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Adenosine 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.We constructed a genetic instrument by selecting variants associated withMendelian randomization analyses revealed that genetically reduced ACLY expression was associated with reduced risk of CKD but had no effect on either eGFR or ACR. Further evaluation of ACLY in kidney disease is warranted.

It has been postulated that rare coding variants (RVs; MAF5%, 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 12 novel gene-phenotype relationships. Finally, we demonstrated that in silico pathogenicity prediction (variant-level) and gene-level annotations do not generally enrich for RVs that over-contribute to complex trait variance, and thus, novel methods are needed to predict RV functionality.

Data analyses from Swedish individuals with newly diagnosed diabetes have suggested that diabetes could be classified into five subtypes that differ with respect to the progression of dysglycaemia and the incidence of diabetes consequences. We assessed this classification in a multiethnic cohort of participants with established and newly diagnosed diabetes, randomly allocated to insulin glargine vs standard care. In total, 7017 participants from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were assigned to the five predefined diabetes subtypes (namely, severe auto-immune diabetes, severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes, mild age-related diabetes) based on the age at diabetes diagnosis, BMI, HbA1c, fasting C-peptide levels and the presence of glutamate decarboxylase antibodies at baseline. Differences between diabetes subtypes in cardiovascular and renal outcomes were investigated using Cox regression models for a median follow-up of 6.2 years. We also compared the effect of glargine vs standard care on hyperglycaemia, defined by having a mean post-randomisation HbA1c ≥6.5%, between subtypes. The five diabetes subtypes were replicated in the ORIGIN trial and exhibited similar baseline characteristics in Europeans and Latin Americans, compared with the initially described clusters in the Swedish cohort. We confirmed differences in renal outcomes, with a higher incidence of events in the severe insulin-resistant diabetes subtype compared with the mild age-related diabetes subtype (i.e., chronic kidney disease stage 3A: HR 1.49 [95% CI 1.31, 1.71]; stage 3B: HR 2.25 [1.82, 2.78]; macroalbuminuria: HR 1.56 [1.22, 1.99]). No differences were observed in the incidence of retinopathy and cardiovascular diseases after adjusting for multiple hypothesis testing. Diabetes subtypes also differed in glycaemic response to glargine, with a particular benefit of receiving glargine (vs standard care) in the severe insulin-deficient diabetes subtype compared with the mild age-related diabetes subtype, with a decreased occurrence of hyperglycaemia by 13% (OR 1.36 [1.30, 1.41] on glargine; OR 1.49 [1.43, 1.57] on standard care; p for interaction subtype × intervention = 0.001). Cluster analysis enabled the characterisation of five subtypes of diabetes in a multiethnic cohort. Both the incidence of renal outcomes and the response to insulin varied between diabetes subtypes. These findings reinforce the clinical utility of applying precision medicine to predict comorbidities and treatment responses in individuals with diabetes. ORIGIN trial, ClinicalTrials.gov NCT00069784.

ImportanceBody mass index (BMI) is an easily obtainable surrogate for adiposity. However, there is substantial variability in body composition and adipose tissue distribution between individuals with the same BMI. Furthermore, previous literature is conflicting regarding the optimal BMI linked with the lowest mortality risk.ObjectiveTo determine which of BMI, fat mass index (FMI), and waist-to-hip (WHR) is the strongest and most consistent causal predictor for mortality.DesignWe created a case-control cohort using all incident deaths from the UK Biobank (UKB; 2006 to 2022).Setting22 Clinical assessment centres across the United Kingdom.ParticipantsWe partitioned UKB British participants (N= 387,672) into a discovery (N = 337,078) and validation cohort (N = 50,594), the latter consisting of 25,297 deaths and 25,297 randomly selected age- and sex-matched controls. The discovery cohort was used to derive genetically-determined adiposity measures while the validation cohort was used for all other analyses. Relationships between exposures and outcomes were analyzed through both observational and Mendelian randomization (MR) analyses to infer causality.ExposuresBMI, FMI and WHR.Main Outcomes and MeasuresAll-cause mortality; Cause-specific mortality (cancer, cardiovascular disease (CVD), respiratory disease, or other causes).ResultsObservational relationships between measured BMI and FMI with all-cause mortality were J-shaped, whereas the relationship with WHR was linear. Genetically-determined WHR had a stronger association with all-cause mortality compared to BMI or FMI (OR per SD increase of WHR (95% CI): 1.51 (1.32 – 1.72); 1.29 (1.20 – 1.38) for BMI, and 1.45 (1.36 – 1.54) for FMI, heterogeneity PPP > 0.05).Conclusions and RelevanceWHR has the strongest and most consistent causal association with risk of mortality irrespective of BMI, with the effect being stronger in males than females. Clinical recommendations and interventions should prioritize adiposity distribution rather than mass.Key PointsQuestionAmong body mass index (BMI), fat mass index (FMI), or waist-to-hip (WHR) ratio, what is the optimal adiposity measure for predicting mortality outcomes in adults?FindingsIn this Mendelian randomization study consisting of 387,672 British adult participants from the UK Biobank (UKB), WHR was found to have the strongest and most consistent causal relationship with all-cause and cause-specific mortality.MeaningWHR was the most robust predictor of mortality risk and may serve as a more appropriate target for health care intervention.

