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Background and Aims There is an ongoing need to recognize early kidney injury and its progression in structural chronic pathologies. The proteins neutrophil-gelatinase-associated lipocalin (NGAL), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases 2 (TIMP2), kidney injury molecule-1 (KIM-1), C-X-C motif chemokine 9 (CXCL9), transforming growth factor-beta 1 (TGF-β1), solute carrier family 22 member 2 (SLC22A2), nephrin, cubilin, and uromodulin (UMOD) 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 UMOD could be quantified in this population, whereas nephrin, SLC22A2, and CXCL9 were below their detection limits. Urine creatinine and osmolality 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, body mass index, 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, Conclusion We present dilution-normalized and sex-stratified urinary reference intervals of kidney injury biomarkers in a middle-aged Caucasian population.

Introduction To understand how individuals (self-)manage obesity, insight is needed into how patients perceive their condition and how this perception translates into health outcomes (e.g., health-related quality of life, HRQOL). Our objectives were (1) to examine illness perceptions in individuals with overweight and obesity, and (2) to investigate associations of these perceptions with physical and mental HRQOL. Methods In a cross-sectional analysis of the Netherlands Epidemiology of Obesity Study (n = 6432; 52% women), illness perceptions were assessed using the Brief Illness Perception Questionnaire, and HRQOL was assessed using the 36-Item Short-Form Health Survey. Illness perceptions were calculated for different categories of overall, abdominal, and metabolically unhealthy obesity. We investigated associations of illness perceptions with HRQOL using BMI-stratified multivariable linear regression analyses. Results Compared to individuals with normal weight, individuals with obesity believed to a higher extent that their condition had more serious consequences [Mean Difference (95%CI): 1.8 (1.6-2.0)], persisted for a longer time [3.4 (3.2-3.6)], manifested in more symptoms [3.8 (3.6-4.0)], caused more worry [4.2 (3.9-4.4)] and emotional distress [2.0 (1.8-2.2)], but was more manageable with medical treatment [3.1 (2.9-3.4)]. They perceived to a lesser extent that they had personal control [-2.2 (-2.4, -2.0)] and understanding [-0.3 (-0.5, -0.1)] regarding their condition. These negative perceptions were less pronounced in individuals with abdominal obesity. Behaviour/Lifestyle was attributed by 73% of participants to be the cause of their obesity. Stronger negative illness perceptions were associated with impaired HRQOL, particularly the physical component. Conclusion Individuals with obesity perceived their conditions as threatening, and this seemed somewhat stronger in individuals with overall obesity than those with abdominal obesity. Behaviour/Lifestyle is a crucial target intervention and empowering self-management behaviour to achieve a healthy body weight may deliver promising results. In addition, strategies that aim to change negative perceptions of obesity into more adaptive ones may improve HRQOL.

Background and aims: The accumulation of fat increases the formation of lipid perox-ides, which are partly scavenged by alpha-tocopherol (a-TOH). Here, we aimed to investigate the associations between different measures of (abdominal) fat and levels of urinary a-TOH metab-olites in middle-aged individuals. Methods and results: In this cross-sectional analysis in the Netherlands Epidemiology of Obesity study (N Z 511, 53% women; mean [SD] age of 55 [6.1] years), serum a-TOH and a-TOH metab-olites from 24-h urine were measured as alpha-tocopheronolactone hydroquinone (a-TLHQ, oxidized) and alpha-carboxymethyl-hydroxychroman (a-CEHC, enzymatically converted) using liquid-chromatography-tandem mass spectrometry. Body mass index and total body fat were measured, and abdominal subcutaneous and visceral adipose tissue (aSAT and VAT) were as-sessed using magnetic resonance imaging. Using multivariable-adjusted linear regression ana -lyses, we analysed the associations of BMI, TBF, aSAT and VAT with levels of urinary a-TOH metabolites, adjusted for confounders. We observed no evidence for associations between body fat measures and serum a-TOH. Higher BMI and TBF were associated with lower urinary levels of TLHQ (0.95 [95%CI: 0.90, 1.00] and 0.94 [0.88, 1.01] times per SD, respectively) and with lower TLHQ relative to CEHC (0.93 [0.90, 0.98] and 0.93 [0.87, 0.98] times per SD, respectively). We observed similar associations for VAT (TLHQ: 0.94 [0.89, 0.99] times per SD), but not for aSAT. Conclusions: Opposite to our research hypothesis, higher abdominal adiposity was moderately associated with lower levels of oxidized a-TOH metabolites, which might reflect lower vitamin E antioxidative activity in individuals with higher abdominal fat instead. (c) 2021 The Author(s). Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian 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/).

Self-report and nicotine detection are methods to measure smoking exposure and can both lead to misclassification. It is important to highlight discrepancies between these two methods in the context of epidemiological research.The aim of this cross-sectional study is to assess the agreements between self-reported smoking status and nicotine metabolite detection.Data of 599 participants from the Netherlands Epidemiology of Obesity study were used to compare serum metabolite levels of five nicotine metabolites (cotinine, hydroxy-cotinine, cotinineIn 94% of the self-reported current smokers, at least one metabolite was present, versus in 19% of the former smokers and in 10% of the never smokers. In none of the never smokers, cotinine-The agreement between self-reported smoking status and metabolite information was high. This indicates that self-reported smoking status is generally reliable.

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 (N-max 118,460), microalbuminuria (N-max 54,116), and impaired renal function (N-max 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 cm(2), 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 cm(2), 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. (C) 2019 by the National Kidney Foundation, Inc. All rights reserved.

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 of physical activity in COPD included patients with severe COPD. Therefore, the aim of this study was to explore which patient characteristics were related with 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 sociodemographic, 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 level of physical activity among COPD patients with mild or moderate airflow obstruction. Thus, integrating it into the physical activity plans could help to increase physical activity level of the patients.

