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Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Receptores Opioides delta , Receptores Opioides delta/metabolismo , Receptores Opioides delta/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Insulina/metabolismo , Secreción de Insulina/efectos de los fármacos , Secreción de Insulina/genética , AdultoRESUMEN
INTRODUCTION: Urological consultations for erectile dysfunction (ED) are increasing worldwide. Penile prosthesis (PP) implantations are performed when other treatments are unsuccessful. However, there is no data regarding PP implantations in France beyond the year 2016. OBJECTIVES: This study aimed to describe the changes in the number and type of PP implants used for the treatment of ED in France from 2016 to 2021 and the hospitalization rates following implantation using French national data from the Program for the Medicalization of Information Systems (PMSI). MATERIALS AND METHODS: We analyzed data on PP implantations in all France hospitals. PPs were coded into three types according to the Common Classification of Medical Procedures (CCAM). The number of patients admitted to hospital with complications twelve months after implantation was also recorded. RESULTS: During the study period, 3675 men received 3868 PPs in France. A gradual increase in the total number of implanted PPs was observed, with an overall increase of 33.8%. In 2020, there was a sharp decline in the number of implanted PPs, primarily owing to the COVID-19 pandemic. The most commonly used implant was PPs with an extracavernous compartment, comprising 85% of all PPs. Twelve months after implantation, only 1-2% of the patients were rehospitalized. CONCLUSION: PP implantation surgeries are highly reproducible and have a low incidence of complications, in terms of rehospitalization after one year of placement (1.8%). Moreover, there was an increase in the demand for penile prosthesis implantations in France between 2016 and 2021. LEVEL OF EVIDENCE: 4: Descriptive epidemiological study.
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AIM: The risk of cardiorenal events remains high among patients with diabetes and chronic kidney disease (CKD), despite the prescription of recommended treatments. We aimed to determine whether the attainment of a combination of nephroprotection targets at baseline (glycated haemoglobin <7.0%, urinary albumin-creatinine ratio <300 mg/g, blood pressure <130/80 mmHg, renin-angiotensin system inhibition) was associated with better cardiorenal outcomes and lower mortality. MATERIALS AND METHODS: From the prospective French CKD-REIN cohort, we studied 1260 patients with diabetes and CKD stages 3-4 (estimated glomerular filtration rate: 15-60 ml/min/1.73 m2); 69% were men, and at inclusion, mean ± SD age: 70 ± 10 years; estimated glomerular filtration rate: 33 ± 11 ml/min/1.73 m2. The median follow-up was 4.9 years. RESULTS: In adjusted Cox regression models, the attainment of two nephroprotection targets was consistently associated with a lower risk of cardiorenal events [hazard ratio 0.70 (95% confidence interval 0.57-0.85)], incident kidney failure with replacement therapy [0.58 (0.43-0.77)], four major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure) [0.75 (0.57-0.99)] and all-cause mortality [0.59 (0.42-0.82)] when compared with the attainment of zero or one target. For patients with a urinary albumin-creatinine ratio ≥300 mg/g, those who attained at least two targets had lower hazard ratios for cardiorenal events [0.61 (0.39-0.96)], four major adverse cardiovascular events [0.53 (0.28-0.98)] and all-cause mortality [0.35 (0.17-0.70)] compared with those who failed to attain any targets. CONCLUSIONS: These findings suggest that the attainment of a combination of nephroprotection targets is associated with better cardiorenal outcomes and a lower mortality rate in people with diabetic kidney disease.