Objective To assess the respiratory function and sleep characteristics of obese adults and children. Methods All patients with non-syndromic, severe obesity (BMI ≥ 3 z-scores for children and ≥ 40.00 kg/m2 for adults), referred for pulmonary function tests at Lille University Hospital, were retrospectively included. Results A total of 69 children (mean ± SD BMI 36.8 ± 6.7 and mean BMI z-score 4.7 ± 1.0) and 70 adults were included (mean BMI 45.7 ± 6.2). Metabolic syndrome was diagnosed in 13 children (26%) and 40 adults (80%). Reduced lung volumes were observed in 34 children (50.0%) and 16 adults (24.0%) and both the mean functional residual capacity (FRC) and the mean residual volume (RV) were lower in children than in adults (FRC: −1.7 ± 2.1 z-score in children vs. −1.0 ± 1.1 in adults, P = 0.026; and RV: −0.8 ± 1.2 z-score in children vs. −0.1 ± 1.1 in adults, P = 0.002). The prevalence of severe obstructive sleep apnea syndrome was greater in adults (40.7% vs. 18.8%, P = 0.007). Children had a higher average oxygen saturation (median of 96.0% [91.0–98.0] vs. 93.0% [76.0–97.0] in adults, P Conclusion Obesity has consequences for lung volumes in children; however, a longitudinal study is needed to determine the impact on pulmonary expansion and growth.

Vaspin (visceral adipose tissue-derived serpinA12) is an adipokine suspected to be involved in type 2 diabetes (T2D) pathogenesis, linking obesity and T2D. We sought to assess epidemiological and genetic associations of vaspin with T2D and related variables. We assessed the relationship of body-mass index (BMI) and waist-hip ratio (WHR) and plasma vaspin concentration, along with the relationship between plasma vaspin and adiposity-related variables and T2D in (i) a case-cohort within the Prospective Urban and Rural Epidemiology (PURE) prospective multi-country study (N=10,052) , and (ii) the Outcome Reduction with Initial Glargine Intervention (ORIGIN) Trial (N=7,840) of participants with dysglycemia. We next investigated the predictive value of vaspin for T2D risk. All models adjusted for age, sex, and ethnicity. Using two-sample Mendelian randomization (MR) , we analyzed if genetically higher vaspin is causal for T2D. The MR analysis used 34 independent genetic variants (linkage disequilibrium r2 In PURE, a 1 unit increase in BMI and WHR was associated with a 0.01 SD (95% CI 0.01 - 0.02; P = 2.04x10−15) and 0.45 SD (95% CI, 0.21 - 0.70; P = 2.87 × 10−4) increase in plasma vaspin respectively. A 1 SD increase in plasma vaspin was associated with higher triglycerides (0.09 mmol/L; 95% CI, 0.07 - 0.12, P = 4.08x10−13) . Directionally-consistent associations were observed in ORIGIN. A 1 SD increase in plasma vaspin was associated with a 19% increase in incident T2D risk in PURE (HR, 1.19; 95% CI, 1.12 - 1.26; P = 6.36x10−8) and a 16% increase in prevalent T2D in ORIGIN (OR, 1.16; 95% CI, 1.07 - 1.25; P = 2.17x10−4) . Sensitivity analyses showed vaspin's specificity for T2D. Genetically-higher vaspin was associated with increased BMI-adjusted T2D risk (OR, 1.02; 95% CI, 1.00 - 1.03; P = 5.46x10−3) . Our data suggests that vaspin is a predictor for T2D risk, a modest causal factor for T2D development, and might represent a potential T2D therapeutic target. Disclosure H. Wang: None. M. Chong: None. N. Perrot: None. J. Feiner: None. S. Hess: Employee; Sanofi. S. Yusuf: None. H. C. Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. G. Pare: Advisory Panel; Amgen Inc., Bayer AG, Sanofi, Research Support; Bayer AG. M. Pigeyre: n/a. Funding PURE biomarker study was sponsored by Bayer and CIHR. Origin (NCT00069784) and the biomarker-substudy in Origin were sponsored by Sanofi and CIHR.

Diabetes (DM) can be classified into 5 subtypes characterized by distinct progression in dysglycaemia and complications. Using 5 clinical variables, we categorized 7017 participants from the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial into 1/auto-immune DM (n=241) , 2/insulin-deficient DM (n=1594) , 3/insulin-resistant DM (n=914) , 4/obesity-related DM (n=1595) , 5/age-related DM (n=2673) .Yet, whether blood biomarkers are associated with these subtypes is unknown. Forward-selection logistic regression models were used to identify biomarkers that were each independent determinant of one cluster versus the others, among 233 selected cardiometabolic proteins measured at baseline. Models were adjusted for age, sex, ethnicity, C-peptide level, diabetes duration. A total of 13, 2, 7 and biomarkers were independent determinants of DM subtypes 2 to 5 respectively (all P Disclosure M.Pigeyre: n/a. H.C.Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. L.Groop: None. S.Hess: Employee; Sanofi. G.Pare: Advisory Panel; Amgen Inc., Bayer AG, Sanofi, Research Support; Bayer AG. Funding NCT00069784 Canadian Institute of Health Research Sanofi

