Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1,2,3,4,5,6,7. This detailed knowledge of the genetic... Show moreGenome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1,2,3,4,5,6,7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8,9,10,11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases. Show less
Per- and polyfluoroalkyl substances (PFAS) are widely used and persistent chemicals, leading to ubiquitous exposure. Although high PFAS levels have been associated with an adverse cardiovascular... Show morePer- and polyfluoroalkyl substances (PFAS) are widely used and persistent chemicals, leading to ubiquitous exposure. Although high PFAS levels have been associated with an adverse cardiovascular risk profile, the distribution of levels and relations with cardio-metabolic risk markers in the general population have not been fully characterized. We assessed the association between blood levels of perfluorooctaneic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) and a range of lipoproteins and metabolites as well as clinical lipid measurements. We used data from participants of the Netherlands Epidemiology of Obesity study (NEO) (n = 584) and the Rhineland Study (n = 1962), jointly spanning an age range of 30 to 89 years. PFAS were measured with the Metabolon HD4 platform, and lipoprotein and metabolite profiles were measured using Nightingale's nuclear magnetic resonance-spectroscopy platform, and mainly comprised lipoprotein markers. Using linear regression analyses, we quantified age-, sex-, and education-adjusted associations of PFOA, PFOS, and PFHxS with clinical lipid measurements and 224 lipoproteins and metabolites. Higher levels of PFAS, particularly PFOS and PFHxS, were associated with higher concentrations of total lipid, cholesterol and phospholipid content in most HDL, IDL, LDL, and VLDL subclasses. The effect sizes were age-dependent for the majority of the associations, with the deleterious effects of PFAS being generally stronger in people below compared to those above median age. Our observation that in the general population even low PFAS concentrations are associated with an unfavorable lipid profile, calls for further critical regulation of PFAS substances. Show less
Vegte, Y. van de; Eppinga, R.N.; Ende, M.Y. van der; Hagemeijer, Y.; Mahendran, Y.V.; Salfati, E.Y.; ... ; DCCT EDIC Res Grp 2023
The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher... Show moreThe genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke.Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development. Show less
Christen, T.; Mutsert, R. de; Smit, R.A.; Dijk, K.W. van; Lamb, H.J.; Rosendaal, F.R.; ... ; Trompet, S. 2023
Background and aims: Leptin has been associated with adverse effects on cardiovascu-lar disease, but the effect of confounding by body fat in these associations remains unclear. To investigate... Show moreBackground and aims: Leptin has been associated with adverse effects on cardiovascu-lar 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 cardiovas-cular disease using Mendelian randomisation.Methods and results: Leptin concentrations, total body fat and diverse measures of subclinical car-diovascular disease were determined in participants of the Netherlands Epidemiology of Obesity study. Linear regression between leptin concentration and measures of heart function, ECG mea-sures, 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 Z 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 mg (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 cardiovascu-lar 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. 2023 The Authors. Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Ital-ian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Background: It is unclear to what extent mental health and negative life events (NLEs) contribute to weight change in patients with overweight. This study aimed to evaluate the association of... Show moreBackground: It is unclear to what extent mental health and negative life events (NLEs) contribute to weight change in patients with overweight. This study aimed to evaluate the association of anxiety, depression, NLEs and quality of life (QoL) with weight change over ten years in middle-aged individuals with overweight.Methods: Population-based cohort study of 2889 middle-aged men and women with a body mass index ≥27 kg/m2. Relative weight change over ten years was defined as weight loss (≤- 5 %), stable weight (between >- 5 % and <5 %) or weight gain (≥5 %). At baseline, participants reported anxiety symptoms, depressive symptoms, recent (last year) and distant (lifetime) NLEs, and a mental component summary of QoL. With multinomial logistic regression adjusting for potential confounding, we examined the association of mental health and NLEs with weight change after a median (25th, 75th percentiles) follow-up of 