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Enfermedades Cardiovasculares , Diabetes Mellitus , Nefropatías Diabéticas , Insuficiencia Cardíaca , Insuficiencia Renal Crónica , Masculino , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Femenino , Nefropatías Diabéticas/complicaciones , Estudios de Cohortes , Estudios Prospectivos , Creatinina , Insuficiencia Cardíaca/complicaciones , Albúminas , Enfermedades Cardiovasculares/etiología , Tasa de Filtración GlomerularRESUMEN
OBJECTIVE: Rare variants in DYRK1B have been described in some patients with central obesity, type 2 diabetes, and early-onset coronary disease. Owing to the limited number of conducted studies, the broader impact of DYRK1B variants on a larger scale has yet to be investigated. RESEARCH DESIGN AND METHODS: DYRK1B was sequenced in 9,353 participants from a case-control study for obesity and type 2 diabetes. Each DYRK1B variant was functionally assessed in vitro. Variant pathogenicity was determined using criteria from the American College of Medical Genetics and Genomics (ACMG). The effect of pathogenic or likely pathogenic (P/LP) variants on metabolic traits was assessed using adjusted mixed-effects score tests. RESULTS: Sixty-five rare, heterozygous DYRK1B variants were identified and were not associated with obesity or type 2 diabetes. Following functional analyses, 20 P/LP variants were pinpointed, including 6 variants that exhibited a fully inhibitory effect (P/LP-null) on DYRK1B activity. P/LP and P/LP-null DYRK1B variants were associated with increased BMI and obesity risk; however, the impact was notably more pronounced for the P/LP-null variants (effect of 8.0 ± 3.2 and odds ratio of 7.9 [95% CI 1.2-155]). Furthermore, P/LP-null variants were associated with higher fasting glucose and type 2 diabetes risk (effect of 2.9 ± 1.0 and odds ratio of 4.8 [95% CI 0.85-37]), while P/LP variants had no effect on glucose homeostasis. CONCLUSIONS: P/LP, total loss-of-function DYRK1B variants cause monogenic obesity associated with type 2 diabetes. This study underscores the significance of conducting functional assessments in order to accurately ascertain the tangible effects of P/LP DYRK1B variants.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/genética , Estudios de Casos y Controles , Obesidad/complicaciones , Obesidad/genética , Fenotipo , GlucosaRESUMEN
AIMS/HYPOTHESIS: GLIS3 encodes a transcription factor involved in pancreatic beta cell development and function. Rare pathogenic, bi-allelic mutations in GLIS3 cause syndromic neonatal diabetes whereas frequent SNPs at this locus associate with common type 2 diabetes risk. Because rare, functional variants located in other susceptibility genes for type 2 diabetes have already been shown to strongly increase individual risk for common type 2 diabetes, we aimed to investigate the contribution of rare pathogenic GLIS3 variants to type 2 diabetes. METHODS: GLIS3 was sequenced in 5471 individuals from the Rare Variants Involved in Diabetes and Obesity (RaDiO) study. Variant pathogenicity was assessed following the criteria established by the American College of Medical Genetics and Genomics (ACMG). To address the pathogenic strong criterion number 3 (PS3), we conducted functional investigations of these variants using luciferase assays, focusing on capacity of GLIS family zinc finger 3 (GLIS3) to bind to and activate the INS promoter. The association between rare pathogenic or likely pathogenic (P/LP) variants and type 2 diabetes risk (and other metabolic traits) was then evaluated. A meta-analysis combining association results from RaDiO, the 52K study (43,125 individuals) and the TOPMed study (44,083 individuals) was finally performed. RESULTS: Through targeted resequencing of GLIS3, we identified 105 rare variants that were carried by 395 participants from RaDiO. Among them, 49 variants decreased the activation of the INS promoter. Following ACMG criteria, 18 rare variants were classified as P/LP, showing an enrichment in the last two exons compared with the remaining exons (p<5×10-6; OR>3.5). The burden of these P/LP variants was strongly higher in individuals with type 2 diabetes (p=3.0×10-3; OR 3.9 [95% CI 1.4, 12]), whereas adiposity, age at type 2 diabetes diagnosis and cholesterol levels were similar between variant carriers and non-carriers with type 2 diabetes. Interestingly, all carriers with type 2 diabetes were sensitive to oral sulfonylureas. A total of 7 P/LP variants were identified in both 52K and TOPMed studies. The meta-analysis of association studies obtained from RaDiO, 52K and TOPMed showed an enrichment of P/LP GLIS3 variants in individuals with type 2 diabetes (p=5.6×10-5; OR 2.1 [95% CI 1.4, 2.9]). CONCLUSIONS/INTERPRETATION: Rare P/LP GLIS3 variants do contribute to type 2 diabetes risk. The variants located in the distal part of the protein could have a direct effect on its functional activity by impacting its transactivation domain, by homology with the mouse GLIS3 protein. Furthermore, rare P/LP GLIS3 variants seem to have a direct clinical effect on beta cell function, which could be improved by increasing insulin secretion via the use of sulfonylureas.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Ratones , Animales , Recién Nacido , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Regulación de la Expresión Génica , Células Secretoras de Insulina/metabolismo , Mutación , Proteínas de Unión al ADN/metabolismo , Proteínas Represoras/metabolismo , Transactivadores/metabolismoRESUMEN