BACKGROUND AND AIMS UMOD is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is the most abundant protein in urine and related to chronic kidney disease, hypertension and pathogen defense. Through basolateral release from kidney epithelial cells, uromodulin also reaches the blood, where its function is largely unknown. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin in seven cohorts using two complementary assays. METHOD Separate genome-wide association study meta-analyses for circulating uromodulin were conducted for the antibody-based assay (five cohorts, N = 13 985) and the aptamer-based SOMAscan assay (two cohorts, N = 18 070). Genome-wide significant loci were placed into their functional genomic context using RNA-seq, ATAC-seq and Hi-C data generated from primary human kidney tissue. An array of downstream genetic analyses was then performed for significant loci, including fine-mapping, colocalization analyses and gene-by-gene interaction analyses. The B4GALNT2 p.Cys466Arg allele was expressed in MDCK cells and studied by immunofluorescence and Western blotting analyses. RESULTS We detected and replicated 13 genome-wide significant loci (P CONCLUSION This study provides human genetic evidence of new pathway members of uromodulin and delivers novel insights into its determinants and systemic role in the circulation.

OBJECTIVE To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS A two-sample MR analysis included 17 independent genetic variants associated with ACE serum concentration in 4,147 participants from the Outcome Reduction with Initial Glargine INtervention (ORIGIN) (clinical trial reg. no. NCT00069784) trial, and their effects on type 2 diabetes risk were estimated from 18 studies of the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. A genetic risk score (GRS) underpinning lower ACE concentration was then tested for association with type 2 diabetes prevalence in 341,872 participants, including 16,320 with type 2 diabetes, from the UK Biobank. MR estimates were compared after standardization for blood pressure change, with the estimate obtained from a randomized controlled trial (RCT) meta-analysis of ACE inhibitors versus placebo (n = 31,200). RESULTS Genetically lower ACE concentrations were associated with a lower risk of type 2 diabetes (odds ratio [OR] per SD 0.92 [95% CI 0.89–0.95]; P = 1.79 × 10−7). This result was replicated in the UK Biobank (OR per SD 0.97 [0.96–0.99]; P = 8.73 × 10−4). After standardization, the ACE GRS was associated with a larger decrease in type 2 diabetes risk per 2.4-mmHg lower mean arterial pressure (MAP) compared with that obtained from an RCT meta-analysis (OR per 2.4-mmHg lower MAP 0.19 [0.07–0.51] vs. 0.76 [0.60–0.97], respectively; P = 0.007 for difference). CONCLUSIONS These results support the causal protective effect of ACE inhibitors on type 2 diabetes risk and may guide therapeutic decision making in clinical practice.

Fibroblast growth factor 23 (FGF-23) is associated with a range of cardiovascular and non-cardiovascular diseases in conventional epidemiological studies, but substantial residual confounding may exist. Mendelian randomisation approaches can help control for such confounding. SCALLOP consortium data on 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), of any non-atherosclerotic cardiovascular disease (n=12,652), and of non-cardiovascular diseases previously linked to FGF-23. Measurements of carotid intima-media thickness (CIMT) and left ventricular mass (LVM) were available in a subset. Associations with cardiovascular outcomes were also tested in three large case-control consortia: CARDIOGRAMplusC4D (coronary artery disease, n=181,249 cases), MEGASTROKE (stroke, n=34,217), and HERMES (heart failure, n=47,309). We identified 34 independent variants for circulating FGF-23 which formed a validated genetic score. There were no associations between genetically-predicted FGF-23 and any of the cardiovascular or non-cardiovascular outcomes. In UK Biobank, the odds ratio for any atherosclerotic cardiovascular disease per 1-SD higher genetically-predicted logFGF-23 was 1.03 (95% confidence interval [CI] 0.98-1.08), and for any non-atherosclerotic cardiovascular disease was 1.01 (0.94-1.09). The odds ratios in the case-control consortia were 1.00 (0.97-1.03) for coronary artery disease, 1.01 (0.95-1.07) for stroke, and 1.00 (0.95-1.05) for heart failure. In those with imaging, logFGF-23 was not associated with CIMT or LVM index. This suggests that previously reported observational associations of FGF-23 with risk of atherosclerotic and non-atherosclerotic cardiovascular diseases are unlikely to be causal.

BackgroundATP-citrate lyase (ACLY) inhibition is a promising therapeutic target for dyslipidemia, atherosclerotic cardiovascular disease, non-alcoholic steatohepatitis, and metabolic syndrome. Genetic analysis of its role in chronic kidney disease (CKD) has not been performed.MethodsWe constructed a genetic instrument by selecting variants associated with ACLY expression level in the expression quantitative trait loci genetics consortium (eQTLGen) that includes blood samples from 31,684 participants. In a two-sample Mendelian randomization analysis, we then evaluated the effect of genetically predicted ACLY expression on risk of CKD, estimated glomerular filtration rate (eGFR), and microalbuminuria using the CKD Genetics consortium (CKDGen), United Kingdom biobank, and the Finnish Genetics consortium (FinnGen) totaling 66,396 CKD cases and 958,517 controls.ResultsACLY is constitutively expressed in all cell types including in whole blood. The genetic instrument included 13 variants and explained 1.5% of variation in whole blood ACLY gene expression. A 34% reduction in genetically predicted ACLY expression was associated with a 0.04 mmol/L reduced low-density lipoprotein cholesterol (P = 3.4 × 10−4) and a 9% reduced risk of CKD (stage 3,4,5, dialysis or eGFR below 60 ml/min/1.73m2) (OR = 0.91, 95% C.I. 0.85-0.98, P = 0.008), but no association was observed with eGFR nor microalbuminuria.ConclusionMendelian Randomization analysis provides cautious optimism regarding the possibility of ACLY as a therapeutic target for CKD.

Resume L'issue des grossesses apres chirurgie bariatrique semble favorable, avec une reduction de l'incidence du diabete gestationnel, des troubles hypertensifs et de la macrosomie. Neanmoins, une augmentation de l'incidence des nouveau-nes de petit poids pour l'âge gestationnel et de la prematurite est constatee. Des carences nutritionnelles de severite variable pour la mere et le nouveau-ne et des complications chirurgicales de pronostic potentiellement severe sont observees. Notre groupe de travail multidisciplinaire propose des recommandations elaborees selon la methodologie de la Haute Autorite de sante (HAS) et concernent les questions suivantes : delai entre chirurgie et grossesse, choix de contraception, technique chirurgicale privilegiee pour les femmes en âge de procreer, specificite du parcours obstetrical, modalites de depistage des carences et supplementations nutritionnelles, depistage et gestion du diabete gestationnel, prise de poids optimale, serrage de l'anneau gastrique, conduite a tenir devant une suspicion d'urgence chirurgicale, soins specifiques pendant la periode post-partum et pour les nouveau-nes.

L’évolution des grossesses après chirurgie bariatrique apparaît favorable avec une diminution des risques de diabète gestationnel, d’hypertension et de macrosomie fœtale, mais une augmentation des risques de petit poids de naissance pour l’âge gestationnel et de prématurité des nouveau-nés. Sont également reportées des carences nutritionnelles plus oumoins sévères chez les mères et les nouveau-nés, ainsi que des complications chirurgicales de pronostic parfois défavorable. BARIA-MAT est un groupe de travail multidisciplinaire, proposant des recommandations de bonnes pratiques cliniques, élaborées selon la méthodologie de la Haute Autorité de santé. Les questions abordées par le groupe ont inclus : délai entre chirurgie et grossesse, choix de contraception, technique chirurgicale privilégiée pour les femmes en âge de procréer, spécificité du parcours obstétrical, modalités de dépistage des carences et supplémentations nutritionnelles, dépistage et gestion du diabète gestationnel, prise de poids optimale, ajustement de l’anneau gastrique, conduite à tenir devant une suspicion d’urgence chirurgicale, soins spécifiques pendant la période post-partum et pour les nouveau-nés.

Background: Novel, effective, and safe drugs are warranted for treatment of ischemic stroke. Circulating protein biomarkers with causal genetic evidence represent promising drug targets, but no systematic screen of the proteome has been performed. Methods: First, using Mendelian randomization (MR) analyses, we assessed 653 circulating proteins as possible causal mediators for 3 different subtypes of ischemic stroke: large artery atherosclerosis, cardioembolic stroke, and small artery occlusion. Second, we used MR to assess whether identified biomarkers also affect risk for intracranial bleeding, specifically intracerebral and subarachnoid hemorrhages. Third, we expanded this analysis to 679 diseases to test a broad spectrum of side effects associated with hypothetical therapeutic agents for ischemic stroke that target the identified biomarkers. For all MR analyses, summary-level data from genome-wide association studies (GWAS) were used to ascertain genetic effects on circulating biomarker levels versus disease risk. Biomarker effects were derived by meta-analysis of 5 GWAS (N≤20 509). Disease effects were derived from large GWAS analyses, including MEGASTROKE (N≤322 150) and UK Biobank (N≤408 961) studies. Results: Several biomarkers emerged as causal mediators for ischemic stroke. Causal mediators for cardioembolic stroke included histo-blood group ABO system transferase, coagulation factor XI, scavenger receptor class A5 (SCARA5), and tumor necrosis factor–like weak inducer of apoptosis (TNFSF12). Causal mediators for large artery atherosclerosis included ABO, cluster of differentiation 40, apolipoprotein(a), and matrix metalloproteinase-12. SCARA5 (odds ratio [OR]=0.78; 95% CI, 0.70–0.88; P =1.46×10 −5 ) and TNFSF12 (OR=0.86; 95% CI, 0.81–0.91; P =7.69×10 −7 ) represent novel protective mediators of cardioembolic stroke. TNFSF12 also increased the risk of subarachnoid (OR=1.53; 95% CI, 1.31–1.78; P =3.32×10 −8 ) and intracerebral (OR=1.34; 95% CI, 1.14–1.58; P =4.05×10 −4 ) hemorrhages, whereas SCARA5 decreased the risk of subarachnoid hemorrhage (OR=0.61; 95% CI, 0.47–0.81; P =5.20×10 −4 ). Multiple side effects beyond stroke were identified for 6 of 7 biomarkers, most (75%) of which were beneficial. No adverse side effects were found for coagulation factor XI, apolipoprotein(a), and SCARA5. Conclusions: Through a systematic MR screen of the circulating proteome, causal roles for 5 established and 2 novel biomarkers for ischemic stroke were identified. Side-effect profiles were characterized to help inform drug target prioritization. In particular, SCARA5 represents a promising target for treatment of cardioembolic stroke, with no predicted adverse side effects.

OBJECTIVE Observations of a metabolically unhealthy normal weight phenotype suggest that a lack of favorable adiposity contributes to an increased risk of type 2 diabetes. We aimed to identify causal blood biomarkers linking favorable adiposity with type 2 diabetes risk for use in cardiometabolic risk assessments. RESEARCH DESIGN AND METHODS A weighted polygenic risk score (PRS) underpinning metabolically favorable adiposity was validated in the UK Biobank (n = 341,872) and the Outcome Reduction With Initial Glargine Intervention (ORIGIN Trial) (n = 8,197) and tested for association with 238 blood biomarkers. Associated biomarkers were investigated for causation with type 2 diabetes risk using Mendelian randomization and for its performance in predictive models for incident major adverse cardiovascular events (MACE). RESULTS Of the 238 biomarkers tested, only insulin-like growth factor–binding protein (IGFBP)-3 concentration was associated with the PRS, where a 1 unit increase in PRS predicted a 0.28-SD decrease in IGFBP-3 blood levels (P < 0.05/238). Higher IGFBP-3 levels causally increased type 2 diabetes risk (odds ratio 1.26 per 1 SD genetically determined IGFBP-3 level [95% CI 1.11–1.43]) and predicted a higher incidence of MACE (hazard ratio 1.13 per 1 SD IGFBP-3 concentration [95% CI 1.07–1.20]). Adding IGFBP-3 concentrations to the standard clinical assessment of metabolic health enhanced the prediction of incident MACE, with a net reclassification improvement of 11.5% in normal weight individuals (P = 0.004). CONCLUSIONS We identified IGFBP-3 as a novel biomarker linking a lack of favorable adiposity with type 2 diabetes risk and a predictive marker for incident cardiovascular events. Using IGFBP-3 blood concentrations may improve the risk assessment of cardiometabolic diseases.

Mitochondrial DNA copy number (mtDNA-CN) is an accessible blood-based measurement believed to capture underlying mitochondrial function. The specific biological processes underpinning its regulation, and whether those processes are causative for disease, is an area of active investigation. We developed a novel method for array-based mtDNA-CN estimation suitable for biobank-scale studies, called “AutoMitoC”. We applied AutoMitoC to 395,781 UKBiobank study participants and performed genome and exome-wide association studies, identifying novel common and rare genetic determinants. Overall, genetic analyses identified 73 loci for mtDNA-CN, which implicated several genes involved in rare mtDNA depletion disorders, dNTP metabolism, and the mitochondrial central dogma. Rare variant analysis identified SAMHD1 mutation carriers as having higher mtDNA-CN (beta=0.23 SDs; 95% CI, 0.18-0.29; P=2.6×10−19), a potential therapeutic target for patients with mtDNA depletion disorders, but at increased risk of breast cancer (OR=1.91; 95% CI, 1.52-2.40; P=2.7×10−8). Finally, Mendelian randomization analyses suggest a causal effect of low mtDNA-CN on dementia risk (OR=1.94 per 1 SD decrease in mtDNA-CN; 95% CI, 1.55-2.32; P=7.5×10−4). Altogether, our genetic findings indicate that mtDNA-CN is a complex biomarker reflecting specific mitochondrial processes related to mtDNA regulation, and that these processes are causally related to human diseases.

BackgroundEpidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes.MethodsSingle-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 x 10-8) with systolic blood pressure in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Inverse-variance weighted random- effects models were used to examine associations between genetically-proxied inhibition of these drug targets and risk of cancer. Multivariable Mendelian randomization and colocalisation analyses were employed to examine robustness of findings to violations of Mendelian randomization assumptions.ResultsGenetically-proxied ACE inhibition equivalent to a 1 mmHg reduction in systolic blood pressure was associated with increased odds of colorectal cancer (OR 1.13, 95% CI 1.06-1.22; P = 3.6 x 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02-1.92; P = 0.035). There was little evidence of association of genetically-proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94-1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92-1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99-1.13; P = 0.08). Genetically-proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers.ConclusionGenetically-proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomised controlled trials for these medications.

Measures of obesity, including body mass index (BMI) and waist circumference (WC), do not fully capture the complexity of obesity-related health risks. This study identified distinct classes of obesity-related characteristics and evaluated their associations with BMI, WC, and percent body fat (%BF) using cross-sectional data from 30,096 participants aged 45-85 in the Canadian Longitudinal Study on Aging (2011-2015). Sixteen obesity-related variables, including behavioural, metabolic, physical health, and mental health/social factors, were included in a latent class analysis to identify distinct classes of participants. Adjusted odds ratios (OR) were estimated from logistic regression for associations between each class and obesity defined by BMI, WC and %BF. Six latent classes were identified: "low-risk" (39.8%), "cardiovascular risk" (19.4%), "metabolic risk" (16.9%), "sleep and mental health risk" (12.1%), "multiple and complex risk" (6.7%), and "cardiometabolic risk" (5.1%). Compared to "low-risk", all classes had increased odds of BMI-, WC- and %BF-defined obesity. For example, the "complex and multiple risk" class was associated with obesity by BMI (OR: 10.70, 95% confidence interval (CI): 9.51, 12.04), WC (OR: 9.21, 95% CI: 8,15, 10,41) and %BF (OR: 7.54, 95% CI: 6.21, 9.16). Distinct classes of obesity-related characteristics were identified and were strongly associated with obesity defined by multiple measures.