9.7 (9.0-10.5) years.Results: In 51 % participants weight was stable, 33 % participants lost weight and 17 % gained weight. Mild (odds ratio 1.36; 95 % confidence interval 1.05-1.75), and moderate to very severe depressive symptoms (1.43; 0.97-2.12) and four or more distant NLEs (1.35; 1.10-1.67) were associated with weight gain. Anxiety symptoms, the mental component summary of QoL were not associated with either weight gain or weight loss.Limitations: Due to the observational design residual confounding cannot be excluded.Conclusion: Our study suggests that depressive symptoms or having experienced distant NLEs are associated with weight gain over time in middle-aged individuals with overweight. These subgroups might benefit from proactive attention from their health care providers.Keywords: Body weight changes; Life change events; Longitudinal study; Mental health; Overweight. Show less
BackgroundIt is unclear to what extent mental health and negative life events (NLEs) contribute to weight changein patients with overweight. This study aimed to evaluate the association of anxiety... Show moreBackgroundIt is unclear to what extent mental health and negative life events (NLEs) contribute to weight changein patients with overweight. This study aimed to evaluate the association of anxiety, depression, NLEs and quality of life (QoL) with weight change over ten years in middle-aged individuals with overweight.MethodsPopulation-based cohort study of 2889 middle-aged men and women with a body mass index ≥27 kg/m2. Relative weight change over ten years was defined as weight loss (≤− 5 %), stable weight (between >− 5 % and <5 %) or weight gain (≥5 %). At baseline, participants reported anxiety symptoms, depressive symptoms, recent (last year) and distant (lifetime) NLEs, and a mental component summary of QoL. With multinomial logistic regression adjusting for potential confounding, we examined the association of mental health and NLEs with weight change after a median (25th, 75th percentiles) follow-up of 9.7 (9.0–10.5) years.ResultsIn 51 % participants weight was stable, 33 % participants lost weight and 17 % gained weight. Mild (odds ratio 1.36; 95 % confidence interval 1.05–1.75), and moderate to very severe depressive symptoms (1.43; 0.97–2.12) and four or more distant NLEs (1.35; 1.10–1.67) were associated with weight gain. Anxiety symptoms, the mental component summary of QoL were not associated with either weight gain or weight loss.LimitationsDue to the observational design residual confounding cannot be excluded.ConclusionOur study suggests that depressive symptoms or having experienced distant NLEs are associated with weight gain over time in middle-aged individuals with overweight. These subgroups might benefit from proactive attention from their health care providers. Show less
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,... Show moreBackground 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 x 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: . 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. Show less
Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of... Show moreIdentifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.Mathieson et al. carried out a genome-wide association study of reproductive success (number of children born) in humans, revealing the importance of diverse neuro-endocrine and behavioural factors. Show less
Background: Current guidelines aim to limit the dietary glycemic index (GI) and intake of saturated fatty acids (SFA). Several studies have shown favorable effects of low-GI or low-SFA diets on... Show moreBackground: Current guidelines aim to limit the dietary glycemic index (GI) and intake of saturated fatty acids (SFA). Several studies have shown favorable effects of low-GI or low-SFA diets on intrahepatic lipid content (IHL), but these studies were performed under overfeeding conditions or extreme differences in GI or SFA to maximize the contrast between diets. By combining changes in GI and SFA, we can mimic how people can improve their diet in a realistic setting. Objectives: We investigated the effect on liver fat content and substrate metabolism of both reducing GI and replacing SFA with polyunsaturated fat in practically realistic amounts under isocaloric conditions. Design and Methods: In a randomized crossover study, thirteen overweight participants consumed two diets, one high in GI and SFA (high GI/SFA) and one low in GI and SFA (low GI/SFA) with identical macronutrient composition, for two weeks each. Diets were equal in caloric content, consisted of habitual food items, and had a macronutrient composition that can be easily achieved in daily life. At the end of each intervention, IHL content/composition and liver glycogen were measured by magnetic resonance spectroscopy. Additionally, fasted and postprandial hepatic de novo