OBJECTIVE: Human functional genomics has proven powerful in discovering drug targets for common metabolic disorders. Through this approach, we investigated the involvement of the purinergic receptor P2RY1 in type 2 diabetes (T2D). METHODS: P2RY1 was sequenced in 9,266 participants including 4,177 patients with T2D. In vitro analyses were then performed to assess the functional effect of each variant. Expression quantitative trait loci (eQTL) analysis was performed in pancreatic islets from 103 pancreatectomized individuals. The effect of P2RY1 on glucose-stimulated insulin secretion was finally assessed in human pancreatic beta cells (EndoCßH5), and RNA sequencing was performed on these cells. RESULTS: Sequencing P2YR1 in 9,266 participants revealed 22 rare variants, seven of which were loss-of-function according to our in vitro analyses. Carriers, except one, exhibited impaired glucose control. Our eQTL analysis of human islets identified P2RY1 variants, in a beta-cell enhancer, linked to increased P2RY1 expression and reduced T2D risk, contrasting with variants located in a silent region associated with decreased P2RY1 expression and increased T2D risk. Additionally, a P2RY1-specific agonist increased insulin secretion upon glucose stimulation, while the antagonist led to decreased insulin secretion. RNA-seq highlighted TXNIP as one of the main transcriptomic markers of insulin secretion triggered by P2RY1 agonist. CONCLUSION: Our findings suggest that P2RY1 inherited or acquired dysfunction increases T2D risk and that P2RY1 activation stimulates insulin secretion. Selective P2RY1 agonists, impermeable to the blood-brain barrier, could serve as potential insulin secretagogues.
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Diabetes Mellitus Tipo 2 , Islotes Pancreáticos , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Genómica , Glucosa/metabolismo , Receptores Purinérgicos P2Y1/genética , Receptores Purinérgicos P2Y1/metabolismoRESUMEN
Inflammation has been associated with renal diseases. The Interferon Regulatory Factor (IRF)-5 is a key transcription factor in the pro-inflammatory polarization of M1-like macrophages. GWAS have reported that the IRF5 locus is associated with autoimmune diseases and with the estimated glomerular filtration rate (eGFR). We study whether allelic variations in IRF5 are associated with the incidence of chronic kidney disease (CKD) in a general population. We genotyped eleven IRF5 SNPs in the French D.E.S.I.R. cohort from the general population (n = 4820). Associations of SNPs with baseline renal parameters were assessed. Data were analyzed for three endpoints during a 9-year follow-up, incidence of:at least stage 3 CKD, the KDIGO criterion "certain drop in eGFR", and incidence of micro/macro albuminuria. In the cross-sectional analysis, rs10954213 and rs10954214 were associated with eGFR and rs1874328 with urinary albumin/creatinine ratio (ACR). Rs3807306, rs11761199, rs78658945, rs1874328, rs10954213 and rs11770589 were associated with the incidence of stage 3 CKD in multi-adjusted models. Rs4731532, rs3807306, and rs11761199 were associated with the incidence of CKD defined by the KDIGO. Rs4731532, rs3807306, rs11761199 and rs79288514 were associated with the incidence of micro/macro albuminuria. Our results support the hypothesis of the importance of IRF5 mediated macrophage polarization in the etiology of CKD.
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Albuminuria , Insuficiencia Renal Crónica , Humanos , Albuminuria/complicaciones , Albuminuria/epidemiología , Factor V , Incidencia , Estudios Transversales , Interferones , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/complicaciones , Factores Reguladores del Interferón/genética , Factores de RiesgoRESUMEN
The glucagon-like peptide 1 receptor (GLP1R) is a major drug target with several agonists being prescribed in individuals with type 2 diabetes and obesity1,2. The impact of genetic variability of GLP1R on receptor function and its association with metabolic traits are unclear with conflicting reports. Here, we show an unexpected diversity of phenotypes ranging from defective cell surface expression to complete or pathway-specific gain of function (GoF) and loss of function (LoF), after performing a functional profiling of 60 GLP1R variants across four signalling pathways. The defective insulin secretion of GLP1R LoF variants is rescued by allosteric GLP1R ligands or high concentrations of exendin-4/semaglutide in INS-1 823/3 cells. Genetic association studies in 200,000 participants from the UK Biobank show that impaired GLP1R cell surface expression contributes to poor glucose control and increased adiposity with increased glycated haemoglobin A1c and body mass index. This study defines impaired GLP1R cell surface expression as a risk factor for traits associated with type 2 diabetes and obesity and provides potential treatment options for GLP1R LoF variant carriers.
