Circulating BMP10 Levels Associate With Late Postoperative Atrial Fibrillation and Left Atrial Endomysial Fibrosis.

BACKGROUND: Serum bone morphogenetic protein 10 (BMP10) blood levels are a marker for history of atrial fibrillation (AF) and for major adverse cardiovascular events in patients with AF, including stroke, AF recurrences after catheter ablations, and mortality. The predictive value of BMP10 in patients undergoing cardiac surgery and association with morphologic properties of atrial tissues are unknown. OBJECTIVES: This study sought to study the correlation between BMP10 levels and preoperative clinical traits, occurrence of early and late postoperative atrial fibrillation (POAF), and atrial fibrosis in patients undergoing cardiac surgery. METHODS: Patients with and without preoperative AF history undergoing first cardiac surgery were included (RACE V, n = 147). Preoperative blood biomarkers were analyzed, left (n = 114) and right (n = 125) atrial appendage biopsy specimens were histologically investigated after WGA staining, and postoperative rhythm was monitored continuously with implantable loop recorders (n = 133, 2.5 years). RESULTS: Adjusted multinomial logistic regression indicated that BMP10 accurately reflected a history of persistent AF (OR: 1.24, 95% CI: 1.10-1.40, P = 0.001), similar to NT-pro-BNP. BMP10 levels were associated with increased late POAF90 occurrence after adjustment for age, sex, AF history, and early POAF occurrence (HR: 1.07 [per 0.1 ng/mL increase], 95% CI: 1.00-1.14, P = 0.041). Left atrial endomysial fibrosis (standardized ß = 0.22, P = 0.041) but not overall fibrosis (standardized Β = 0.12, P = 0.261) correlated with circulating BMP10 after adjustment for age, sex, AF history, reduced LVF, and valvular surgery indication. CONCLUSIONS: Increased BMP10 levels were associated with persistent AF history, increased late POAF incidence, and LAA endomysial fibrosis in a diverse sample of patients undergoing cardiac surgery.

Clinical Predictors of Device-Detected Atrial Fibrillation During 2.5 Years After Cardiac Surgery: Prospective RACE V Cohort.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a frequent complication after cardiac surgery that is associated with late atrial fibrillation (AF) recurrences (late-POAF) and increased morbidity and long-term mortality. OBJECTIVES: This study sought to determine device-detected POAF incidence and to identify clinical variables associated with POAF, both in patients with and without preoperative AF history. METHODS: A total of 133 consecutive patients undergoing cardiac surgery were prospectively enrolled and continuously monitored with an implantable loop recorder for 2.5 years after surgery. Preoperative transthoracic echocardiography, 12-lead electrocardiogram, blood biomarkers, and clinical data were analyzed to develop prediction models for early- and late-POAF. RESULTS: In patients without preoperative AF history, early-POAF within the first 90 postoperative days occurred in 41 (47.1%) of 87 patients. Late-POAF after the first 90 postoperative days occurred in 22 (25%) of 87 patients, and 20 of these patients also had early-POAF during the first 90 days (20 of 22 [91%]). Increased right atrial minimum volume indexed for body surface area (RAVImin) and early-POAF were independently associated with late-POAF. A prediction model for late-POAF, which included RAVImin >11 mL/m2, age >65 years, and early-POAF, achieved an area under the curve of 0.82 (95% CI: 0.72-0.92). For patients with preoperative AF-history, late-POAF recurrences were frequent (22 of 33 [67%]). Increased RAVImin was independently associated with a higher incidence of late-POAF. CONCLUSIONS: In patients with and without AF history, late-POAF recurrences are frequent, including in patients undergoing surgical AF ablation. In patients with no history of AF, late-POAF might be predicted with excellent accuracy by using a combination of preoperative variables. In patients with a history of AF, signs of advanced AF substrate (eg, increased right atrial volumes) were associated with long-term AF recurrences. [Reappraisal of Atrial Fibrillation: Interaction Between Hypercoagulability, Electrical Remodeling, and Vascular Destabilisation in the Progression of AF; NCT03124576].

In situ lipid-loading activates peripheral dendritic cell subsets characterized by cellular ROS accumulation but compromises their capacity to prime naïve T cells.

BACKGROUND AND AIMS: Dendritic cells (DCs), professional antigen-presenting cells, play an important role in pathologies by controlling adaptive immune responses. However, their adaptation to and functionality in hypercholesterolemia, a driving factor in disease onset and progression of atherosclerosis remains to be established. METHODS: In this study, we addressed the immediate impact of high fat diet-induced hypercholesterolemia in low-density lipoprotein receptor deficient (Ldlr-/-) mice on separate DC subsets, their compartmentalization and functionality. RESULTS: While hypercholesterolemia induced a significant rise in bone marrow myeloid and dendritic cell progenitor (MDP) frequency and proliferation rate after high fat diet feeding, it did not affect DC subset numbers in lymphoid tissue. Hypercholesterolemia led to almost immediate and persistent augmentation in granularity of conventional DCs (cDCs), in particular cDC2, reflecting progressive lipid accumulation by these subsets. Plasmacytoid DCs were only marginally and transiently affected. Lipid loading increased co-stimulatory molecule expression and ROS accumulation by cDC2. Despite this hyperactivation, lipid-laden cDC2 displayed a profoundly reduced capacity to stimulate naïve CD4+ T cells. CONCLUSION: Our data provide evidence that in hypercholesterolemic conditions, peripheral cDC2 subsets engulf lipids in situ, leading to a more activated status characterized by cellular ROS accumulation while, paradoxically, compromising their T cell priming ability. These findings will have repercussions not only for lipid driven cardiometabolic disorders like atherosclerosis, but also for adaptive immune responses to pathogens and/or endogenous (neo) antigens under conditions of hyperlipidemia.

Heart Failure, Female Sex, and Atrial Fibrillation Are the Main Drivers of Human Atrial Cardiomyopathy: Results From the CATCH ME Consortium.

BACKGROUND: Atrial cardiomyopathy (atCM) is an emerging prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are hallmarks of atCM. The contribution of etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been quantified. This study aimed to evaluate the association between histological features of atCM and the clinical phenotype. METHODS AND RESULTS: We examined left atrial (LA, n=95) and right atrial (RA, n=76) appendages from a European cohort of patients undergoing cardiac surgery. Quantification of histological atCM features was performed following wheat germ agglutinin/CD31/vimentin staining. The contributions of AF, heart failure, sex, and age to histological characteristics were determined with multiple linear regression models. Persistent AF was associated with increased endomysial fibrosis (LA: +1.13±0.47 µm, P=0.038; RA: +0.94±0.38 µm, P=0.041), whereas total extracellular matrix content was not. Men had larger cardiomyocytes (LA: +1.92±0.72 µm, P<0.001), while women had more endomysial fibrosis (LA: +0.99±0.56 µm, P=0.003). Patients with heart failure showed more endomysial fibrosis (LA: +1.85±0.48 µm, P<0.001) and extracellular matrix content (LA: +3.07±1.29%, P=0.016), and a higher capillary density (LA: +0.13±0.06, P=0.007) and size (LA: +0.46±0.22 µm, P=0.044). Fuzzy k-means clustering of histological features identified 2 subtypes of atCM: 1 characterized by enhanced endomysial fibrosis (LA: +3.17 µm, P<0.001; RA: +2.86 µm, P<0.001), extracellular matrix content (LA: +3.53%, P<0.001; RA: +6.40%, P<0.001) and fibroblast density (LA: +4.38%, P<0.001), and 1 characterized by cardiomyocyte hypertrophy (LA: +1.16 µm, P=0.008; RA: +2.58 µm, P<0.001). Patients with fibrotic atCM were more frequently female (LA: odds ratio [OR], 1.33, P=0.002; RA: OR, 1.54, P=0.004), with persistent AF (LA: OR, 1.22, P=0.036) or heart failure (LA: OR, 1.62, P<0.001). Hypertrophic features were more common in men (LA: OR=1.33, P=0.002; RA: OR, 1.54, P=0.004). CONCLUSIONS: Fibrotic atCM is associated with female sex, persistent AF, and heart failure, while hypertrophic features are more common in men.

GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

Genetic insights into resting heart rate and its role in cardiovascular disease.

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.

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

Standing genetic variation affects phenotypic heterogeneity in an SCN5A-mutation founder population with excess sudden cardiac death.

BACKGROUND: The Worm Study, ascertained from a multigeneration pedigree segregating a single amino acid deletion in SCN5A (c.4850_4852delTCT, p.(Phe1617del), rs749697698), is characterized by substantial phenotypic heterogeneity and overlap of sudden cardiac death, long-QT syndrome, cardiac conduction disease, Brugada syndrome, and isorhythmic atrioventricular dissociation. Linkage analysis for a synthetic trait derived from these phenotypes identified a single peak (logarithm of the odds [LOD] = 4.52) at the SCN5A/SCN10A/SCN11A locus on chromosome 3. OBJECTIVE: This study explored the role of additional genetic variation in the chromosome 3 locus as a source of phenotypic heterogeneity in the Worm Study population. METHODS: Genotypes underlying the linkage peak (n = 70) were characterized using microarrays. Haplotypes were determined using family-aware phasing and a population-specific reference panel. Variants with minor allele frequencies >0.10 were tested for association with cardiac conduction disease and isorhythmic dissociation using LAMP and logistic regression. RESULTS: Only 1 haplotype carried the p.Phe1617del/rs749697698 deletion, suggesting relatively recent development (∼18 generations); this haplotype contained 5 other missense variants spanning SCN5A/SCN10A/SCN11A. Noncarrier haplotypes (n = 74) ranged in frequency from 0.5% to 5%. Although no variants were associated with cardiac conduction disease, a homozygous missense variant in SCN10A was associated with isorhythmic dissociation after correction for multiple comparisons (odds ratio 11.23; 95% confidence interval 2.76-23.39; P = 1.2 × 10-4). This variant (rs12632942) was previously associated with PR interval. CONCLUSION: Our data suggest that other variants, alongside a pathogenic mutation, are associated with phenotypic heterogeneity. Single-mutation screening may be insufficient to predict electrical heart disease in patients and family members. In the Worm Study population, segregating a pathogenic SCN5A mutation, compound variation in the SCN5A/SCN10A/SCN11A locus determines arrhythmic outcome.

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Preoperative P-wave parameters and risk of atrial fibrillation after cardiac surgery: a meta-analysis of 20 201 patients.

OBJECTIVES: To evaluate the role of P-wave parameters, as defined on preprocedural electrocardiography (ECG), in predicting atrial fibrillation after cardiac surgery [postoperative atrial fibrillation (POAF)]. METHODS: PubMed, Cochrane library and Embase were searched for studies reporting on P-wave parameters and risk of POAF. Meta-analysis of P-wave parameters reported by at least 5 different publications was performed. In case of receiver operator characteristics (ROC-curve) analysis in the original publications, an ROC meta-analysis was performed to summarize the sensitivity and specificity. RESULTS: Thirty-two publications, with a total of 20 201 patients, contributed to the meta-analysis. Increased P-wave duration, measured on conventional 12-lead ECG (22 studies, Cohen's d = 0.4, 95% confidence interval: 0.3-0.5, P < 0.0001) and signal-averaged ECG (12 studies, Cohen's d = 0.8, 95% confidence interval: 0.5-1.2, P < 0.0001), was a predictor of POAF independently from left atrial size. ROC meta-analysis for signal-averaged ECG P-wave duration showed an overall sensitivity of 72% (95% confidence interval: 65-78%) and specificity of 68% (95% confidence interval: 58-77%). Summary ROC curve had a moderate discriminative power with an area under the curve of 0.76. There was substantial heterogeneity in the meta-analyses for P-wave dispersion and PR-interval. CONCLUSIONS: This meta-analysis shows that increased P-wave duration, measured on conventional 12-lead ECG and signal-averaged ECG, predicted POAF in patients undergoing cardiac surgery.

Atrial fibrillation in the presence and absence of heart failure enhances expression of genes involved in cardiomyocyte structure, conduction properties, fibrosis, inflammation, and endothelial dysfunction.

BACKGROUND: Little is known about genome-wide changes in the atrial transcriptome as a cause or consequence of atrial fibrillation (AF), and the effect of its common and clinically relevant comorbidity-heart failure (HF). OBJECTIVE: The purpose of this study was to explore candidate disease processes for AF by investigating gene expression changes in atrial tissue samples from patients with and without AF, stratified by HF. METHODS: RNA sequencing was performed in right and left atrial appendage tissue in 195 patients undergoing open heart surgery from centers participating in the CATCH-ME consortium (no history of AF, n = 91; paroxysmal AF, n = 53; persistent/permanent AF, n = 51). Analyses were stratified into patients with/without HF (n = 75/120) and adjusted for age, sex, atrial side, and a combination of clinical characteristics. RESULTS: We identified 35 genes associated with persistent AF compared to patients without a history of AF, both in the presence or absence of HF (false discovery rate <0.05). These were mostly novel associations, including 13 long noncoding RNAs. Genes were involved in regulation of cardiomyocyte structure, conduction properties, fibrosis, inflammation, and endothelial dysfunction. Gene set enrichment analysis identified mainly inflammatory gene sets to be enriched in AF patients without HF, and gene sets involved in cellular respiration in AF patients with HF. CONCLUSION: Analysis of atrial gene expression profiles identified numerous novel genes associated with persistent AF, in the presence or absence of HF. Interestingly, no consistent transcriptional changes were associated with paroxysmal AF, suggesting that AF-induced changes in gene expression predominate other changes.

Rationale and Design of the ISOLATION Study: A Multicenter Prospective Cohort Study Identifying Predictors for Successful Atrial Fibrillation Ablation in an Integrated Clinical Care and Research Pathway.

Introduction: Continuous progress in atrial fibrillation (AF) ablation techniques has led to an increasing number of procedures with improved outcome. However, about 30-50% of patients still experience recurrences within 1 year after their ablation. Comprehensive translational research approaches integrated in clinical care pathways may improve our understanding of the complex pathophysiology of AF and improve patient selection for AF ablation. Objectives: Within the "IntenSive mOlecular and eLectropathological chAracterization of patienTs undergoIng atrial fibrillatiOn ablatioN" (ISOLATION) study, we aim to identify predictors of successful AF ablation in the following domains: (1) clinical factors, (2) AF patterns, (3) anatomical characteristics, (4) electrophysiological characteristics, (5) circulating biomarkers, and (6) genetic background. Herein, the design of the ISOLATION study and the integration of all study procedures into a standardized pathway for patients undergoing AF ablation are described. Methods: ISOLATION (NCT04342312) is a two-center prospective cohort study including 650 patients undergoing AF ablation. Clinical characteristics and routine clinical test results will be collected, as well as results from the following additional diagnostics: determination of body composition, pre-procedural rhythm monitoring, extended surface electrocardiogram, biomarker testing, genetic analysis, and questionnaires. A multimodality model including a combination of established predictors and novel techniques will be developed to predict ablation success. Discussion: In this study, several domains will be examined to identify predictors of successful AF ablation. The results may be used to improve patient selection for invasive AF management and to tailor treatment decisions to individual patients.

Low Density Lipoprotein Exposure of Plasmacytoid Dendritic Cells Blunts Toll-like Receptor 7/9 Signaling via NUR77.

BACKGROUND: Pathogens or trauma-derived danger signals induced maturation and activation of plasmacytoid dendritic cells (pDCs) is a pivotal step in pDC-dependent host defense. Exposure of pDC to cardiometabolic disease-associated lipids and proteins may well influence critical signaling pathways, thereby compromising immune responses against endogenous, bacterial and viral pathogens. In this study, we have addressed if hyperlipidemia impacts human pDC activation, cytokine response and capacity to prime CD4+ T cells. METHODS AND RESULTS: We show that exposure to pro-atherogenic oxidized low-density lipoproteins (oxLDL) led to pDC lipid accumulation, which in turn ablated a Toll-like receptor (TLR) 7 and 9 dependent up-regulation of pDC maturation markers CD40, CD83, CD86 and HLA-DR. Moreover, oxLDL dampened TLR9 activation induced the production of pro-inflammatory cytokines in a NUR77/IRF7 dependent manner and impaired the capacity of pDCs to prime and polarize CD4+ T helper (Th) cells. CONCLUSION: Our findings reveal profound effects of dyslipidemia on pDC responses to pathogen-derived signals.

Considerations for the Assessment of Substrates, Genetics and Risk Factors in Patients with Atrial Fibrillation.

Successful translation of research focussing on atrial arrhythmogenic mechanisms has potential to provide a mechanism-tailored classification and to support personalised treatment approaches in patients with AF. The clinical uptake and clinical implementation of new diagnostic techniques and treatment strategies require translational research approaches on various levels. Diagnostic translation involves the development of clinical diagnostic tools. Additionally, multidisciplinary teams are required for collaborative translation to describe genetic mechanisms, molecular pathways, electrophysiological characteristics and concomitant risk factors. In this article, current approaches for AF substrate characterisation, analysis of genes potentially involved in AF and strategies for AF risk factor assessment are summarised. The authors discuss challenges and obstacles to clinical translation and implementation into clinical practice.

Clinical and electrophysiological predictors of device-detected new-onset atrial fibrillation during 3 years after cardiac surgery.

AIMS: Postoperative atrial fibrillation (POAF) after cardiac surgery is an independent predictor of stroke and mortality late after discharge. We aimed to determine the burden and predictors of early (up to 5th postoperative day) and late (after 5th postoperative day) new-onset atrial fibrillation (AF) using implantable loop recorders (ILRs) in patients undergoing open chest cardiac surgery. METHODS AND RESULTS: Seventy-nine patients without a history of AF undergoing cardiac surgery underwent peri-operative high-resolution mapping of electrically induced AF and were followed 36 months after surgery using an ILR (Reveal XT™). Clinical and electrophysiological predictors of late POAF were assessed. POAF occurred in 46 patients (58%), with early POAF detected in 27 (34%) and late POAF in 37 patients (47%). Late POAF episodes were short-lasting (mostly between 2 min and 6 h) and showed a circadian rhythm pattern with a peak of episode initiation during daytime. In POAF patients, electrically induced AF showed more complex propagation patterns than in patients without POAF. Early POAF, right atrial (RA) volume, prolonged PR time, and advanced age were independent predictors of late POAF. CONCLUSIONS: Late POAF occurred in 47% of patients without a history of AF. Patients who develop early POAF, with higher age, larger RA, or prolonged PR time have a higher risk of developing late POAF and may benefit from intensified rhythm follow-up after cardiac surgery. CLINICALTRIALS.GOV NUMBER: NCT01530750.

Dynamic risk assessment to improve quality of care in patients with atrial fibrillation: the 7th AFNET/EHRA Consensus Conference.

AIMS: The risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes. METHODS AND RESULTS: This article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence. CONCLUSION: The remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.