lipogenesis and glycemic and metabolic responses were investigated. Results: IHL was significantly lower (-28%) after the two-week low-GI/SFA diet (2.4 +/- 0.5% 95% CI [1.4, 3.4]) than after the two-week high-GI/SFA diet (3.3 +/- 0.6% 95% CI [1.9, 4.7], p < 0.05). Although hepatic glycogen content, hepatic de novo lipogenesis, hepatic lipid composition, and substrate oxidation during the night were similar between the two diets, the glycemic response to the low-GI/SFA diet was reduced (p < 0.05). Conclusions: Changes in macronutrient quality can already have drastic effects on liver fat content and postprandial glycemia after two weeks and even when energy content and the percentage of total fat and carbohydrate remains unchanged. Show less
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... Show moreTandem 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. Show less
Alshehri, T.; Mook-Kanamori, D.O.; Mutsert, R. de; Penninx, B.W.J.H.; Rosendaal, F.R.; Cessie, S. le; Milaneschi, Y. 2022
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... Show moreBackground: 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 (beta = 0.03, 95%CI: 0.01; 0.05), while there was no association between GRS-MHA and AES (beta =-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. Show less
Velde, J.H.P.M. van der; Boone, S.C.; Winters-van Eekelen, E.; Hesselink, M.K.C.; Schrauwen-Hinderling, V.B.; Schrauwen, P.; ... ; Mutsert, R. de 2022
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... Show moreAims/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 (12:0018:00 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/m(2). 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. Show less
Duijl, T.T. van; Ruhaak, R.; Hoogeveen, E.; Mutsert, R. de; Rosendaal, F.; Cessie, S. le; ... ; Cobbaert, C. 2022
Background and aims: There is an ongoing need to recognize early kidney injury and its progression in structural chronic pathologies. The proteins NGAL, IGFBP7, TIMP2, KIM-1, CXCL9, TGF-beta 1,... Show moreBackground and aims: There is an ongoing need to recognize early kidney injury and its progression in structural chronic pathologies. The proteins NGAL, IGFBP7, TIMP2, KIM-1, CXCL9, TGF-beta 1, SLC22A2, nephrin, cubilin and uromodulin have been proposed as early kidney injury biomarkers. To guide clinical interpretation, their urinary concentrations should be accompanied by reference intervals, which we here establish in a representative Dutch middle-aged population. Materials and Methods: The 24-h urine samples from 1443 Caucasian middle-aged men and women, were analyzed for the biomarkers by quantitative LC-MS/MS. Biomarker excretion per 24-h were calculated, and urine creatinine and osmolality were measured for dilution normalization. This population was characterized by demographic and anthropometric parameters, comorbid conditions, and conventional kidney function measures. Results: NGAL, IGFBP7, TIMP2, KIM-1 and uromodulin could be quantified in this population, whereas nephrin, SLC22A2 and CXCL9 were below their detection limits. Urine creatinine and osmolality ( r= -were correlated to urine volume (r = -0.71; -0.74) and to IGFBP7 (r = 0.73; 0.71) and TIMP2 (r = 0.71; 0.69). Crude and normalized biomarker concentrations were affected by sex, but not by age, BMI, smoking, kidney function or common comorbid conditions. The reference intervals (men; women) were 18-108; 21-131 pmol IGFBP7/mmol creatinine, 1- 63; 4-224 pmol NGAL/mmol creatinine, 7-48; 7- 59 pmol TIMP2/mmol creatinine, <1-9; <1-12 pmol KIM-1/mmol creatinine and 0.1-1.2; 0.1-1.7 mg uromodulin/mmol creatinine. Conclusion: We present dilution-normalized and sex-stratified urinary reference intervals of kidney injury biomarkers in a middle-aged Caucasian population. Show less
A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.Reduced glomerular filtration rate ... Show moreA large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n(DM) = 178,691, n(noDM) = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM. Show less
Sigit, F.S.; Trompet, S.; Tahapary, D.L.; Harbuwono, D.S.; Cessie, S. le; Rosendaal, F.R.; Mutsert, R. de 2022