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Glucemia , Diabetes Mellitus Tipo 2 , Humanos , Insulina/metabolismo , Diabetes Mellitus Tipo 2/genética , Adiposidad/genética , Obesidad/genéticaRESUMEN
PURPOSE: To evaluate three partial nephrectomies (PN) procedures: open (OPN), standard laparoscopy (LPN), and robot-assisted laparoscopy (RAPN), for the risk of initial complications and rehospitalization for two years after the surgery. MATERIALS AND METHODS: From the French national hospital database (PMSI-MCO), every hospitalization in French hospitals for renal tumor PN in 2016-2017 were extracted. Complications were documented from the initial hospitalization and any rehospitalization over two years. Chi-square and ANOVA tests compared the frequency of complications and length of initial hospitalization between the three surgical procedures. Relative risks (RR) and 95% confidence intervals were computed. RESULTS: The 9119 initial hospitalizations included 4035 OPN, 1709 LPN, and 1900 RAPN; 1475 were excluded as the laparoscopic procedure performed was not determined. The average length of hospitalization was 8.1, 6.2, and 4.5 days for OPN, LPN, and RAPN, respectively. Compared to OPN, there were fewer complications at the time of initial hospitalization for the mini-invasive procedures: 29% for OPN vs. 20% for LPN (0.70 [0.63;0.78]) and 12% for RAPN (RR=0.43, 95%CI [0.38;0.49]). For RAPN compared to LPN, there were fewer haemorrhages (RR=0.55 [0.43;0.72]), anemia (0.69 {0.48;0.98]), and sepsis (0.51 [0.36;0.71]); during follow up, there were fewer urinary tract infections (0.64 [0.45;0.91]) but more infectious lung diseases (1.69 [1.03;2.76]). Over the two-year postoperative period, RAPN was associated with fewer acute renal failures (RR=0.73 [0.55;0.98]), renal abscesses (0.41 [0.23;0.74]), parietal complications (0.69 [0.52;0.92]) and urinary tract infections (0.54 [0.40;0.73]) than for OPN. CONCLUSIONS: Conservative renal surgery is associated with postoperative morbidity related to the surgical procedure fashion. Mini-invasive procedures, especially robot-assisted surgery, had fewer complications and shorter hospital lengths of stay.
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Laparoscopía , Procedimientos Quirúrgicos Robotizados , Robótica , Humanos , Laparoscopía/efectos adversos , Nefrectomía/efectos adversos , Procedimientos Quirúrgicos Robotizados/efectos adversos , HospitalizaciónRESUMEN
PURPOSE: In France, transurethral resection of the prostate (TURP) is still the most commonly used surgical treatment for medium sized benign prostatic hyperplasia (BPH), but the Holmium Laser Enucleation of the Prostate (HoLEP) and laser vaporization procedures are becoming more common. For these three surgical procedures, we evaluate the initial complications, the short term (3 months) and the 4-12-month postoperative complications necessitating re-hospitalization. METHODS: From the French national hospital data base (PMSI-MCO), all hospitalizations for BPH treatment in 2018 were extracted. We document the complications during the initial hospitalization and any subsequent rehospitalizations during the one-year postoperative period. RESULTS: In 2018, 67,220 patients were treated for BPH: 46,242 TURP, 13,509 HoLEP and 7469 laser vaporization. Age and anticoagulation medications were similar for men treated by the three procedures, but TURP patients were more often hypertensive. Infections and hemorrhagic complications were the most common complications at the initial hospitalization: 17%, 10%, 13% for infections and 15%, 8.1%, 11% for hemorrhagic complications respectively, and TURP performed worse than the other two procedures at the initial hospitalization. During the first three months and then the subsequent nine months, there were fewer complications than initially, with little difference between the three procedures, all differences being less than 1%. CONCLUSION: Laser vaporization techniques led to fewer complications. However, the PMSI-MCO only registers complications during hospitalizations. This study should be extended to non-hospitalized, more minor complications.
