Marie Pigeyre

Diabetes is a common chronic disease that affects up to 10% of adults worldwide. 1 People with diabetes are at high risk for a wide variety of serious health consequences including, but not limited to, myocardial infarctions, strokes, heart failure, blindness, kidney failure, lower limb amputations, cognitive impairment, and many cancers. This increased risk is independent of other risk factors, is causally related to increased plasma glucose concentrations for cardiovascular events and some of the other consequences, 2, 3 and doubles the risk of all-cause death. 4Diabetes is diagnosed when a person’s plasma glucose or HbA1c concentration (which is directly correlated to glucose concentration) is consistently at or above 7· 0 mmol/L for fasting plasma glucose and 48 mmol/mol (6· 5%) for HbA1c. 5 These thresholds were chosen because they were at the inflection point of the risk association between glucose …

OBJECTIVE To determine whether adiposity depots modulate vaspin levels and whether vaspin predicts type 2 diabetes (T2D) risk, through epidemiological and genetic analyses. RESEARCH DESIGN AND METHODS We assessed the relationship of plasma vaspin concentration with incident and prevalent T2D and adiposity-related variables in 1) the Prospective Urban and Rural Epidemiology (PURE) biomarker substudy (N = 10,052) and 2) the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial (N = 7,840), using regression models. We then assessed whether vaspin is causally associated with T2D and whether genetic variants associated with MRI-measured adiposity depots modulate vaspin levels, using two-sample Mendelian randomization (MR). RESULTS A 1-SD increase in circulating vaspin levels was associated with a 16% increase …

BackgroundEpigenetic modifications, particularly DNA methylation (DNAm) in cord blood, are an important biological marker of how external exposures during gestation can influence the in-utero environment and subsequent offspring development. Despite the recognized importance of DNAm during gestation, comparative studies to determine the consistency of these epigenetic signals across different ethnic groups are largely absent. To address this gap, we first performed epigenome-wide association studies (EWAS) of gestational age (GA) using newborn cord blood DNAm comparatively in a white European (n= 342) and a South Asian (n= 490) birth cohort living in Canada. Then, we capitalized on established cord blood epigenetic GA clocks to examine the associations between maternal exposures, offspring characteristics and epigenetic GA, as well as GA acceleration, defined as the residual difference between epigenetic and chronological GA at birth.ResultsIndividual EWASs identified 1,211 and 1,543 differentially methylated CpGs associated with GA in white European and South Asian cohorts, respectively, with a similar distribution of effects. We confirmed that Bohlin’s cord blood GA clock was robustly correlated with GA in white Europeans (r= 0.71; p= 6.0× 10− 54) and South Asians (r= 0.66; p= 6.9× 10− 64). In both cohorts, Bohlin’s clock was positively associated with newborn weight and length, and negatively associated with parity, newborn female sex, and gestational diabetes. Exclusive to South Asians, the GA clock was positively associated with the newborn ponderal index, while pre-pregnancy weight and gestational weight …

Background and Aims Few studies have compared arm and ankle blood pressures (BPs) with regard to peripheral artery disease (PAD) and mortality. These relationships were assessed using data from three large prospective clinical trials. Methods Baseline BP indices included arm systolic BP (SBP), diastolic BP (DBP), pulse pressure (arm SBP minus DBP), ankle SBP, ankle–brachial index (ABI, ankle SBP divided by arm SBP), and ankle–pulse pressure difference (APPD, ankle SBP minus arm pulse pressure). These measurements were categorized into four groups using quartiles. The outcomes were PAD (the first occurrence of either peripheral revascularization or lower-limb amputation for vascular disease), the composite of PAD or death, and all-cause death. Results Among 40 747 participants without baseline PAD (age 65.6 years, men 68.3 …

ObjectivesThe association of diabetes, and COVID-19 infection has been studied extensively; however, the occurrence of diabetic ketoacidosis (DKA) or hyperglycemic/hyperosmolar states (HHS) in adults during the lockdown has not been well characterized. In this study, we aimed to identify the impact of the lockdown on occurrence and severity of DKA/HHS admissions and glycemic management.MethodsA retrospective chart review was conducted of patients admitted to Hamilton Health Sciences with a diagnosis of DKA or HHS from April to September 2019 (pre-lockdown) and from April to September 2020 (lockdown). Adult (≥18 years old) nonpregnant patients with a single admission in the study period were included for study.ResultsThere were 229 admissions related to diabetes, with 171 admissions meeting the inclusion criteria (n=92 pre-lockdown, n=79 lockdown). In the lockdown group, 51.8% of the …