In this study, we aimed to investigate differences in lifestyle factors and prevalence of metabolic syndrome (MetS) in the Indonesian population between 2013 and 2018. In addition, we investigated... Show moreIn this study, we aimed to investigate differences in lifestyle factors and prevalence of metabolic syndrome (MetS) in the Indonesian population between 2013 and 2018. In addition, we investigated whether adherence to the 2015-released national healthy lifestyle guideline ('GERMAS') is associated with MetS in different sex, age, urban/rural, and BMI categories. We performed cross-sectional analyses in individuals aged > 15 of the 2013 (n = 34,274) and 2018 (n = 33,786) Indonesian National Health Surveys. A stratified, multi-stage, systematic random sampling design and the probability proportional to size method were used to select households in the 34 provinces across the country. MetS was defined according to the Joint Interim Statement Criteria, and adherence to 'GERMAS' guideline was defined as fulfilling the national healthy lifestyle recommendations of > 150 min/ week physical activity (PA), > 5 portions/day fruit and vegetable (FV), no smoking (NS), and no alcohol consumption (NA). We examined the associations of each lifestyle factor with MetS using logistic regression categorised by sex, age groups, urban/rural, and BMI, and adjusted for sociodemographic factors. We observed that men who adhered to the guideline had lower odds ratio of MetS [OR(95%CI) associated with PA: 0.85 (0.75-0.97); NA: 0.75(0.56-1.00)] than non-adherent men. Middle-aged adults who adhered to the guideline had lower OR of MetS [PA: 0.85(0.72-1.01); FV: 0.78(0.62-0.99); NA: 0.66(0.46-0.93)] than non-adherent adults < 45 years. The adherent urban population had lower OR of MetS [FV: 0.85(0.67-1.07); NA: 0.74(0.52-1.07)] than the non-adherent urban population. Those with overweight or obesity who adhered to the guideline had relatively lower odds of MetS than those who did not. In conclusion, in this nationally representative study, adherence to the 'GERMAS' guideline may confer cardiometabolic health benefits to several groups of the Indonesian population, particularly men, middle-aged, those with overweight and obesity, and potentially urban population. Show less
Aims: To quantify metabolic impairment via a one-factor approach with confirmatory factor analysis (CFA) including MRI-derived visceral and subcutaneous adipose tissues and to associate it with... Show moreAims: To quantify metabolic impairment via a one-factor approach with confirmatory factor analysis (CFA) including MRI-derived visceral and subcutaneous adipose tissues and to associate it with diastolic dysfunction. Methods: In this cross-sectional analysis, 916 participants (53% female, mean age (SD): 56 (6)) underwent abdominal and cardiovascular MRI. With CFA a metabolic-load factor of metabolic-syndrome variables and visceral and subcutaneous adipose tissues was constructed. A piecewise structural equation model approach with adjustment for confounding factors was used to determine associations with left-ventricular diastolic function, cardiac morphology and hemodynamics. Results: Model fitting excluding blood pressure and waist circumference but including visceral and subcutaneous adipose tissues, fasting glucose, HDL-c and triglycerides was used to construct the metabolic-load factor. Evaluating measurement invariance demonstrated sex-specificity. Change in mitral early/late peak filling rate ratio was -0.12 for both males [-0.20; -0.05, p > 0.05] and females [-0.17; -0.07, p > 0.001] per SD of metabolicload factor. Change in deceleration time of mitral early filling was -11.83 ms in females [-17.38; -6.27] per SD of metabolic-load factor. Conclusion: A single latent metabolic-load factor via CFA including MRI-derived adipose tissues increased sensitivity for metabolic impairment obsoleting waist circumference and is associated with a decreased leftventricular diastolic function, more apparent in females than in males. Show less
Velzen, D. van; Wiepjes, C.; Nota, N.; Raalte, D. van; Mutsert, R. de; Simsek, S.; Heijer, M. den 2022
Context: In trans women receiving hormone therapy, body fat and insulin resistance increases, with opposite effects in trans men. These metabolic alterations may affect the risk of developing type... Show moreContext: In trans women receiving hormone therapy, body fat and insulin resistance increases, with opposite effects in trans men. These metabolic alterations may affect the risk of developing type 2 diabetes in trans women and trans men. Context: We aimed to compare the incidence of type 2 diabetes of adult trans women and trans men during hormone therapy with rates from their birth-assigned sex in the general population. Methods: Retrospective data from the Amsterdam Cohort of Gender Dysphoria with transgender individuals on hormone therapy between 1972 and 2018 were linked to a nationwide health data registry. Because no central registry of diabetes is available, the occurrence of diabetes was inferred from the first dispense of a glucose-lowering agent. Standardized incidence ratios (SIR) were computed for trans women and trans men in comparison with the same birth sex from the general population. Results: Compared with their birth-assigned sex in the general population, no difference in the incidence of type 2 diabetes mellitus was observed in trans women (N = 2585, 90 cases; SIR 0.94; 95% CI, 0.76-1.14) or trans men (N = 1514, 32 cases; SIR 1.40; 95% CI, 0.96-1.92). Conclusion: Despite studies reporting an increase in insulin resistance in feminizing hormone therapy and a decrease in insulin resistance in masculinizing hormone therapy, the incidence of diabetes in transgender individuals after initiation of hormone therapy was not different compared with the general population. Show less