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Terapia por Láser , Láseres de Estado Sólido , Hiperplasia Prostática , Resección Transuretral de la Próstata , Masculino , Humanos , Hiperplasia Prostática/cirugía , Hiperplasia Prostática/complicaciones , Próstata/cirugía , Resección Transuretral de la Próstata/efectos adversos , Resección Transuretral de la Próstata/métodos , Readmisión del Paciente , Resultado del Tratamiento , Terapia por Láser/métodos , Hospitales , Láseres de Estado Sólido/uso terapéuticoRESUMEN
AIMS/HYPOTHESIS: The euglycaemic-hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC. METHODS: We measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained (R2). RESULTS: A standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R2 0.444 [0.391, 0.497]; ULSAM to RISC R2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2. CONCLUSIONS/INTERPRETATION: A plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences.
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Enfermedades Cardiovasculares , Resistencia a la Insulina , Masculino , Adulto , Humanos , Estudios Longitudinales , Proteómica , Estudios Transversales , InsulinaRESUMEN
To evaluate the cost-effectiveness of robotic-assisted surgery compared to open surgery in the context of partial nephrectomy for small kidney tumor management. This is a retrospective study using data from 395 patients operated on by either robot-assisted surgery (RAPN) or by open partial nephrectomy (OPN); one hospital performed RAPN exclusively and the second hospital, OPN exclusively. Cost-effectiveness analysis was conducted from the perspective of the National Health Insurance System (NHIS) by considering the costs of the initial hospital stay and the cost of complications. Clinical outcome was defined by the avoidance of major complications during the 12 months postoperatively. Major complications were absent in 82% of patients in the OPN group and 93% of patients in the RAPN group, with 11% in favor of robotic assistance (p < 0.001). The average cost per patient, including the costs of complications, were, respectively, 9637 and 8305 for the OPN and RAPN groups. Robotic assistance was associated with a 1332 lower cost (p < 0.001). The incremental cost-effectiveness ratio (ICER) is estimated at - 12,039 . From the perspective of the public payer, robotic assistance was associated with a lower rate of postoperative complications and a lower average cost per patient. Robotic-assisted surgery was an efficient alternative to open surgery in partial nephrectomy. Trial registration number: NCT05089006 (October 22, 2021).
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Neoplasias Renales , Procedimientos Quirúrgicos Robotizados , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Estudios Retrospectivos , Análisis Costo-Beneficio , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Nefrectomía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: Rare biallelic pathogenic mutations in PCSK1 (encoding proprotein convertase subtilisin/kexin type 1 [PC1/3]) cause early-onset obesity associated with various endocrinopathies. Setmelanotide has been approved for carriers of these biallelic mutations in the past 3 years. We aimed to perform a large-scale functional genomic study focusing on rare heterozygous variants of PCSK1 to decipher their putative impact on obesity risk. METHODS: This case-control study included all participants with overweight and obesity (ie, cases) or healthy weight (ie, controls) from the RaDiO study of three community-based and one hospital-based cohort in France recruited between Jan 1, 1995, and Dec 31, 2000. In adults older than 18 years, healthy weight was defined as BMI of less than 25·0 kg/m2, overweight as 25·0-29·9 kg/m2, and obesity as 30·0 kg/m2 or higher. Participants with type 2 diabetes had fasting glucose of 7·0 mmol/L or higher or used treatment for hyperglycaemia (or both) and were negative for islet or insulin autoantibodies. Functional assessment of rare missense variants of PCSK1 was performed. Pathogenicity clusters of variants were determined with machine learning. The effect of each cluster of PCSK1 variants on obesity was assessed using the adjusted mixed-effects score test. FINDINGS: All 13 coding exons of PCSK1 were sequenced in 9320 participants (including 7260 adults and 2060 children and adolescents) recruited from the RaDiO study. We detected 65 rare heterozygous PCSK1 variants, including four null variants and 61 missense variants that were analysed in vitro and clustered into five groups (A-E), according to enzymatic activity. Compared with the wild-type, 15 missense variants led to complete PC1/3 loss of function (group A; reference) and rare exome variant ensemble learner (REVEL) led to 15 (25%) false positives and four (7%) false negatives. Carrying complete loss-of-function or null PCSK1 variants was significantly associated with obesity (six [86%] of seven carriers vs 1518 [35%] of 4395 non-carriers; OR 9·3 [95% CI 1·5-177·4]; p=0·014) and higher BMI (32·0 kg/m2 [SD 9·3] in carriers vs 27·3 kg/m2 [6·5] in non-carriers; mean effect π 6·94 [SE 1·95]; p=0·00029). Clusters of PCSK1 variants with partial or neutral effect on PC1/3 activity did not have an effect on obesity or overweight and on BMI. INTERPRETATION: Only carriers of heterozygous, null, or complete loss-of-function PCSK1 variants cause monogenic obesity and, therefore, might be eligible for setmelanotide. In silico tests were unable to accurately detect these variants, which suggests that in vitro assays are necessary to determine the variant pathogenicity for genetic diagnosis and precision medicine purposes. FUNDING: Agence Nationale de la Recherche, European Research Council, National Center for Precision Diabetic Medicine, European Regional Development Fund, Hauts-de-France Regional Council, and the European Metropolis of Lille.