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 0.10). 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. Electronic supplementary material The online version of this article (10.1007/s40119-019-00151-9) contains supplementary material, which is available to authorized users.

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 (β: −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 (β: −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 β-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic β-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.

Supplemental Digital Content is available in the text., Background: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the CHREBP locus and dyslipidemia. Methods: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near CHREBP were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake. Results: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16–3.07] mg/dL per allele; P

BACKGROUND AND OBJECTIVES The effects of endocrinological treatment on cardiovascular risk profile in transgender adolescents are unknown. In this retrospective cohort study, we aim to investigate these effects and assess obesity and dyslipidemia prevalence in transgender adolescents at 22 years compared with peers. METHODS Changes in BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), glucose, homeostatic model assessment for insulin resistance (HOMA-IR), and lipid values during treatment, along with the prevalence of obesity and dyslipidemia at 22 years, were recorded in 71 transwomen and 121 transmen who started gonadotropin-releasing hormone agonists in their adolescence (15 years), with a subsequent addition of sex hormones (17 years). RESULTS In transwomen, changes in BMI (+3.0; 95% confidence interval [CI] 1.6 to 4.4), SBP (–2 mmHg; 95% CI –7 to 3), DBP (+10 mmHg; 95% CI 7 to 14), glucose (0.0 mmol/L; 95% CI –0.2 to 0.2), HOMA-IR (+0.6; 95% CI –0.6 to 1.9), and lipid values were similar or more favorable compared with peers. The same was true for transmen regarding changes in BMI (+2.3; 95% CI 1.7 to 2.9), SBP (+7 mmHg; 95% CI 3 to 10), DBP (+7 mmHg; 95% CI 5 to 10), glucose (+0.1 mmol/L; 95% CI –0.1 to 0.3), HOMA-IR (–0.2; 95% CI –0.8 to 0.3), and lipid values. At age 22, obesity prevalence was 9.9% in transwomen, 6.6% in transmen, 2.2% in ciswomen, and 3.0% in cismen. CONCLUSIONS Generally, endocrinological treatment in transgender adolescents is safe regarding cardiovascular risk. Because obesity is more prevalent in transgender adolescents compared with peers, body weight management should be important during the medical trajectory.

Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ∼200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenicFMR1premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Background: In trans women receiving hormone therapy, body fat and insulin resistance increases, with opposite effects in trans men. These metabolic alterations may increase or decrease the risk of developing type 2 diabetes in trans women and trans men, respectively. Currently, there is no data on the incidence of type 2 diabetes in transgender individuals. 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 was available, the occurrence of diabetes was deferred from the first dispense of a glucose-lowering agent. Standardized incidence ratios (SIR) were computed for trans women and trans men in comparison with respectively men and women from the general population. Findings: Compared to their birth 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). Interpretation: Despite studies reporting an increase in insulin resistance in feminizing hormone therapy and an increase in insulin sensitivity in masculinizing hormone therapy, the incidence of type 2 diabetes in transgender individuals after initiation of hormone therapy was not different compared to the general population. Earlier studies on the effect of hormone therapy on insulin sensitivity in transgender individuals might have revealed specific effects of cyproterone acetate rather than effects of estradiol. Funding: None to declare. Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Medical Ethics Committee of the Amsterdam University Medical Centre

BackgroundSleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease.MethodsWe used AMV (N=17,370) combined with two-sample MR (N=38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.ResultsWe found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (−0.08 standard deviation (SD)[95% confidence interval (CI): −0.12, −0.03] in AMV and −0.03SD [−0.07, −0.003] in MR), higher glycoprotein acetyls (0.08SD [95%CI: 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (−0.04SD [−0.08, 0.00] in AMV and - 0.05SD [−0.09, −0.02] in MR) and lower phospholipids in very large HDL particles (−0.04SD [−0.08, 0.002] in AMV and −0.05SD [−0.08, −0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1-hour [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.ConclusionsWhilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10(−6)) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

Background Body mass index (BMI)-associated loci are used to explore the effects of obesity using Mendelian randomization (MR), but the contribution of individual tissues to risks remains unknown. We aimed to identify tissue-grouped pathways of BMI-associated loci and relate these to cardiometabolic disease using MR analyses. Methods Using Genotype-Tissue Expression (GTEx) data, we performed overrepresentation tests to identify tissue-grouped gene sets based on mRNA-expression profiles from 634 previously published BMI-associated loci. We conducted two-sample MR with inverse-variance-weighted methods, to examine associations between tissue-grouped BMI-associated genetic instruments and type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), with use of summary-level data from published genome-wide association studies (T2DM: 74 124 cases, 824 006 controls; CAD: 60 801 cases, 123 504 controls). Additionally, we performed MR analyses on T2DM and CAD using randomly sampled sets of 100 or 200 BMI-associated genetic variants. Results We identified 17 partly overlapping tissue-grouped gene sets, of which 12 were brain areas, where BMI-associated genes were differentially expressed. In tissue-grouped MR analyses, all gene sets were similarly associated with increased risks of T2DM and CAD. MR analyses with randomly sampled genetic variants on T2DM and CAD resulted in a distribution of effect estimates similar to tissue-grouped gene sets. Conclusions Overrepresentation tests revealed differential expression of BMI-associated genes in 17 different tissues. However, with our biology-based approach using tissue-grouped MR analyses, we did not identify different risks of T2DM or CAD for the BMI-associated gene sets, which was reflected by similar effect estimates obtained by randomly sampled gene sets.