Boone, S.C.; Smeden, M. van; Rosendaal, F.R.; Cessie, S. le; Groenwold, R.H.H.; Jukema, J.W.; ... ; Mutsert, R. de 2022
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... Show moreVisceral 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 R-2 from 0.50 to 0.58 with a decrease in the root-mean-square error (RMSE) from 45.6 to 41.5 cm(2) and with overall good calibration. Further addition of predominantly lipoprotein-related metabolites from the Nightingale platform did not improve the optimism-corrected R-2 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 (R-2 = 0.63, RMSE = 42.4 cm(2), calibration slope = 0.94) but lower in MESA (R-2 = 0.44, RMSE = 60.7 cm(2), 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. Show less
Klaver, M.; Velzen, D. van; Blok, C. de; Nota, N.; Wiepjes, C.; Defreyne, J.; ... ; Mutsert, R. de 2022
Introduction: Excess visceral fat increases the risk of type 2 diabetes and cardiovascular disease and is influenced by sex hormones. Our aim was to investigate changes in visceral fat and the... Show moreIntroduction: Excess visceral fat increases the risk of type 2 diabetes and cardiovascular disease and is influenced by sex hormones. Our aim was to investigate changes in visceral fat and the ratio of visceral fat to total body fat (VAT/TBF) and their associations with changes in lipids and insulin resistance after 1 year of hormone therapy in trans persons. Methods: In 179 trans women and 162 trans men, changes in total body and visceral fat estimated with dual-energy X-ray absorptiometry before and after 1 year of hormone therapy were related to lipids and insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)] with linear regression analysis. Results: In trans women, total body fat increased by 4.0 kg (95% CI 3.4, 4.7), while the amount of visceral fat did not change (-2 grams; 95% CI -15, 11), albeit with a large range from -318 to 281, resulting in a decrease in the VAT/TBF ratio of 17% (95% CI 15, 19). In trans men, total body fat decreased with 2.8 kg (95% CI 2.2, 3.5), while the amount of visceral fat did not change (3 g; 95% CI -10, 16; range -372, 311), increasing the VAT/TBF ratio by 14% (95% CI 10, 17). In both groups, VAT/TBF was not associated with changes in blood lipids or HOMA-IR. Conclusions: Hormone therapy in trans women and trans men resulted in changes in VAT/TBF, mainly due to changes in total body fat and were unrelated to changes in cardiometabolic risk factors, which suggests that any unfavorable cardiometabolic effects of hormone therapy are not mediated by changes in visceral fat or VAT/TBF. Show less
Buul, A.R. van; Kasteleyn, M.J.; Poberezhets, V.; Bonten, T.N.; Mutsert, R. de; Hiemstra, P.S.; ... ; Taube, C. 2022
Physical inactivity is already present among patients with chronic obstructive pulmonary disease (COPD) of mild or moderate airflow obstruction. Most previous studies that reported on determinants... Show morePhysical inactivity is already present among patients with chronic obstructive pulmonary disease (COPD) of mild or moderate airflow obstruction. Most previous studies that reported on determinants of physical activity in COPD included patients with severe COPD. Therefore, this study aimed to explore which patient characteristics were related to physical activity in COPD patients with mild or moderate airflow obstruction. Cross-sectional analyses were performed on patients selected from the population-based Netherlands Epidemiology of Obesity study. Patients were included if they had a physician-diagnosed COPD GOLD 0-2 or had newly diagnosed COPD GOLD 1-2. Physical activity was evaluated using the Short Questionnaire to Assess Health-Enhancing Physical Activity (SQUASH) questionnaire and reported in hours per week of metabolic equivalents (MET-h/week). Associations between sociodernographic, lifestyle, clinical and functional characteristics were examined using regression analysis. 323 patients were included in research (77 with physician-diagnosed and 246 with newly diagnosed COPD). We found that physical activity was positively associated with pulmonary function: FEV1 (regression coefficient 0.40 (95% CI 0.09,0.71)) and FVC (regression coefficient 0.34 (95% CI 0.06,0.61)). Physical activity was associated with anxiety (regression coefficient -0.9 (95% CI 0.3,1.6)) only for physician-diagnosed patients. Lung function and anxiety level determine the level of physical activity among COPD patients with mild or moderate airflow obstruction. Thus, adjusting physical activity plans accordingly could help to increase physical activity level of the patients. Show less