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Diabetes Mellitus Tipo 2 , Obesidad , Sobrepeso , Proproteína Convertasa 1 , Adolescente , Adulto , Niño , Humanos , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/genética , Obesidad/genética , Sobrepeso/genética , Medicina de Precisión , Proproteína Convertasa 1/genéticaRESUMEN
AIMS/HYPOTHESIS: Diabetes has been recognised as a pejorative prognostic factor in coronavirus disease 2019 (COVID-19). Since diabetes is typically a disease of advanced age, it remains unclear whether diabetes remains a COVID-19 risk factor beyond advanced age and associated comorbidities. We designed a cohort study that considered age and comorbidities to address this question. METHODS: The Coronavirus SARS-CoV-2 and Diabetes Outcomes (CORONADO) initiative is a French, multicentric, cohort study of individuals with (exposed) and without diabetes (non-exposed) admitted to hospital with COVID-19, with a 1:1 matching on sex, age (±5 years), centre and admission date (10 March 2020 to 10 April 2020). Comorbidity burden was assessed by calculating the updated Charlson comorbidity index (uCCi). A predefined composite primary endpoint combining death and/or invasive mechanical ventilation (IMV), as well as these two components separately, was assessed within 7 and 28 days following hospital admission. We performed multivariable analyses to compare clinical outcomes between patients with and without diabetes. RESULTS: A total of 2210 pairs of participants (diabetes/no-diabetes) were matched on age (mean±SD 69.4±13.2/69.5±13.2 years) and sex (36.3% women). The uCCi was higher in individuals with diabetes. In unadjusted analysis, the primary composite endpoint occurred more frequently in the diabetes group by day 7 (29.0% vs 21.6% in the no-diabetes group; HR 1.43 [95% CI 1.19, 1.72], p<0.001). After multiple adjustments for age, BMI, uCCi, clinical (time between onset of COVID-19 symptoms and dyspnoea) and biological variables (eGFR, aspartate aminotransferase, white cell count, platelet count, C-reactive protein) on admission to hospital, diabetes remained associated with a higher risk of primary composite endpoint within 7 days (adjusted HR 1.42 [95% CI 1.17, 1.72], p<0.001) and 28 days (adjusted HR 1.30 [95% CI 1.09, 1.55], p=0.003), compared with individuals without diabetes. Using the same adjustment model, diabetes was associated with the risk of IMV, but not with risk of death, within 28 days of admission to hospital. CONCLUSIONS/INTERPRETATION: Our results demonstrate that diabetes status was associated with a deleterious COVID-19 prognosis irrespective of age and comorbidity status. TRIAL REGISTRATION: ClinicalTrials.gov NCT04324736.
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COVID-19 , Diabetes Mellitus , COVID-19/epidemiología , Estudios de Cohortes , Comorbilidad , Diabetes Mellitus/epidemiología , Femenino , Humanos , Masculino , Pronóstico , SARS-CoV-2RESUMEN
AIM: - Understanding DNA methylation dynamics associated with progressive hyperglycaemia exposure could provide early diagnostic biomarkers and an avenue for delaying type 2 diabetes mellitus (T2DM). We aimed to identify DNA methylation changes during a 6-year period associated with early hyperglycaemia exposure using the longitudinal D.E.S.I.R. METHODS: - We selected individuals with progressive hyperglycaemia exposure based on T2DM diagnostic criteria: 27 with long-term exposure, 34 with short-term exposure and 34 normoglycaemic controls. DNA from blood at inclusion and at the 6-year visit was subjected to methylation analysis using 850K methylation-EPIC arrays. A linear mixed model was used to perform an epigenome-wide association study (EWAS) and identify methylated changes associated with hyperglycaemia exposure during a 6-year time-period. RESULTS: - We did not identify differentially methylated sites that reached false discovery rate (FDR)-significance in our cohort. Based on EWAS, we focused our analysis on methylation sites that had a constant effect during the 6 years across the hyperglycaemia groups compared to controls and found the most statistically significant site was the reported cg19693031 probe (TXNIP). We also performed an EWAS with HbA1c, using the inclusion and the 6-year methylation data and did not identify any FDR-significant CpGs. CONCLUSIONS: - Our study reveals that DNA methylation changes are not robustly associated with hyperglycaemia exposure or HbA1c during a short-term period, however, our top loci indicate potential interest and should be replicated in larger cohorts.