High adiponectin concentrations are generally regarded as beneficial with regard to cardiometabolic health, but have been paradoxically associated with increased cardiovascular disease risk, specifically heart failure, in individuals at high cardiovascular risk. We aimed to investigate the association between adiponectin and heart function parameters, and inversely, we estimated the effect of genetically-determined heart function and NT-proBNP as the main marker of heart failure on adiponectin using Mendelian randomisation. Observational analyses between adiponectin and measures of heart function, i.e. E/A ratio, left, and right ventricular ejection fraction, were performed in participants of the Netherlands Epidemiology of Obesity (NEO) study, assessed by MRI of the heart (n = 1,138). Two-sample Mendelian randomisation analyses were conducted to estimate the effect of NT-proBNP and heart function on adiponectin concentrations using publicly-available summary statistics (ADIPOGen; the PLATO trial). The mean (standard deviation) age was 56 (6) years and mean body mass index was 26 (4) kg/m2. Per five μg/mL higher adiponectin, the E/A ratio was −0.05 (95 % CI: −0.10, −0.01) lower, left ventricle ejection fraction was −0.5 % (95 % CI: −1.1, 0.1) lower, and right ventricle ejection fraction was 0.5 % (95 % CI: −0.1, 1.2) higher. Genetically-determined NT-proBNP was causally related to adiponectin concentrations in ADIPOGen: per doubling of genetically-determined NT-proBNP, adiponectin concentrations were 11.4 % (95 % CI: 1.7, 21.6) higher. With causal MR methods we showed that NT-proBNP affects adiponectin concentrations, while adiponectin is not associated with heart function parameters. Therefore, reverse causation may explain the adiponectin paradox observed in previous studies.

Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10−3) and higher fasting insulin (0.030 ± 0.005 [log e pmol/l], p = 2.0 × 10−10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the β-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 log e pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant. In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses’ Health Study).

Purpose To explore the experiences and preferences of population-based research participants to whom an incidental finding was communicated. Materials and Methods Of the 2580 participants of the Netherlands Epidemiology of Obesity (NEO) study who underwent magnetic resonance imaging (MRI) scanning of the abdomen, heart, and/or brain, an incidental finding with presumed health importance was disclosed to 56 (2%) participants. These participants were invited to discuss their experiences regarding the communication of the finding by the NEO research team in a focus group discussion. Transcripts of the discussions were analyzed using thematic content analysis with an open coding system. Results Twenty-three persons participated in four discussions: 57% male; mean age 58 years; 74% findings were suspect for a malignancy. Overall, the participants were grateful for the disclosure of the incidental finding. They had assumed that any finding would be disclosed, and this was an important reason to participate in research. None regretted their informed consent to be notified about incidental findings. Disclosure of the finding had great impact on the lives of most participants. Difficulties with the transition from research participant to patient were frequently mentioned. Conclusion This study provides information to improve the communication of incidental findings by 1) giving clear information about which findings will be disclosed, and 2) demarcating the transition from research participant to patient, by making clear arrangements with medical specialists to guarantee careful follow-up of the finding. Level of Evidence: 3 J. Magn. Reson. Imaging 2017.

Background and aims: The separate cardiovascular effects of type 2 diabetes and adiposity remain to be examined. This study aimed to investigate the role of insulin resistance in the relations of visceral (VAT), abdominal subcutaneous (aSAT) adipose tissue and total body fat (TBF) to cardiovascular remodeling.Methods and results: In this cross-sectional analysis of the population-based Netherlands Epidemiology of Obesity study, 914 middle-aged individuals (46% men) were included. Participants underwent magnetic resonance imaging. Standardized linear regression coefficients (95%CI) were calculated, adjusted for potential confounding factors. All fat depots and insulin resistance (HOMA-IR), separate from VAT and TBF, were associated with lower mitral early and late peak filling rate ratios (E/A): -0.04 (-0.09;0.01) per SD (54 cm(2)) VAT; -0.05 (-0.10;0.00) per SD (94 cm(2)) aSAT; -0.09 (-0.16;-0.02) per SD (8%) TBF; -0.11 (-0.17;-0.05) per 10-fold increase in HOMA-IR, whereas VAT and TBF were differently associated with left ventricular (LV) end-diastolic volume: -8.9 (-11.7;-6.1) mL per SD VAT; +5.4 (1.1;9.7) mL per SD TBF. After adding HOMA- IR to the model to evaluate the mediating role of insulin resistance, change in E/A was -0.02 (-0.07;0.04) per SD VAT; -0.03 (-0.08;0.02) per SD aSAT; -0.06 (- 0.13;0.01) per SD TBF, and change in LV end-diastolic volume was -7.0 (-9.7;-4.3) mL per SD VAT. In women, adiposity but not HOMA-IR was related to higher aortic arch pulse wave velocity.Conclusion: Insulin resistance was associated with reduced diastolic function, separately from VAT and TBF, and partly mediated the associations between adiposity depots and lower diastolic function. (C) 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Dietary macronutrient composition may affect hepatic liver content and its associated diseases, but the results from human intervention trials have been equivocal or underpowered. We aimed to assess the effects of dietary macronutrient composition on liver fat content by conducting a systematic review and meta-analysis of randomized controlled trials in adults. Four databases (PubMed, Embase, Web of Science, and COCHRANE Library) were systematically searched for trials with isocaloric diets evaluating the effect of dietary macronutrient composition (energy percentages of fat, carbohydrates, and protein, and their specific types) on liver fat content as assessed by magnetic resonance techniques, computed tomography or liver biopsy. Data on change in liver fat content were pooled by random or fixed-effects meta-analyses and expressed as standardized mean difference (SMD). We included 26 randomized controlled trials providing data for 32 comparisons on dietary macronutrient composition. Replacing dietary fat with carbohydrates did not result in changes in liver fat (12 comparisons, SMD 0.01 (95% CI -0.36; 0.37)). Unsaturated fat as compared with saturated fat reduced liver fat content (4 comparisons, SMD -0.80 (95% CI -1.09; -0.51)). Replacing carbohydrates with protein reduced liver fat content (5 comparisons, SMD -0.33 (95% CI -0.54; -0.12)). Our meta-analyses showed that replacing carbohydrates with total fat on liver fat content was not effective, while replacing carbohydrates with proteins and saturated fat with unsaturated fat was. More well-performed and well-described studies on the effect of types of carbohydrates and proteins on liver fat content are needed, especially studies comparing proteins with fats.

Key Points Question Is birth weight associated with type 2 diabetes and glycemic traits? Findings This mendelian randomization study found that a 1-SD decrease in birth weight due to the genetic risk score was associated with a higher risk of type 2 diabetes among European and East Asian populations. In addition, a 1-SD decrease in birth weight was associated with a 0.189-SD increase in fasting glucose concentration, but not with fasting insulin, 2-hour glucose, or hemoglobin A1c level. Meaning A genetic predisposition to lower birth weight was associated with an increased risk of type 2 diabetes and increased fasting glucose, suggesting potential mechanisms through which perturbation of the antenatal and early-life environment affect predisposition to diabetes in later life., This mendelian randomization study examines the association of birth weight with type 2 diabetes and glycemic traits., 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 (β = 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.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

Background Obesity is one of the most important risk factors for osteoarthritis (OA). For long the association between obesity and OA was thought to be explained by increased mechanical loading. However, the role of systemic factors is increasingly recognized, especially in non-weightbearing joints. Obesity is strongly associated with increased levels of circulating fatty acids, which may result in lipotoxicity. However, our knowledge about the effect of different fatty acids on OA is sparse. Objectives To investigate the association of plasma saturated fatty acids (SFAs), monounsaturated fatty acid (MUFAs), polyunsaturated fatty acids (PUFAs), omega (n-)3 and n-6 PUFAs with clinically defined hand and knee OA. Methods In the population-based Netherlands Epidemiology of Obesity (NEO) study, a total of 6,671 middle-aged participants were recruited from the greater area of Leiden. Clinical hand and knee OA were defined by the ACR clinical classification criteria. Blood samples were obtained after an overnight fast and 150 minutes after consumption of a standardized liquid mixed meal containing 600kCal, with 16% of energy (En%) derived from protein, 50 En% from carbohydrates and 34 En% from fat. EDTA-plasma samples were used for a high-throughput proton nuclear magnetic resonance (NMR) metabolomics platform (Nightingale Health Ltd., Helsinki, Finland) to quantify 159 lipid and metabolite measures. For the present analyses the concentrations of fasting and postprandial total fatty acids, SFAs, MUFAs, PUFAs, n-6 PUFAs and n-3 PUFAs in mmol/l were used. Since we are in a postprandial state most of the day, these samples were used for the primary analyses. All fatty acid concentrations were standardized (mean 0, SD 1), to ensure a similar interpretation of the estimated effect. We excluded participants who reported to have inflammatory rheumatic disease or fibromyalgia, with missing physical examination, who were non-fasting at baseline, or reported using lipid-lowering medication. Logistic regression analyses were used to investigate the association between fatty acids and clinical OA phenotypes. All analyses were stratified by sex and corrected for age, education, ethnicity and total body fat percentage. Data are presented as odds ratios (OR) with 95% confidence intervals (CI). Results In the current analysis 5,328 NEO participants were included, with a mean age of 56 years and 58% were women. Hand OA, knee OA and concurrent hand and knee OA were defined in 8%, 10% and 4% of participants, respectively. After correction for possible confounders, total fatty acids, SFA, total PUFA and omega–3 PUFA levels were positively associated with clinical hand OA in men, with OR (95% CI) of 1.24 (1.01; 1.53), 1.23 (1.00 – 1.50), 1.26 (1.00 – 1.58) and 1.24 (1.01 – 1.52), respectively. Although not significant, similar effect estimates were observed for men with concurrent hand and knee OA, but not for clinical knee OA alone. In women no associations were seen of any of the fatty acids with clinical hand or knee OA. Analyses of the association between fasting fatty acid levels and clinical hand and knee OA showed rather similar results, with slightly lowered ORs and wider confidence intervals. Conclusion Quantitively measured plasma postprandial SFA and PUFA levels were significantly associated with hand OA in men. In women no associations were found. Intriguingly, although SFA and omega-3 PUFAs are deemed to have opposing effects on inflammation, both were positively associated with hand OA. Future research is warranted to replicate the association and determine whether there is a causal role for plasma fatty acid levels in hand OA. Disclosure of Interests Marieke Loef Grant/research support from: Innovative Medicines Initiative Joint Undertaking under Grant Agreement n° 115770, Andreea Ioan-Facsinay Shareholder of: Johnson & Johnson, Dennis Mook Consultant for: Part-time clinical research consultant for Metabolon, Inc., Ko Willems van Dijk: None declared, Renee de Mutsert: None declared, Margreet Kloppenburg Grant/research support from: Pfizer, IMI-APPROACH (Grant Agreement n° 115770), Consultant for: GlaxoSmithKline, Merck-Serono, Abbvie, Levicept, Pfizer, Frits Rosendaal: None declared

Background In osteoarthritis (OA) patients health-related quality of life (HRQoL) is decreased. Whether patients with OA seeking care in a rheumatology outpatient clinic experience more impact on HRQoL than those in the general population is unknown. Objectives To investigate the impact of hand OA on physical and mental HRQoL in the general population, and to investigate the difference in impact between patients who have, and who have not been referred to a medical specialist. Methods In the population-based Netherlands Epidemiology of Obesity (NEO) study, middle-aged participants were recruited from the greater area of Leiden. In the Hand OSTeoArthritis in Secondary care (HOSTAS) study, patients with a rheumatologist’s diagnosis of primary hand OA were recruited from the outpatient clinic at the Leiden University Medical Center, a secondary and tertiary referral center. In both cohorts, hand and knee OA was defined by the ACR clinical classification criteria. Patients with fibromyalgia or inflammatory rheumatic conditions were excluded. Fur the current analyses, only patients classified with hand OA alone were included. HRQoL was measured with the SF-36 questionnaire; we calculated standardized scores on a scale of 0 to 100 with subsequent application of a norm-based transformation (mean 50, standard deviation 10). Linear regression analyses, corrected for age, sex, education, ethnicity and BMI, were used to study cross-sectional associations between OA and HRQoL. Data are presented as regression coefficients with 95% confidence intervals (CI). Because a suitable reference group without OA was lacking in the HOSTAS study, these patients were compared to the normative value of 50. Previous research concluded a minimal clinically important difference of 2 points on the SF-36 scale, which was used to assess clinical relevance of differences in scores. Results Of the 6,334 NEO participants 8% were classified with only hand OA and 4% were classified concurrent hand and knee OA. The HOSTAS cohort consisted of a total of 538 patients with hand OA, of whom 57% fulfilled the ACR criteria for only hand OA and 32% was defined with concurrent hand and knee OA. In the population-based NEO study, mean PCS was reduced with -2.4 (-3.6; -1.3) in participants with only hand OA, compared to participants without hand or knee OA (table 1). The subscales bodily pain and physical functioning were affected the most with mean differences of –3.4 (-4.6; -2.2) and -2.1 (-3.0; -1.1). Mental HRQoL was not reduced in participants with only hand OA, compared to participants without OA. In the population-based cohort 14% of participants with hand OA reported to have visited a medical specialist for OA. Participants with hand OA that have been referred to a medical specialist showed a lower physical HRQoL with a mean difference in the PCS of –3.9 (-6.7; -1.2), but no difference in mental HRQoL, compared with participants with hand OA that have not reported consulting secondary care for OA (table 2). In patients with only hand OA from the outpatient clinic, the PCS (-3.5), bodily pain (-4.9), vitality (-2.5) and role functioning – physical (-2.2) scales were clinically relevantly reduced, but mental HRQOL was not affected. Conclusion Participants with hand OA from the general population had a clinically relevant lower physical HRQoL, but not mental HRQoL. Physical HRQoL was further reduced in patients consulting secondary care and in co-occurrence with knee OA. Hence, patients with hand OA in secondary care experience more impact on physical HRQoL than patients in the general population. Disclosure of Interests: Marieke Loef Grant/research support from: Innovative Medicines Initiative Joint Undertaking under Grant Agreement n° 115770, Wendy Damman: None declared, Renee de Mutsert: None declared, Frits Rosendaal: None declared, Margreet Kloppenburg Grant/research support from: Pfizer, IMI-APPROACH (Grant Agreement n° 115770), Consultant for: GlaxoSmithKline, Merck-Serono, Abbvie, Levicept, Pfizer

The antioxidant vitamin E (&alpha, tocopherol, &alpha, TOH) protects lipids from oxidation by reactive oxygen species. We hypothesized that lifestyle factors associate with vitamin E metabolism marked by urinary &alpha, tocopheronolactone hydroquinone (&alpha, TLHQ) and &alpha, carboxymethyl-hydroxychroman (&alpha, CEHC levels), as potential reflection of lipid oxidation. We conducted a cross-sectional study in the Netherlands Epidemiology of Obesity Study. Serum &alpha, TOH, and urinary &alpha, TLHQ and &alpha, CEHC were quantified by liquid chromatography coupled with tandem mass spectrometry. Information on the lifestyle factors (sleep, physical activity (PA), smoking and alcohol) were collected through questionnaires. Multivariable linear regression analyses were performed to assess the associations between the lifestyle factors and &alpha, TOH measures. A total of 530 participants (46% men) were included with mean (SD) age of 56 (6) years. Of the examined lifestyle factors, only poor sleep was associated with a higher serum &alpha, TOH (mean difference: 4% (95% CI: 1, 7%)). Current smoking was associated with higher urinary &alpha, CEHC (32%: (14%, 53%)), with evidence of a dose&ndash, response relationship with smoking intensity (low pack years, 24% (2, 52%), high pack years, 55% (25, 93%)). Moderate physical activity was associated with a lower &alpha, TLHQ relative to &alpha, CEHC (&minus, 17%: (&minus, 26, &minus, 6%), compared with low PA). Only specific lifestyle factors associate with vitamin E metabolism. Examining serum &alpha, TOH does not provide complete insight in vitamin E antioxidant capacity.

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.

SummaryMetabolic dysregulation in multiple tissues alters glucose homeostasis and influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits (fasting glucose [FG], fasting insulin [FI], two-hour glucose [2hGlu] and glycated hemoglobin [HbA1c]), we investigated associations of exome-array variants in up to 144,060 individuals without diabetes of multiple ancestries. Single-variant analyses identified novel associations at 21 coding variants in 18 novel loci, whilst gene-based tests revealed signals at two genes, TF (HbA1c) and G6PC (FG, FI). Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and pancreatic islets for FG regulation, implicated adipose tissue in FI and the gut in 2hGlu, and suggested a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that a novel FG/FI association at the liver-enriched G6PC transcript was driven by multiple rare loss-of-function variants. The FG/HbA1c-associated, islet-specific G6PC2 transcript also contained multiple rare functional variants, including two alleles within the same codon with divergent effects on glucose levels. Our findings highlight the value of integrating genomic and functional data to maximize biological inference.Highlights23 novel coding variant associations (single-point and gene-based) for glycemic traits51 effector transcripts highlighted different pathway/tissue signatures for each traitThe exocrine pancreas and gut influence fasting and 2h glucose, respectivelyMultiple variants in liver-enriched G6PC and islet-specific G6PC2 influence glycemia

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin concentrations in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We confirmed five previously established and identified five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The novel missense Val94Met (rs17151919) variant in LEP was common in individuals with African ancestry ( minor allele frequency ( MAF) AFR=8%; MAFEUR=0.02%) and was associated with 0.34 standard deviations lower leptin concentrations per Met94 allele in adults (P=2x10-16, n=3,901). Using in vitro analyses, we showed that the Met94 allele decreases leptin secretion (P=0.025). The Met94 allele was associated with higher BMI in young African-ancestry children (P=0.002, n=2,030) but not in adults, suggesting leptin regulates early adiposity.