BackgroundPre-pregnancy obesity and excessive gestational weight gain (GWG) are established risk factors for adverse pregnancy, delivery and birth outcomes. Pregnancy is an ideal moment for nutritional interventions in order to establish healthier lifestyle behaviors in women at high risk of obstetric and neonatal complications.MethodsElectronic-Personalized Program for Obesity during Pregnancy to Improve Delivery (ePPOP-ID) is an open multicenter randomized controlled trial which will assess the efficacy of an e-health web-based platform offering a personalized lifestyle program to obese pregnant women in order to reduce the rate of labor procedures and delivery interventions in comparison to standard care. A total of 860 eligible pregnant women will be recruited in 18 centers in France between 12 and 22 weeks of gestation, randomized into the intervention or the control arm and followed until 10 weeks of postpartum.The intervention is based on nutrition, eating behavior, physical activity, motivation and well-being advices in which personalization is central, as well as the use of a mobile/tablet application. Inputs includes data from the medical record of participants (medical history, anthropometric data), from the web platform (questionnaires on dietary habits, eating behavior, physical activity and motivation in both groups), and adherence to the program (time of connection for the intervention group only). Data are collected at inclusion, 32 weeks, delivery and 10 weeks postpartum. As primary outcome, we will use a composite endpoint score of obstetrical interventions during labor and delivery, defined as caesarean section and instrumental delivery (forceps and vacuum extractor). Secondary outcomes will consist of data routinely collected as part of usual antenatal and perinatal care, such as GWG, hypertension, preeclampsia, as well as fetal and neonatal outcomes including premature birth, gestational age at birth, birth weight, macrosomia, Apgar score, arterial umbilical cord pH, neonatal traumatism, hyperbilirubinemia, respiratory distress syndrome, transfer in neonatal intensive care unit, and neonatal adiposity. Post-natal outcomes will be duration of breastfeeding, maternal weight retention and child weight at postnatal visit.DiscussionThe findings of the ePPOP-ID trial will help design e-health intervention program for obese women in pregnancy.Trial registrationClinicalTrials.govIdentifier:NCT02924636/ October 5th 2016.

Testosterone products are prescribed to males for a variety of possible health benefits, but causal effects are unclear. Evidence from randomized trials are difficult to obtain, particularly regarding effects on long-term or rare outcomes. Mendelian randomization analyses were performed to infer phenome-wide effects of free testosterone on 461 outcomes in 161,268 males from the UK Biobank study. Lifelong increased free testosterone had beneficial effects on increased bone mineral density, and decreased body fat; adverse effects on decreased HDL, and increased risks of prostate cancer, androgenic alopecia, spinal stenosis, and hypertension; and context-dependent effects on increased hematocrit and decreased C-reactive protein. No benefit was observed for type 2 diabetes, cardiovascular or cognitive outcomes. Mendelian randomization suggests benefits of long-term increased testosterone should be considered against adverse effects, notably increased prostate cancer and hypertension. Well-powered randomized trials are needed to conclusively address risks and benefits of testosterone treatment on these outcomes., eLife digest Men experience a gradual decline in their testosterone levels as they grow older. However, the effects of testosterone and the consequences of supplementation on the human body have been unclear. Scientists use so-called randomized controlled trials to establish cause-and-effect and to reduce bias. In these experiments, participants are randomly assigned to a either a treatment group (that receives the intervention being tested) or a control group (that either receives an alternative intervention, a dummy or placebo, or no intervention at all). Randomization ensures that both groups are balanced, and any resulting differences can be attributed to the treatment. However, randomized controlled trials are time-consuming and expensive, so trials of testosterone have had relatively small numbers of participants and short follow-up periods. This makes it difficult to draw conclusions about any potential effects of testosterone administration on less common diseases in men. Now, Paré et al. investigated the effects of naturally produced testosterone using Mendelian randomization, which mimics randomized trials by exploiting the fact that parents randomly pass on their unique genetic variants to their children at conception. This random assignment of genetic variants leads to its informal namesake, “nature’s clinical trial”, and provides the ability to study cause-and-effect for any genetically determined factors, such as testosterone levels. Paré et al. studied the long-term effects of testosterone on 22 diseases previously explored in randomized controlled trials, and hundreds of other traits and diseases that have not been investigated in any randomized controlled trials yet. The Mendelian randomization analysis made it possible to examine the effects of lifelong naturally elevated testosterone levels on 469 traits and diseases. Paré et al. found that testosterone increased the density of bone mineral and decreased body fat. However, it also increased the risks of prostate cancer, high blood pressure, baldness and a condition affecting the spine. It also increased the number of red blood cells and decreased a marker of inflammation, which may be beneficial or detrimental depending on the context. This shows that genetic analyses can be powerful methods to prioritize the allocation of limited resources towards investigating the most pressing clinical questions. The results of this study may help inform physicians and patients about the effects of long-term testosterone use. Ultimately, large randomized controlled trials are needed to conclusively address the cause-and-effect on these diseases.

Summary Background Angiotensin-converting enzyme 2 (ACE2) is an endogenous counter-regulator of the renin–angiotensin hormonal cascade. We assessed whether plasma ACE2 concentrations were associated with greater risk of death or cardiovascular disease events. Methods We used data from the Prospective Urban Rural Epidemiology (PURE) prospective study to conduct a case-cohort analysis within a subset of PURE participants (from 14 countries across five continents: Africa, Asia, Europe, North America, and South America). We measured plasma concentrations of ACE2 and assessed potential determinants of plasma ACE2 levels as well as the association of ACE2 with cardiovascular events. Findings We included 10 753 PURE participants in our study. Increased concentration of plasma ACE2 was associated with increased risk of total deaths (hazard ratio [HR] 1·35 per 1 SD increase [95% CI 1·29–1·43]) with similar increases in cardiovascular and non-cardiovascular deaths. Plasma ACE2 concentration was also associated with higher risk of incident heart failure (HR 1·27 per 1 SD increase [1·10–1·46]), myocardial infarction (HR 1·23 per 1 SD increase [1·13–1·33]), stroke (HR 1·21 per 1 SD increase [1·10–1·32]) and diabetes (HR 1·44 per 1 SD increase [1·36–1·52]). These findings were independent of age, sex, ancestry, and traditional cardiac risk factors. With the exception of incident heart failure events, the independent relationship of ACE2 with the clinical endpoints, including death, remained robust after adjustment for BNP. The highest-ranked determinants of ACE2 concentrations were sex, geographic ancestry, and body-mass index (BMI). When compared with clinical risk factors (smoking, diabetes, blood pressure, lipids, and BMI), ACE2 was the highest ranked predictor of death, and superseded several risk factors as a predictor of heart failure, stroke, and myocardial infarction. Interpretation Increased plasma ACE2 concentration was associated with increased risk of major cardiovascular events in a global study. Funding Canadian Institute of Health Research, Heart & Stroke Foundation of Canada, and Bayer.

New trials of dementia prevention are needed to test novel strategies and agents. Large, simple, cardiovascular trials have successfully discovered treatments with moderate but worthwhile effects to prevent heart attack and stroke. The design of these trials may hold lessons for the dementia prevention. Here we outline suitable populations, interventions and outcomes for large simple trials in dementia prevention. We consider what features are needed to maximise efficiency. Populations could be selected by age, clinical or genetic risk factors or clinical presentation. Patients and their families prioritise functional and clinical outcomes over cognitive scores and levels of biomarkers. Loss of particular functions or dementia diagnoses therefore are most meaningful to participants and potential patients and can be measured in large trials. The size of the population and duration of follow-up needed for dementia prevention trials will be a major challenge and will need collaboration between many clinical investigators, funders and patient organisations.

Disease risk varies significantly between ethnic groups, however, the clinical significance and implications of these observations are poorly understood. Investigating ethnic differences within the human proteome may shed light on the impact of ancestry on disease risk. We used admixture mapping to explore the impact of genetic ancestry on 237 cardiometabolic biomarkers in 2,216 Latin Americans within the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study. We developed a variance component model in order to determine the proportion of variance explained by inter-ancestry differences, and we applied it to the biomarker panel. Multivariable linear regression was used to identify and localize genetic loci affecting biomarker variability between ethnicities. Variance component analysis revealed that 5% of biomarkers were significantly impacted by genetic admixture (p < 0.05/237), including C-peptide, apolipoprotein-E, and intercellular adhesion molecule 1. We also identified 46 regional associations across 40 different biomarkers (p < 1.13 × 10(−6)). An independent analysis revealed that 34 of these 46 regions were associated at genome-wide significance (p < 5 × 10(−8)) with their respective biomarker in either Europeans or Latin populations. Additional analyses revealed that an admixture mapping signal associated with increased C-peptide levels was also associated with an increase in diabetes risk (odds ratio [OR] = 6.07 per SD, 95% confidence interval [CI] 1.44 to 25.56, p = 0.01) and surrogate measures of insulin resistance. Our results demonstrate the impact of ancestry on biomarker levels, suggesting that some of the observed differences in disease prevalence have a biological basis, and that reference intervals for those biomarkers should be tailored to ancestry. Specifically, our results point to a strong role of ancestry in insulin resistance and diabetes risk.

The recent global obesity epidemic is attributed to major societal and environmental changes, such as excessive energy intake and sedentary lifestyle. However, exposure to 'obesogenic' environments does not necessarily result in obesity at the individual level, as 40-75% of body mass index variation in population is attributed to genetic differences. The thrifty genotype theory posits that genetic variants promoting efficient food sequestering and optimal deposition of fat during periods of food abundance were evolutionarily advantageous for the early hunter-gatherer and were positively selected. However, the thrifty genotype is likely too simplistic and fails to provide a justification for the complex distribution of obesity predisposing gene variants and for the broad range of body mass index observed in diverse ethnic groups. This review proposes that gene pleiotropy may better account for the variability in the distribution of obesity susceptibility alleles across modern populations. We outline the lazy-thrifty versus peppy-thrifty genotype hypothesis and detail the body of evidence in the literature in support of this novel concept. Future population genetics and mathematical modelling studies that account for pleiotropy may further improve our understanding of the evolutionary origins of the current obesity epidemic.

The Niemann–Pick type C1 (NPC1) protein regulates the transport of cholesterol and fatty acids from late endosomes/lysosomes and has a central role in maintaining lipid homeostasis. NPC1 loss-of-function mutations in humans cause NPC1 disease, a rare autosomal-recessive lipid-storage disorder characterized by progressive and lethal neurodegeneration, as well as liver and lung failure, due to cholesterol infiltration. In humans, genome-wide association studies and post–genome-wide association studies highlight the implication of common variants in NPC1 in adult-onset obesity, body fat mass, and type 2 diabetes. Heterozygous human carriers of rare loss-of-function coding variants in NPC1 display an increased risk of morbid adult obesity. These associations have been confirmed in mice models, showing an important interaction with high-fat diet. In this review, we describe the current state of knowledge for NPC1 variants in relationship to pleiotropic effects on metabolism. We provide evidence that NPC1 gene variations may predispose to common metabolic diseases by modulating steroid hormone synthesis and/or lipid homeostasis. We also propose several important directions of research to further define the complex roles of NPC1 in metabolism. This review emphasizes the contribution of NPC1 to obesity and its metabolic complications.

The Pakistani population is extensively diverse, indicating a genetic admixture of European and Central/West Asian migrants with indigenous South Asian gene pools. Pakistanis are organized in different ethnicities/castes based on cultural, linguistic and geographical origin. While Pakistan is facing a rapid nutritional transition, the rising prevalence of obesity is driving a growing burden of health complications and mortality. This represents a unique opportunity for the research community to study the interplay between obesogenic environmental changes and obesity predisposing genes in the time frame of one generation. This review recapitulates the ancestral origins of Pakistani population, the societal determinants of the rise in obesity and its governmental management. We describe the contribution of syndromic, monogenic non-syndromic and polygenic obesity genes identified in the Pakistani population. We then discuss the utility of gene identification approaches based on large consanguineous families and original gene × environment interaction study designs in discovering new obesity genes and causal pathways. Elucidation of the genetic basis of obesity in the Pakistani population may result in improved methods of obesity prevention and treatment globally.

Eating disorders (ED) including anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED) affect up to 5% of the population in Western countries. Risk factors for developing an ED include personality traits, family environment, gender, age, ethnicity, and culture. Despite being moderately to highly heritable with estimates ranging from 28 to 83%, no genetic risk factors have been conclusively identified. Our objective was to explore evolutionary theories of EDs to provide a new perspective on research into novel biological mechanisms and genetic causes of EDs. We developed a framework that explains the possible interactions between genetic risk and cultural influences in the development of ED. The framework includes three genetic predisposition categories (people with mainly AN restrictive gene variants, people with mainly BED variants, and people with gene variants predisposing to both diseases) and a binary variable of either the presence or absence of pressure to be thin. We propose novel theories to explain the overlapping characteristics of the subtypes of AN (binge/purge and restrictive), BN, and BED. For instance, mutations/structural gene variants in the same gene causing opposite effects or mutations in nearby genes resulting in partial disequilibrium for the genes causing AN (restrictive) and BED may explain the overlap of phenotypes seen in AN (binge/purge).

Resume La chirurgie bariatrique semble diminuer l’incidence du diabete gestationnel (DG) chez les femmes obeses, toutefois la question « Comment definir, depister et prendre en charge le DG apres chirurgie bariatrique ? » reste ouverte, alors que la litterature ne permet pas pour l’instant de repondre avec un haut niveau de preuve. Considerant le risque (pour la mere et l’enfant) d’une exposition a des valeurs glycemiques anormales, nous proposons dans cet article une strategie pragmatique de depistage du DG chez les femmes apres chirurgie bariatrique.

International audience; The hypothalamus contains integrative systems that support life, including physiological processes such as food intake, energy expenditure and reproduction. Here, we show that anorexia nervosa patients, contrary to normal weight and constitutionally lean individuals, respond with a paradoxical reduction in hypothalamic levels of glutamate/glutamine (Glx) upon feeding. This reversal of the Glx response is associated with decreased wiring in the arcuate nucleus and increased connectivity in the lateral hypothalamic area, which are involved in the regulation on a variety of physiological and behavioral functions including the control of food intake and energy balance. The identification of distinct hypothalamic neurochemical dysfunctions and associated structural variations in anorexia nervosa paves the way for the development of new diagnostic and treatment strategies in conditions associated with abnormal body mass index and a maladaptive response to negative energy balance.

PURPOSE OF REVIEW This review is a comprehensive update on recent discoveries on the genetics of early-onset coronary artery disease (EOCAD), and how those findings can be translated to advance its medical management. RECENT FINDINGS To date, a total of 266 common variants of modest effect size have been reported to be associated with CAD, but many still warrant functional studies. Rare variants impacting the function of at least 10 genes are now well characterized in Mendelian EOCAD. Estimations of minor allele frequencies in multiple ancestries from large genetic databases have allowed us to estimate the prevalence of Mendelian forms of EOCAD. In fact, the prevalence of Mendelian mutations varies markedly between ancestries, ranging from 1 : 289 to 1 : 153 for familial hypercholesterolemia. Mendelian forms of EOCAD support three major biological pathways, including lipid metabolism, vascular wall integrity and function, and thrombosis. Furthermore, combining common variants of modest effect into polygenic risk scores (PRS) has shown to be effective at identifying individuals at high risk of CAD. SUMMARY Mendelian forms of EOCAD highlight the importance of lipid metabolism, yet prevalence in many non-European populations remains to be clarified. Polygenic EOCAD affects more individuals and, in many cases, confers a higher risk of EOCAD than rare Mendelian mutations. Thus, sequencing of target genes and the derivation of PRSs can be used to identify high-risk patients, leading to more personalized therapeutic approaches.