It has been postulated that rare coding variants (RVs; MAF < 0.01) contribute to the “missing” heritability of complex traits. We developed a framework, the Rare variant heritability (RARity) estimator, to assess RV heritability (h2RV) without assuming a particular genetic architecture. We applied RARity to 31 complex traits in the UK Biobank (n = 167,348) and showed that gene-level RV aggregation suffers from 79% (95% CI: 68-93%) loss of h2RV. Using unaggregated variants, 27 traits had h2RV > 5%, with height having the highest h2RV at 21.9% (95% CI: 19.0-24.8%). The total heritability, including common and rare variants, recovered pedigree-based estimates for 11 traits. RARity can estimate gene-level h2RV, enabling the assessment of gene-level characteristics and revealing 11, previously unreported, gene-phenotype relationships. Finally, we demonstrated that in silico pathogenicity prediction …

Decline in cognitive function is the most feared aspect of ageing. Poorer midlife cognitive function is associated with increased dementia and stroke risk. The mechanisms underlying variation in cognitive function are uncertain. Here, we assessed associations between 1160 proteins’ plasma levels and two measures of cognitive function, the digit symbol substitution test (DSST) and the Montreal Cognitive Assessment in 1198 PURE-MIND participants. We identified five DSST performance-associated proteins (NCAN, BCAN, CA14, MOG, CDCP1), with NCAN and CDCP1 showing replicated association in an independent cohort, GS (N=1053). MRI-assessed structural brain phenotypes partially mediated (8-19%) associations between NCAN, BCAN, and MOG, and DSST performance. Mendelian randomisation analyses suggested higher CA14 levels might cause larger hippocampal volume and increased stroke risk, whilst higher CDCP1 levels might increase intracranial aneurysm risk. Our findings highlight candidates for further study and the potential for drug repurposing to reduce risk of stroke and cognitive decline.AcronymsAverage causal mediation effect (ACME); brevican (BCAN); carbonic anhydrase 14 (CA14); cluster of differentiation 6 (CD6); CUB-domain containing protein 1 (CDCP1); confidence interval (CI); cerebral microbleed (CMB); cerebrospinal fluid (CSF); digit symbol substitution test (DSST); extracellular matrix (ECM); false discovery rate (FDR); Generation Scotland imaging subsample (GS); Generation Scotland: Scottish Family Health Study (GS:SFHS); instrumental variable (IV); inverse variance weighted (IVW); myelin …

Heart failure (HF), a syndrome of symptomatic fluid overload due to cardiac dysfunction, is the most rapidly growing cardiovascular disorder. Despite recent advances, mortality and morbidity remain high and treatment innovation is challenged by limited understanding of aetiology in relation to disease subtypes. Here we harness the de-confounding properties of genetic variation to map causal biology underlying the HF phenotypic spectrum, to inform the development of more effective treatments. We report a genetic association analysis in 1.9 million ancestrally diverse individuals, including 153,174 cases of HF; 44,012 of non-ischaemic HF; 5,406 cases of non-ischaemic HF with reduced ejection fraction (HFrEF); and 3,841 cases of non-ischaemic HF with preserved ejection fraction (HFpEF). We identify 66 genetic susceptibility loci across HF subtypes, 37 of which have not previously been reported. We map the aetiologic contribution of risk factor traits and diseases as well as newly identified effector genes for HF, demonstrating differential risk factor effects on disease subtypes. Our findings highlight the importance of extra-cardiac tissues in HF, particularly the kidney and the vasculature in HFpEF. Pathways of cellular senescence and proteostasis are notably uncovered, including IGFBP7 as an effector gene for HFpEF. Using population approaches causally anchored in human genetics, we provide fundamental new insights into the aetiology of heart failure subtypes that may inform new approaches to prevention and treatment.

Estimated glomerular filtration rate (eGFR) impacts the concentration of plasma biomarkers confounding biomarker association studies of eGFR with reverse causation. To identify biomarkers causally associated with eGFR, we performed a proteome-wide Mendelian randomization study. Genetic variants nearby biomarker coding genes were tested for association with plasma concentration of 1,161 biomarkers in a multi-ancestry sample of 12,066 participants from the Prospective Urban and Rural Epidemiological (PURE) study. Using two-sample Mendelian randomization, individual variants’ effects on biomarker concentration were correlated with their effects on eGFR and kidney traits from published genome-wide association studies (GWAS). Genetically altered concentrations of 22 biomarkers were associated with eGFR above a Bonferroni-corrected significance threshold. Five biomarkers were previously …

ImportanceCardiometabolic parameters are established risk factors for COVID-19 severity. The identification of causal or protective biomarkers for COVID-19 severity may facilitate the development of novel therapies.ObjectiveTo identify protein biomarkers that promote or reduce COVID-19 severity and that mediate the association of cardiometabolic risk factors with COVID-19 severity.Design, Setting, and ParticipantsThis genetic association study using 2-sample mendelian randomization (MR) was conducted in 2022 to investigate associations among cardiometabolic risk factors, circulating biomarkers, and COVID-19 hospitalization. Inputs for MR included genetic and proteomic data from 4147 participants with dysglycemia and cardiovascular risk factors collected through the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial. Genome-wide association study summary statistics were obtained from …

BackgroundFibroblast growth factor-23 (FGF-23) is associated with a range of cardiovascular and noncardiovascular diseases in conventional epidemiological studies, but substantial residual confounding may exist. Mendelian randomization approaches can help control for such confounding.MethodsSCALLOP Consortium data of 19,195 participants were used to generate an FGF-23 genetic score. Data from 337,448 UK Biobank participants were used to estimate associations between higher genetically predicted FGF-23 concentration and the odds of any atherosclerotic cardiovascular disease (n= 26,266 events), nonatherosclerotic cardiovascular disease (n= 12,652), and noncardiovascular diseases previously linked to FGF-23. Measurements of carotid intima-media thickness and left ventricular mass were available in a subset. Associations with cardiovascular outcomes were also tested in three large case …

Background/Objectives: Various biological mechanisms involved in type 2 diabetes (T2D) have been unveiled through converging evidence in common variants from Genome wide association studies (GWAS) and rare or low frequency variants (RV/LFV) from Exome wide association studies (EXWAS). We hypothesized that a two-pronged approach interrogating both RV/LFV and common variants could yield identification of new pathways involved in T2D.Methods: Protein-altering RV/LFV burden was tested for T2D association in an EXWAS of 11,731 cases and 149,613 controls in the UKBiobank. Significant encoded proteins were then investigated using 2-sample Mendelian randomization for causal association with T2D and related variables. Protein quantitative trait loci were estimated in the Prospective Urban and Rural Epidemiological study (N= 11,020) and tested against GWAS-summary statistics of T2D and …

Type 2 diabetes (T2D) predisposes to cardiovascular disease (CVD), but it is still unclear why some individuals with T2D are at disproportionately higher or lower risk. In this study, we employed a genetic stratification method to investigate the main clinical features that differ between two diabetogenic profiles associated concordantly with susceptibility for CVD or discordantly with protection against CVD. Quantifying concordant and discordant genetic predispositions improved CVD risk prediction, especially in men, correctly reassigning higher predicted risk to 5.4% of new male cases of MACE in UK Biobank. Moreover, higher genetically determined discordance reduced the risk associated with MACE in men. In-depth comparisons across a wide spectrum of phenotypes uncovered significant disparities between these two profiles. Subsequent causal inference analyses highlighted critical features of very-low-density lipoprotein particles influencing the discordance between T2D and CVD. We prioritized 8 distinct discordant genomic loci with potential protective effects traits against CVD in individuals with T2D. These findings provide clinically relevant valuable insights for personalized approaches to prevent and treat CVD in individuals with T2D.

BACKGROUNDVarious biological mechanisms involved in Type 2 Diabetes (T2D) have been unveiled through converging evidence in common frequency variants from Genome wide association studies (GWAS) and rare or low frequency variants (RV/LFVs) from Exome wide association studies (EXWAS). We hypothesized that a two-pronged approach interrogating both common variants and RV/LFVs could yield identification of new diabetes genes.METHODS AND RESULTSPer gene protein-altering RV/LFV burden was tested for association with T2D risk in an EXWAS of 11,731 cases and 149,613 controls in the UKBiobank. We used a logistic regression model adjusted for age, sex, and the top 20 genetic principal components of the Caucasian European cohort. Proteins encoded by significant genes were then investigated using two-sample Mendelian randomization (MR) for causal association with T2D and …

Aims/hypothesisIndividuals with diabetes can be clustered into five subtypes using up to six routinely measured clinical variables. We hypothesised that circulating protein levels might be used to distinguish between these subtypes. We recently used five of these six variables to categorise 7017 participants from the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial into these subtypes: severe autoimmune diabetes (SAID, n=241), severe insulin-deficient diabetes (SIDD, n=1594), severe insulin-resistant diabetes (SIRD, n=914), mild obesity-related diabetes (MOD, n=1595) and mild age-related diabetes (MARD, n=2673).MethodsForward-selection logistic regression models were used to identify a subset of 233 cardiometabolic protein biomarkers that were independent determinants of one subtype vs the others. We then assessed the performance of adding identified biomarkers (one after one …

ImportanceBody mass index (BMI) is an easily obtained adiposity surrogate. However, there is variability in body composition and adipose tissue distribution between individuals with the same BMI, and there is controversy regarding the BMI associated with the lowest mortality risk.ObjectiveTo evaluate which of BMI, fat mass index (FMI), and waist-to-hip (WHR) has the strongest and most consistent association with mortality.Design, Setting, and ParticipantThis cohort study used incident deaths from the UK Biobank (UKB; 2006-2022), which includes data from 22 clinical assessment centers across the United Kingdom. UKB British participants of British White ancestry (N = 387 672) were partitioned into a discovery cohort (n = 337 078) and validation cohort (n = 50 594), with the latter consisting of 25 297 deaths and 25 297 controls. The discovery cohort was used to derive genetically determined …

There is increasing evidence that the complexity of the retinal vasculature measured as fractal dimension, Df, might offer earlier insights into the progression of coronary artery disease (CAD) before traditional biomarkers can be detected. This association could be partly explained by a common genetic basis; however, the genetic component of Df is poorly understood. We present a genome-wide association study (GWAS) of 38,000 individuals with white British ancestry from the UK Biobank aimed to comprehensively study the genetic component of Df and analyse its relationship with CAD. We replicated 5 Df loci and found 4 additional loci with suggestive significance (P < 1e−05) to contribute to Df variation, which previously were reported in retinal tortuosity and complexity, hypertension, and CAD studies. Significant negative genetic correlation estimates support the inverse relationship between Df and CAD, and …

Background Atrial fibrillation (AF) is a cardiac arrhythmia associated with an elevated risk of stroke, heart failure, and mortality. However, preventative therapies are needed with ancillary benefits on its cardiovascular comorbidities. Lipoprotein(a) (Lp[a]) is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), which itself increases AF risk, but it remains unknown whether Lp(a) is a causal mediator of AF independent of ASCVD. Objectives This study investigated the role of Lp(a) in AF and whether it is independent of ASCVD. Methods Measured and genetically predicted Lp(a) levels were tested for association with 20,432 cases of incident AF in the UK Biobank (N = 435,579). Mendelian randomization analyses were performed by using summary-level data for AF from publicly available genome-wide association studies (N = 1,145,375). Results In the UK Biobank, each 50 nmol/L (23 mg/dL …

IntroductionAdenosine triphosphate-citrate lyase (ACLY) inhibition is a therapeutic strategy under investigation for atherosclerotic cardiovascular disease, nonalcoholic steatohepatitis, and metabolic syndrome. Mouse models suggest that ACLY inhibition could reduce inflammation and kidney fibrosis. Genetic analysis of ACLY in chronic kidney disease (CKD) has not been performed.MethodsWe constructed a genetic instrument by selecting variants associated with ACLY expression in the expression quantitative trait loci genetics consortium (eQTLGen) from blood samples from 31,684 participants. In a 2-sample Mendelian randomization analysis, we evaluated the effect of genetically predicted ACLY expression on the risk of CKD, estimated glomerular filtration rate (eGFR), and albumin-to-creatinine ratio (ACR) using the CKD Genetics (CKDGen) consortium, UK Biobank, and the Finnish Genetics (FinnGen …

YALING TANG, MARIE PIGEYRE, XIUQIN SUN, MARIO LUCA MORIERI, HETAL SHAH, GUILLAUME PARE, HERTZEL C. GERSTEIN, KENT TAYLOR, VASAN S. RAMACHANDRAN, JEROME I. ROTTER, STEPHEN S. RICH, JAMES B. MEIGS, ALISA MANNING, JOSYF MYCHALECKYJ, ALESSANDRO DORIA, CONSORTIUM NHLBI TRANS-OMICS FOR PRECISION MEDICINE (TOPMED); 1276-P: Transancestral Genomic Analysis Links Dysregulation of Valine Metabolism to the Development of Heart Failure in Type 2 Diabetes. Diabetes 1 June 2022; 71 (Supplement_1): 1276–P. https://doi. org/10.2337/db22-1276-P