Publisher's version (útgefin grein)., Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria., Competing interests: Karsten B. Sieber is full-time employee of GlaxoSmithKline. Gardar Sveinbjornsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir and Kari Stefansson are full-time employees of deCODE genetics, Amgen Inc. John Danesh is member of the Novartis Cardiovascular and Metabolic Advisory Board, received grant support from Novartis. Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Wolfgang Koenig received modest consultation fees for advisory board meetings from Amgen, DalCor, Kowa, Novartis, Pfizer and Sanofi, and modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer and Sanofi. Anna I. Podgornaia and Dermot F. Reilly are employees of Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA. Kevin Ho disclosed a research and financial relationship with Sanofi-Genzyme. Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Markus Scholz: Consultancy of and grant support from Merck Serono not related to this project. Adam S. Butterworth received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. Anna Köttgen received grant support from Gruenenthal not related to this project. The other authors declare no competing interests.

Genetic studies have identified “favourable adiposity” variants - where the allele associated with higher adiposity is associated with lower risk of type 2 diabetes. We took a novel approach to find more of these alleles and find the underlying mechanisms. We first performed a genome wide association study (GWAS) of body fat percentage using 451000 individuals from UK Biobank. Second, we used published genetic data in a multivariate test to find alleles associated with higher adiposity but a “favourable” metabolic phenotype: higher HDL-C, adiponectin, sex hormone binding globulin, but lower triglycerides, fasting insulin and alanine transaminase. Third, we used abdominal imaging data from 4 studies to define the adiposity phenotype in more detail. We identified 620 variants associated with body fat percentage (p “Favourable adiposity” alleles associated with higher BMI but lower risk of type 2 diabetes are characterized by higher subcutaneous but lower liver fat. Disclosure H. Yaghootkar: None. Y. Ji: None. A.M. Yiorkas: None. F. Frau: None. D. Mook-Kanamori: None. R. de Mutsert: None. J. Tyrrell: None. S.E. Jones: None. R. Beaumont: None. A.R. Wood: None. L. Thomas: None. K.V. Allebrandt: None. N. Stefan: Consultant; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca, OmniaMed Ltd.. H. Staiger: None. E. Pearson: Speaker's Bureau; Self; Eli Lilly and Company. A.I. Blakemore: None. J.D. Bell: None. T.M. Frayling: None.

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such “favourable adiposity” alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined magnetic resonance imaging (MRI) data with genome-wide association studies (GWAS) of body fat % and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity, but a favourable metabolic profile. Consistent with previous studies, individuals carrying more “favourable adiposity” alleles had higher body fat % and higher BMI, but lower risk of type 2 diabetes, heart disease and hypertension. These individuals also had higher subcutaneous fat, but lower liver fat and lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14 and IRS1, whilst the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified “favourable adiposity” alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglyceride in metabolically low risk depots. Diabetes UK RD Lawrence fellowship, European Research Council, Wellcome Trust and Royal Society grant, European Regional Development Fund, Medical Research Council, German Federal Ministry of Education and Research, German Research Foundation, Innovative Medicines Initiative Joint Undertaking, European Union's Seventh Framework Programme, Dutch Science Organisation, Scottish Government Health Directorates, Scottish Funding Council and Medical Research Council UK and the Wellcome Trust.

Objective This study aimed to investigate the associations of sleep duration and sleep quality with visceral adipose tissue (VAT) in middle-aged individuals. Methods In this cross-sectional analysis of baseline measurements of the Netherlands Epidemiology of Obesity (NEO) study, participants underwent anthropometry and completed the Pittsburgh Sleep Quality Index (PSQI) for assessing short sleep duration (as sex-specific age-adjusted percentiles) and poor quality (PSQI > 5). VAT was assessed by magnetic resonance imaging in a random subgroup. We performed linear regression analyses to examine associations of short sleep and poor sleep with measures of body fat, adjusted for confounding, including total body fat in models with VAT. Results A total of 5,094 participants (52% women; mean age of 56 [SD 6] years), 1,947 of whom had VAT measurements, were analyzed. The difference in VAT between poor sleep (PSQI > 5) and good sleep (PSQI ≤ 5) was 7.2cm2 (95% CI: 1.2-13.8) in women and 16.1cm2 (95% CI: 6.2-26.0) in men. These differences attenuated toward the null after the adjustment for total body fat. Similar patterns of associations were observed for short sleep (lowest 10% compared with median 60%). Conclusions Our results suggest that measures of sleep are not specifically associated with a higher amount of VAT.

Background— The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results— We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima–media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima–media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC ( P =3×10 − 10 ). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC ( P =1×10 − 12 ) and 1.4% reduced carotid intima–media thickness ( P =4×10 − 14 ) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P =1×10 − 11 ). Conclusions— Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

Objective To investigate whether obesity and other risk factors interact with knee osteoarthritis (OA) in its adverse impact on health-related quality of life (HRQOL). Methods In 1,262 participants of the Netherlands Epidemiology of Obesity Study, a population-based cohort (age 45–65 years, 53% women, and median body mass index [BMI] 27 kg/m2), knee OA was defined following modified American College of Rheumatology criteria. BMI and fat-free mass (as proxy for muscle mass) were assessed by bioelectrical impedance analysis, and comorbidities by self-report. HRQOL was assessed using the Short Form 36 physical component summary (PCS) score. Linear regression analyses were performed to examine associations between knee OA and PCS score, adjusting for age and sex and stratified for BMI, fat-free mass, and comorbidities. Results Knee OA (prevalence 16%) was associated with a 7.2-points lower PCS score (95% confidence interval −9.5, −4.8). PCS score was also negatively associated with obesity and comorbidities; however, no interaction with knee OA was seen. Low fat-free mass was associated with a lower PCS score and interacted with knee OA in men. Interaction between concurring OA and low fat-free mass attributed to 64% of the decrease in PCS score, as compared with men without OA and with high fat-free mass. Conclusion Knee OA was associated with a lower HRQOL, as were its risk factors, obesity, comorbidities, and low fat-free mass. In men, fat-free mass interacted with knee OA, leading to an additional decrease of HRQOL in the case of concurrence. Especially in the former, improvement of fat-free mass may improve HRQOL in knee OA patients.