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Diabetes Mellitus Tipo 2 , Hiperglucemia , Islas de CpG , Metilación de ADN/genética , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Epigénesis Genética , Estudio de Asociación del Genoma Completo , Hemoglobina Glucada , Humanos , Hiperglucemia/genéticaRESUMEN
AIMS: The aim of this prospective study was to examine CVD risk reduction in type 1 diabetes (1) for people with favourable cardiovascular health metrics and (2) by clustering of these metrics. METHODS: Data from 2313 participants from the EURODIAB Prospective Complications Study were analysed. All had type 1 diabetes (51% men, mean ± SD age 32 ± 9 years). Seven cardiovascular health metrics were studied-smoking, BMI, physical activity, a diet score, total cholesterol/HDL-cholesterol ratio, combined systolic and diastolic BP and HbA1c-divided into favourable/less favourable categories. Cox proportional hazards models were used to calculate HRs (95% CIs) of incident CVD for each metric. Clusters were made by scoring each individual by the number of favourable metrics. RESULTS: A total of 163 people developed incident CVD during a mean ± SD follow-up of 7.2 ± 1.3 years. Participants with more favourable HbA1c levels of <57 mmol/mol (<7.4%) had a 37% significantly lower CVD risk than those with a less favourable HbA1c (HR [95% CI] 0.63 [0.44, 0.91]), and participants with a more favourable BP (systolic BP <112 mmHg and diastolic BP <70 mmHg) had a 44% significantly lower CVD risk than participants in the less favourable BP group (HR [95% CI] 0.56 [0.34, 0.92]). There was a dose-response relation with a lower HR observed with greater clustering of more favourable metrics: people with four or more favourable metrics had an HR of 0.37 (95% CI 0.18, 0.76), adjusted for sex and age at diabetes diagnosis, compared with those with no favourable metrics. CONCLUSIONS/INTERPRETATION: Low HbA1c and low BP were protective cardiovascular health metrics in our study of people with type 1 diabetes. Targeting all cardiovascular health metrics could be more effective in preventing CVD than targeting single metrics.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 1 , Adulto , Presión Sanguínea , Enfermedades Cardiovasculares/prevención & control , Colesterol , Análisis por Conglomerados , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/epidemiología , Femenino , Humanos , Masculino , Estudios Prospectivos , Factores de Riesgo , Adulto JovenRESUMEN
The pathophysiological link between adiposity and blood pressure is not completely understood, and evidence suggests an influence of sex and genetic determinants. We aimed to identify the relationship between adiposity and blood pressure, independent of a robust set of lifestyle and metabolic factors, and to examine the modulating role of sex and Angiotensin-Converting Enzyme (ACE) insertion/deletion (I/D) polymorphisms. In the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) study cohort, 1211 normotensive individuals, aged 30 to 60 years and followed-up after 3.3 years, were characterized for lifestyle and metabolic factors, body composition, and ACE genotype. Body mass index (BMI) and waist circumference (WC) were independently associated with mean arterial pressure, with a stronger relationship in women than men (BMI: r=0.40 versus 0.30; WC: r=0.40 versus 0.30, both P<0.01) and in individuals with the ID and II ACE genotypes in both sexes (P<0.01). The associations of BMI and WC with mean arterial pressure were independent of age, sex, lifestyle, and metabolic variables (standardized regression coefficient=0.17 and 0.18 for BMI and WC, respectively) and showed a significant interaction with the ACE genotype only in women (P=0.03). A 5 cm larger WC at baseline increased the risk of developing hypertension at follow-up only in women (odds ratio, 1.56 [95% CI, 1.15-2.10], P=0.004) and in II genotype carriers (odds ratio, 1.87 [95% CI, 1.09-3.20], P=0.023). The hypertensive effect of adiposity is more pronounced in women and in people carrying the II variant of the ACE genotype, a marker of salt sensitivity.
