 25% KA, 20% HA) (odds ratio=1.02/1.01 for KA/HA, respectively). Orthopaedic surgeons increasingly prescribed the first prescription between 2013 and 2018 (44-69%). General practitioners mostly prescribed consecutive prescriptions (>50%). CONCLUSION: Oxycodone increased as first out-of-hospital prescription between 2013 and 2018. The dose of the first prescribed opioid was associated with the total dose and a small increased risk of prolonged use. First prescriptions were mostly written by orthopaedic surgeons and consecutive prescriptions by general practitioners.

Prevalence of non-alcoholic fatty liver in the general Dutch population and in groups at increased risk.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is defined as a liver fat content ≥5.56%. It is of clinical interest to know the prevalence of NAFLD in people with a combination of metabolic risk factors. We aimed to examine the prevalence of NAFLD, including groups with metabolic risk factors. METHODS AND RESULTS: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity (NEO) study, liver fat content was assessed using proton magnetic resonance spectroscopy (H-MRS). Participants with excessive alcohol consumption or missing values were excluded, leaving a total of 1570 participants for the analyses. Mean (SD) age of the population was 55 years, BMI 25.9 (4.0) kg/m2 and 46% were men. The prevalence of NAFLD was 27% (95% CI 24-30). The prevalence of NAFLD was increased in participants with hypertriglyceridemia (57%, 52-63), obesity (62%, 58-66) and diabetes (69%, 61-77). The prevalence of NAFLD was highest in those with diabetes and obesity (79%, 71-87), obesity and hypertriglyceridemia (81%, 76-86) and with diabetes and hypertriglyceridemia (86%, 77-95). NAFLD was also present in 12% (8-16) of participants without overweight. CONCLUSIONS: The prevalence of NAFLD in a middle-aged population in the Netherlands in 2010 was 27%. The prevalence of NAFLD is particularly increased in individuals with diabetes, obesity, and hypertriglyceridemia. This information may help clinicians and general practitioners in the risk stratification of their patients in daily practice.

The association between leptin and subclinical cardiovascular disease explained by body fat: Observational and Mendelian randomization analyses.

BACKGROUND AND AIMS: Leptin has been associated with adverse effects on cardiovascular disease, but the effect of confounding by body fat in these associations remains unclear. To investigate associations between leptin and heart function and subclinical cardiovascular disease adjusted for total body fat, and to investigate the causal relation between leptin and cardiovascular disease using Mendelian randomisation. METHODS AND RESULTS: Leptin concentrations, total body fat and diverse measures of subclinical cardiovascular disease were determined in participants of the Netherlands Epidemiology of Obesity study. Linear regression between leptin concentration and measures of heart function, ECG measures, and carotid intima media thickness as a measure of subclinical atherosclerosis was adjusted for potential confounding factors, and additionally including total body fat. We analysed the combined effects of genetic variants from a GWAS on leptin concentrations in publicly-available summary statistics of coronary heart disease GWAS (CARDIoGRAMplusC4D, n = 184,305). As many as 6107 men and women, mean (SD) age 56 (6) years, BMI 26 (4) kg/m2, and median leptin concentration 12.1 µg (IQR: 6.7-22.6) were included. In observational analyses, leptin was weakly associated with heart function and subclinical cardiovascular disease, but these associations attenuated when adjusting for total body fat. A doubling of genetically-determined leptin concentration was associated with an odds ratio of cardiovascular disease of 0.69 (0.37, 1.27). CONCLUSION: Observational associations between leptin and subclinical measures of cardiovascular disease were largely explained by differences in total body fat. Results of analyses of genetically-determined leptin and coronary heart disease risk were inconclusive due to a large confidence interval.

What Changes Have Occurred in Opioid Prescriptions and the Prescribers of Opioids Before TKA and THA? A Large National Registry Study.

BACKGROUND: Opioid use before TKA or THA is linked to a higher risk of revision surgery and less functional improvement. In Western countries, the frequency of preoperative opioid use has varied, and robust information on temporal changes in opioid prescriptions over time (in the months before surgery as well as annual changes) and among prescribers is necessary to pinpoint opportunities to improve on low-value care patterns, and when they are recognized, to target physician populations for intervention strategies. QUESTIONS/PURPOSES: (1) What proportion of patients undergoing arthroplasties receive an opioid prescription in the year before TKA or THA, and what were the preoperative opioid prescription rates over time between 2013 and 2018? (2) Does the preoperative prescription rate vary between 12 and 10 months and between 3 and 1 months in the year before TKA or THA, and did it change between 2013 and 2018? (3) Which medical professionals were the main prescribers of preoperative opioids 1 year before TKA or THA? METHODS: This was a large-database study drawn from longitudinally maintained national registry sources in the Netherlands. The Dutch Foundation for Pharmaceutical Statistics was linked to the Dutch Arthroplasty Register from 2013 to 2018. TKAs and THAs performed because of osteoarthritis in patients older than 18 years, which were also uniquely linked by age, gender, patient postcode, and low-molecular weight heparin use, were eligible. Between 2013 and 2018, 146,052 TKAs were performed: 96% (139,998) of the TKAs were performed for osteoarthritis in patients older than 18 years; of them, 56% (78,282) were excluded because of our linkage criteria. Some of the linked arthroplasties could not be linked to a community pharmacy, which was necessary to follow patients over time, leaving 28% (40,989) of the initial TKAs as our study population. Between 2013 and 2018, 174,116 THAs were performed: 86% (150,574) were performed for osteoarthritis in patients older than 18 years, one arthroplasty was excluded because of an outlier opioid dose, and a further 57% (85,724 of 150,574) were excluded because of our linkage criteria. Some of the linked arthroplasties could not be linked to a community pharmacy, leaving 28% (42,689 of 150,574) of THAs, which were performed between 2013 and 2018. For both TKA and THA, the mean age before surgery was 68 years, and roughly 60% of the population were women. We calculated the proportion of patients undergoing arthroplasties who had at least one opioid prescription in the year before arthroplasty and compared data from 2013 to 2018. Opioid prescription rates are given as defined daily dosages and morphine milligram equivalents (MMEs) per arthroplasty. Opioid prescriptions were assessed by preoperative quarter and by operation year. Possible changes over time in opioid exposure were investigated using linear regression, adjusted for age and gender, in which the month of operation since January 2013 was used as the determinant and MME as the outcome. This was done for all opioids combined and per opioid type. Possible changes in opioid prescription rates in the year before arthroplasty were assessed by comparing the time period of 1 to 3 months before surgery with the other quarters. Additionally, preoperative prescriptions per operation year were assessed per prescriber category: general practitioners, orthopaedic surgeons, rheumatologists, and others. All analyses were stratified by TKA or THA. RESULTS: The proportion of patients undergoing arthroplasties who had an opioid prescription before TKA increased from 25% (1079 of 4298) in 2013 to 28% (2097 of 7460) in 2018 (difference 3% [95% CI 1.35% to 4.65%]; p < 0.001), and before THA increased from 25% (1111 to 4451) to 30% (2323 to 7625) (difference 5% [95% CI 3.8% to 7.2%]; p < 0.001). The mean preoperative opioid prescription rate increased over time between 2013 and 2018 for both TKA and THA. For TKA, an adjusted monthly increase of 3.96 MME was observed (95% CI 1.8 to 6.1 MME; p < 0.001). For THA, the monthly increase was 3.8 MME (95% CI 1.5 to 6.0; p = 0.001. For both TKA and THA, there was a monthly increase in the preoperative oxycodone rate (3.8 MME [95% CI 2.5 to 5.1]; p < 0.001 and 3.6 [95% CI 2.6 to 4.7]; p < 0.001, respectively). For TKA, but not for THA, there was a monthly decrease in tramadol prescriptions (-0.6 MME [95% CI -1.0 to -0.2]; p = 0.006). Regarding the opioids prescribed in the year before surgery, there was a mean increase of 48 MME (95% CI 39.3 to 56.7 MME; p < 0.001) for TKA between 10 and 12 months and the last 3 months before surgery. For THA, this increase was 121 MME (95% CI 110 to 131 MME; p < 0.001). Regarding possible differences between 2013 and 2018, we only found differences in the period 10 to 12 months before TKA (mean difference 61 MME [95% CI 19.2 to 103.3]; p = 0.004) and the period 7 to 9 months before TKA (mean difference 66 MME [95% CI 22.0 to 110.9]; p = 0.003). For THA, there was an increase in the MMEs prescribed between 2013 and 2018 for all four quarters, with mean differences ranging from 43.9 to 55.4 MME (p < 0.05). The average proportion of preoperative opioid prescriptions prescribed by general practitioners ranged between 82% and 86% (41,037 of 49,855 for TKA and 49,137 of 57,289 for THA), between 4% and 6% (2924 of 49,855 for TKA and 2461 of 57,289 for THA), by orthopaedic surgeons, 1% by rheumatologists (409 of 49,855 for TKA and 370 of 57,289 for THA), and between 9% and 11% by other physicians (5485 of 49,855 for TKA and 5321 of 57,289 for THA). Prescriptions by orthopaedic surgeons increased over time, from 3% to 7% for THA (difference 4% [95% CI 3.6 to 4.9]) and 4% to 10% for TKA (difference 6% [95% CI 5% to 7%]; p < 0.001). CONCLUSION: Between 2013 and 2018, preoperative opioid prescriptions increased in the Netherlands, mainly because of a shift to more oxycodone prescriptions. We also observed an increase in opioid prescriptions in the year before surgery. Although general practitioners were the main prescribers of preoperative oxycodone, prescriptions by orthopaedic surgeons also increased during the study period. Orthopaedic surgeons should address opioid use and its associated negative effects in preoperative consultations. More intradisciplinary collaboration seems important to limit the prescribing of preoperative opioids. Additionally, research is necessary to assess whether opioid cessation before surgery reduces the risk of adverse outcomes. LEVEL OF EVIDENCE: Level III, therapeutic study.

Apolipoprotein A-V is a potential target for treating coronary artery disease: evidence from genetic and metabolomic analyses.

Triglyceride (TG)-lowering LPL variants in combination with genetic LDL-C-lowering variants are associated with reduced risk of coronary artery disease (CAD). Genetic variation in the APOA5 gene encoding apolipoprotein A-V also strongly affects TG levels, but the potential clinical impact and underlying mechanisms are yet to be resolved. Here, we aimed to study the effects of APOA5 genetic variation on CAD risk and plasma lipoproteins through factorial genetic association analyses. Using data from 309,780 European-ancestry participants from the UK Biobank, we evaluated the effects of lower TG levels as a result of genetic variation in APOA5 and/or LPL on CAD risk with or without a background of reduced LDL-C. Next, we compared lower TG levels via APOA5 and LPL variation with over 100 lipoprotein measurements in a combined sample from the Netherlands Epidemiology of Obesity study (N = 4,838) and the Oxford Biobank (N = 6,999). We found that lower TG levels due to combined APOA5 and LPL variation and genetically-influenced lower LDL-C levels afforded the largest reduction in CAD risk (odds ratio: 0.78 (0.73-0.82)). Compared to patients with genetically-influenced lower TG via LPL, genetically-influenced lower TG via APOA5 had similar and independent, but notably larger, effects on the lipoprotein profile. Our results suggest that lower TG levels as a result of APOA5 variation have strong beneficial effects on CAD risk and the lipoprotein profile, which suggest apo A-V may be a potential novel therapeutic target for CAD prevention.

Evaluation of the Value of Waist Circumference and Metabolomics in the Estimation of Visceral Adipose Tissue.

Visceral adipose tissue (VAT) is a strong prognostic factor for cardiovascular disease and a potential target for cardiovascular risk stratification. Because VAT is difficult to measure in clinical practice, we estimated prediction models with predictors routinely measured in general practice and VAT as outcome using ridge regression in 2,501 middle-aged participants from the Netherlands Epidemiology of Obesity study, 2008-2012. Adding waist circumference and other anthropometric measurements on top of the routinely measured variables improved the optimism-adjusted R2 from 0.50 to 0.58 with a decrease in the root-mean-square error (RMSE) from 45.6 to 41.5 cm2 and with overall good calibration. Further addition of predominantly lipoprotein-related metabolites from the Nightingale platform did not improve the optimism-corrected R2 and RMSE. The models were externally validated in 370 participants from the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS, 2006-2009) and 1,901 participants from the Multi-Ethnic Study of Atherosclerosis (MESA, 2000-2007). Performance was comparable to the development setting in PIVUS (R2 = 0.63, RMSE = 42.4 cm2, calibration slope = 0.94) but lower in MESA (R2 = 0.44, RMSE = 60.7 cm2, calibration slope = 0.75). Our findings indicate that the estimation of VAT with routine clinical measurements can be substantially improved by incorporating waist circumference but not by metabolite measurements.