We aimed to investigate the associations between weight change during adulthood and the amount of abdominal subcutaneous fat, visceral fat, and liver fat at middle age. The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort of 6671 middle-aged men and women. We calculated the percentage of weight change during adulthood based on body weight at middle age and recalled body weight at age 20. Abdominal subcutaneous and visceral adipose tissue were assessed by magnetic resonance imaging (MRI), in addition to hepatic triglyceride content by 1H-MR spectroscopy in a random subgroup (maximum of n = 2580). With multivariable linear regression analysis, we examined the associations between categories of adult weight change, body mass index (BMI) at age 20 and measures of abdominal adiposity at middle age, adjusted for age, sex, ethnicity, lifestyle factors, menopausal status, parity, use of medication and total body fat at middle age. In 2399 participants (54% women), individuals who gained more than 50% of body weight during adulthood had 1.96 (95% CI: 1.64; 2.33) times more visceral adipose tissue at middle age and 2.39 (95% CI: 1.70, 3.36) times more hepatic triglyceride content than weight maintainers (weight change between −5% and 5%). Associations with abdominal subcutaneous adipose tissue were weaker: participants who gained more than 50% of their body weight had 1.54 (95% CI: 1.38, 1.72) times more abdominal subcutaneous adipose tissue compared with weight maintainers. In this population-based study, adult weight gain was associated with relatively more visceral adipose tissue and hepatic triglyceride content at middle age than abdominal subcutaneous adipose tissue. Overall, our study suggests that weight maintenance during adulthood plays an important role in limiting excess visceral adipose tissue and hepatic triglyceride content at middle age.

Contains fulltext : 193359.pdf (Publisher’s version ) (Open Access) BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N=25,508) and "tobacco use disorder" (N=27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses. RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p=2.39x10(-7)) and rs8034191 (p=6.31x10(-7)) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use. 8 p.

BACKGROUND: Abdominal obesity is a well-established risk factor for the development of type 2 diabetes. However, sex differences may exist. We aimed to investigate the associations of abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) with insulin resistance and insulin secretion in men and women. METHODS: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study, fasting and postprandial concentrations of glucose and insulin were measured and abdominal fat depots were assessed using magnetic resonance imaging in 2253 participants (53% women). With linear regression analysis, we examined associations of abdominal SAT and VAT with measures of insulin resistance and insulin secretion in men and women, while adjusting for age, ethnicity, education, smoking habits, alcohol consumption, menopausal state and hormone use in women, and models with VAT additionally for total body fat. RESULTS: Participants had a mean [standard deviation (SD)] age of 56 (6) years, body mass index: 25.9 (3.9) kg/m2, VAT: 89 (55) cm2, and SAT: 235 (95) cm2. In the multivariate models in men, per SD of VAT the homeostatic model assessment of insulin resistance (HOMA-IR) was 20% (95% CI: 14-26) higher, and per SD SAT 21% (15-27) higher. In women, per SD of VAT the HOMA-IR was 40% (29-52) higher, and per SD SAT 12% (6-19) higher. Associations with measures of insulin secretion were weaker than with insulin resistance. CONCLUSIONS: In men, abdominal SAT and VAT were associated with insulin resistance to a similar extent, whereas in women particularly VAT was associated with insulin resistance and insulin secretion. Future studies need to unravel the mechanisms underlying the metabolic effects of visceral fat in women. Simple and less expensive measures that can distinct abdominal subcutaneous and visceral fat are needed for an improved metabolic risk stratification.

High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.

Background Obesity is a risk factor for the development of asthma. In patients with obesity the diagnosis of asthma is often based on symptoms, but without objective measurements. Nevertheless, obesity-associated asthma is recognized as a distinct asthma phenotype. Therefore, this study explores lung function and symptoms in asthma patients with and without obesity. Methods The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort study with 6671 participants (aged 45–65 years) of whom 472 had asthma. Of this latter group, linear regression analysis was used to examine differences in lung function and symptoms between asthma patients with (n = 248) and without obesity (n = 224), and between asthma patients with and without increased FeNO. Analyses were adjusted for confounders. Results Asthma patients with obesity had lower predicted FEV1 and FVC values than patients without obesity [adjusted mean difference (MD) -3.3% predicted, 95% CI -6.5, −0.2; adjusted MD −5.0% predicted, 95% CI -7.8, −2.1]. The prevalence of symptoms was higher in patients with obesity. Asthma patients with obesity and with increased FeNO had lower FEV1 and FEV1/FVC values compared with those with low FeNO (adjusted MD −6.9% predicted, 95% CI -11.7, −2.0; −2.4%, 95% CI -4.6, −0.2). Conclusion Asthma patients with obesity had lower FEV1 and FVC values than patients without obesity. This suggests that patients with obesity have restrictive lung function changes, rather than obstructive changes. Asthma patients with obesity and increased FeNO showed more obstructive changes. FeNO might help to identify patients with eosinophilic inflammation-driven asthma, whereas patients with low FeNO might have an obesity-associated asthma phenotype in which symptoms are partly caused by the obesity. Electronic supplementary material The online version of this article (10.1186/s12931-017-0684-9) contains supplementary material, which is available to authorized users.

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P-7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

Objective Obesity is associated with sympathetic activation, but the role of different fat depots is unclear. The association between body fat, specifically visceral fat, and electrocardiographic measures of sympathetic activation in a population with structurally normal hearts was investigated. Methods In this cross-sectional baseline analysis of the Netherlands Epidemiology of Obesity study, body fat percentage was assessed with BIA and abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) with magnetic resonance (MR) imaging. Mean heart rate (HR) and five other electrocardiographic measures of sympathetic activation were calculated. We performed multivariate linear regression analyses. Results In 868 participants with a mean age(SD) of 55(6) years, BMI of 26(4) kg/m2, 47% men, body fat was associated with HR and two other measures of sympathetic activation. Per sex-specific SD total body fat, the difference in HR was 1.9 beats/min (95% CI: 1.0, 2.9; P

Introduction Fasting metabolite profiles have been shown to distinguish type 2 diabetes (T2D) patients from normal glucose tolerance (NGT) individuals. Objectives We investigated whether, besides fasting metabolite profiles, postprandial metabolite profiles associated with T2D can stratify individuals with impaired fasting glucose (IFG) by their similarities to T2D. Methods Three groups of individuals (age 45–65 years) without any history of IFG or T2D were selected from the Netherlands Epidemiology of Obesity study and stratified by baseline fasting glucose concentrations (NGT (n = 176), IFG (n = 186), T2D (n = 171)). 163 metabolites were measured under fasting and postprandial states (150 min after a meal challenge). Metabolite profiles specific for a high risk of T2D were identified by LASSO regression for fasting and postprandial states. The selected profiles were utilised to stratify IFG group into high (T2D probability ≥ 0.7) and low (T2D probability ≤ 0.5) risk subgroups. The stratification performances were compared with clinically relevant metabolic traits. Results Two metabolite profiles specific for T2D (nfasting = 12 metabolites, npostprandial = 4 metabolites) were identified, with all four postprandial metabolites also being identified in the fasting state. Stratified by the postprandial profile, the high-risk subgroup of IFG individuals (n = 72) showed similar glucose concentrations to the low-risk subgroup (n = 57), yet a higher BMI (difference: 3.3 kg/m2 (95% CI 1.7–5.0)) and postprandial insulin concentrations (21.5 mU/L (95% CI 1.8–41.2)). Conclusion Postprandial metabolites identified T2D patients as good as fasting metabolites and exhibited enhanced signals for IFG stratification, which offers a proof of concept that metabolomics research should not focus on the fasting state alone. Electronic supplementary material The online version of this article (10.1007/s11306-017-1307-7) contains supplementary material, which is available to authorized users.

We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ̂| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.

Background: Obesity is a risk factor for loss of kidney function in the general population, but it is unknown whether it proceeds to affect residual kidney function when patients require dialysis. Our aim was to study the effects of body mass index (BMI) on decline in kidney function and risk to develop anuria after initiation of dialysis therapy. Study Design: Prospective cohort study. Setting & Participants: 1,271 incident dialysis patients from 38 centers in The Netherlands participating in the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) between 1997 and 2006. Predictor: BMI assessed at 3 months after the initiation of dialysis therapy (baseline) and categorized into 4 groups: less than 20, 20 or greater to 25, 25 or greater to 30, and 30 or greater kg/m(2). Outcomes & Measurements: The decrease in measured glomerular filtration rate (mGFR) was determined by means of linear mixed models and adjusted for age, sex, primary kidney disease, dialysis modality, smoking, cardiovascular disease, and normalized protein nitrogen appearance and additionally for proteinuria, blood pressure, and baseline mGFR. Cox regression analysis was used to calculate hazard ratios for the development of anuria. Results: Patients had a mean age of 59 +/- 15 years, BMI of 24.8 +/- 4.1 kg/m(2), and mGFR of 4.7 +/- 3.3 mL/min. During 18 months of follow-up, the decrease in mGFR in patients with normal weight was 1.2 mL/min/y (95% confidence interval [Cl], 0.7 to 1.6). Compared with those values, adjusted losses of mGFR were 0.4 mL/min/y (95% Cl, 0.02 to 0.8) greater for overweight and 1.2 mL/min/y (95% Cl, 0.5 to 1.8) greater for obese patients. In contrast, the decrease in underweight patients was 0.6 mL/min/y (-0.1 to 1.3) less. Anuria occurred in 297 patients;the risk was similar among BMI groups after adjustment for confounders and baseline diuresis. Limitations: Patients with missing BMI or mGFR values at baseline were excluded. Conclusion: Obesity is a strong risk factor for the decline in kidney function after initiation of dialysis therapy. Whether obese dialysis patients might benefit from a healthy weight reduction needs to be studied further. Am J Kidney Dis 53:1014-1023. (C) 2009 by the National Kidney Foundation, Inc.

Clinical epidemiological studies investigate whether an exposure, or risk factor, is causally related to the development or progression of a disease or mortality. It might be of interest to study whether this relation is different in different types of patients. To address such research questions, the presence of interaction among risk factors can be examined. Causal interaction between two risk factors is considered most clinically relevant in epidemiology. Causal interaction occurs when two risk factors act together in causing disease and is explicitly defined as a deviation from additivity on a risk difference scale. Statistical interaction can be evaluated on both an additive (absolute risk) and multiplicative (relative risk) scale, depending on the model that is used. When using logistic regression models, which are multiplicative models, several measures of additive interaction are presented to evaluate whether the magnitude of an association differs across subgroups: the relative excess risk due to interaction (RERI), the attributable proportion due to interaction (AP), or the synergy index (S). For a transparent presentation of interaction effects the recent Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement advises reporting the separate effect of each exposure as well as the joint effect compared with the unexposed group as a joint reference category to permit evaluation of both additive and multiplicative interaction.