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Adiposidad/genética , Presión Sanguínea/genética , Hipertensión/genética , Mutación INDEL , Peptidil-Dipeptidasa A/genética , Polimorfismo de Nucleótido Simple , Adulto , Índice de Masa Corporal , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Circunferencia de la CinturaRESUMEN
Melatonin is a hormone mainly produced by the pineal gland and MT1 is one of the two G protein-coupled receptors (GPCRs) mediating its action. Despite an increasing number of available GPCR crystal structures, the molecular mechanism of activation of a large number of receptors, including MT1, remains poorly understood. The purpose of this study is to elucidate the structural elements involved in the process of MT1's activation using naturally occurring variants affecting its function. Thirty-six nonsynonymous variants, including 34 rare ones, were identified in MTNR1A (encoding MT1) from a cohort of 8687 individuals and their signaling profiles were characterized using Bioluminescence Resonance Energy Transfer-based sensors probing 11 different signaling pathways. Computational analysis of the experimental data allowed us to group the variants in clusters according to their signaling profiles and to analyze the position of each variant in the context of the three-dimensional structure of MT1 to link functional selectivity to structure. MT1 variant signaling profiles revealed three clusters characterized by (1) wild-type-like variants, (2) variants with selective defect of ßarrestin-2 recruitment, and (3) severely defective variants on all pathways. Our structural analysis allows us to identify important regions for ßarrestin-2 recruitment as well as for Gα12 and Gα15 activation. In addition to identifying MT1 domains differentially controlling the activation of the various signaling effectors, this study illustrates how natural variants can be used as tools to study the molecular mechanisms of receptor activation.
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BACKGROUND: Type 2 diabetes (T2D) has been identified as a risk factor for poor oral health, however, a limited number of oral health and T2D characteristics have been studied so far. We sought to assess T2D status, age at diagnosis, duration since diagnosis and treatment in relation to a variety of oral diseases. METHODS: Cross-sectional data were analyzed from the E3N (Etude Epidémiologique auprès de femmes de l'Education Nationale) cohort study which enrolled 60,590 women. Participants self-reported oral health status, and T2D cases were identified using diabetes-specific questionnaires and drug reimbursement insurance databases. Multivariable-adjusted ORs and 95% CIs were estimated using logistic regression models. RESULTS: The mean age (SD) of the women was 70 years (7.2), and 4.7% (n = 2857) had T2D. Compared to women without T2D, women with T2D were more likely to report a poor perceived oral health (OR 1.37 [95% CI 1.18, 1.60]), wearing dental prostheses (1.26 [1.14, 1.39]) and having problems of biting and chewing food (1.19 [1.07, 1.33]). In addition, for women with T2D the age at diagnosis (inversely) and the duration (positively) were associated with the likelihood to report poor oral health. CONCLUSIONS: For women with T2D, duration and age at diagnosis are associated with wearing prostheses, problems of biting and chewing, periodontitis and gingivitis.
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Diabetes Mellitus Tipo 2 , Anciano , Estudios de Cohortes , Estudios Transversales , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Humanos , Salud Bucal , Factores de RiesgoRESUMEN
CONTEXT: High density lipoprotein (HDL) in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects. OBJECTIVE: We investigated the prospective associations between HDL subspecies containing and lacking apolipoprotein (apo) C-III at baseline and insulin sensitivity at year 3. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of 864 healthy volunteers drawn from the relationship between insulin sensitivity and cardiovascular disease (RISC) study, a multicenter European clinical investigation, whose recruitment initiated in 2002, with a follow-up of 3 years. MAIN MEASURES: Insulin sensitivity was estimated from an oral glucose tolerance test at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The apolipoprotein concentrations were measured at baseline by a sandwich enzyme-linked immunosorbent assay (ELISA)-based method. RESULTS: The 2 HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (P-heterogeneityâ =â 0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (P-trendâ =â 0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (P-trendâ =â 0.01), compared to the lowest quintile. No significant association was observed for total HDL, and very low density lipoprotein (VLDL) and low density lipoprotein (LDL) containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III. CONCLUSION: Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment.