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1. Impact of diabetes on COVID-19 prognosis beyond comorbidity burden: the CORONADO initiative

Author

Bertrand, Cariou, Matthieu, Wargny, Anne-Sophie, Boureau, Sarra, Smati, Blandine, Tramunt, Rachel, Desailloud, Maylis, Lebeault, Coralie, Amadou, Deborah, Ancelle, Beverley, Balkau, Lyse, Bordier, Sophie, Borot, Muriel, Bourgeon, Olivier, Bourron, Emmanuel, Cosson, Martin, Eisinger, Céline, Gonfroy-Leymarie, Jean-Baptiste, Julla, Lucien, Marchand, Laurent, Meyer, Dominique, Seret-Bégué, Dominique, Simon, Ariane, Sultan, Charles, Thivolet, Anne, Vambergue, Camille, Vatier, Patrice, Winiszewski, Pierre-Jean, Saulnier, Bernard, Bauduceau, Pierre, Gourdy, Samy, Hadjadj, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Santé publique - Clinique des données [CHU Nantes] (Pôle Hospitalo-Universitaire 11), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Sud Francilien, Université Paris-Saclay, CH Le Havre, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Avicenne [AP-HP], Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Sorbonne Paris Nord, Centre Intégré Nord Francilien de l'Obésité (CINFO), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Sorbonne Paris Nord, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier René Dubos [Pontoise], Hôpital Lariboisière-Fernand-Widal [APHP], Centre hospitalier Saint Joseph - Saint Luc [Lyon], Les Hôpitaux Universitaires de Strasbourg (HUS), Centre Hospitalier de Gonesse, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Société Francophone du Diabète, Partenaires INRAE, CHU Lille, CHU Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital Nord Franche-Comté [Hôpital de Trévenans] (HNFC), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), and MORNET, Dominique

Subjects
Male, SARS-CoV-2, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Diabetes, Charlson index, COVID-19, Comorbidity, Prognosis, [SDV] Life Sciences [q-bio], Death, Cohort Studies, Internal Medicine, Diabetes Mellitus, Humans, Female, Invasive mechanical ventilation
Abstract

International audience; 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

Published
2021

2. Plasma concentrations of lipoproteins and risk of lower-limb peripheral artery disease in people with type 2 diabetes: the SURDIAGENE study

Author

Capucine, Bertrand, Pierre-Jean, Saulnier, Louis, Potier, Mikaël, Croyal, Valentin, Blanchard, Elise, Gand, Stéphanie, Ragot, Fabrice, Schneider, Olivia, Bocock, Laurence, Baillet-Blanco, Gilberto, Velho, Michel, Marre, Ronan, Roussel, Vincent, Rigalleau, Samy, Hadjadj, and Kamel, Mohammedi

Subjects
Male, Time Factors, Apolipoprotein A-I, Incidence, Cholesterol, HDL, Cholesterol, LDL, Middle Aged, Prognosis, Risk Assessment, Peripheral Arterial Disease, Diabetes Mellitus, Type 2, Lower Extremity, Risk Factors, Prevalence, Humans, Female, France, Prospective Studies, Biomarkers, Aged
Abstract

The lipid profile has not been fully investigated in individuals with peripheral artery disease (PAD). We aimed to evaluate the relationship between plasma concentrations of lipoproteins and the prevalence of lower-limb PAD at baseline and its incidence during follow-up in people with type 2 diabetes.Plasma concentrations of total cholesterol, HDL-cholesterol, triacylglycerol and apolipoprotein (Apo) A-I, ApoA-II, ApoB-100 and Apo(a) were measured at baseline using colorimetric or MS methods in the SURDIAGENE cohort. Total cholesterol/HDL-cholesterol ratio, non-HDL-cholesterol and LDL-cholesterol were estimated using computation formulas. Logistic and Cox proportional hazard regression models were fitted to estimate OR or HR, with related 95% CI, for baseline prevalence or incidence of major PAD (lower-limb amputation or requirement of revascularisation) during follow-up by increasing lipoprotein tertiles, after adjustment for key confounders.Among 1468 participants (women 42%, mean ± SD age 65 ± 11 years, duration of diabetes 14 ± 10 years at baseline), 129 (8.8%) had a baseline history of major PAD. Major PAD was less prevalent at baseline in the highest (vs lowest) tertile of HDL-cholesterol (OR 0.42 [95% CI 0.26, 0.71], p = 0.001) and ApoA-I (OR 0.39 [95% CI 0.23, 0.67], p = 0.0007), and more frequent in the highest tertile of total cholesterol/HDL-cholesterol ratio (OR 1.95 [95% CI 1.18, 3.24], p = 0.01). Among 1339 participants without a history of PAD at baseline, incident PAD occurred in 97 (7.2%) during a median (25th-75th percentile) duration of follow-up of 7.1 (4.4-10.7) years, corresponding to 9685 person-years and an incidence rate of 9.8 (95% CI 8.0, 12.0) per 1000 person-years. The risk of incident PAD was lower in the top (vs bottom) tertile of HDL-cholesterol (HR 0.54 [95% CI 0.30, 0.95], p = 0.03) or ApoA-I (HR 0.50 [95% CI 0.28, 0.86], p = 0.01) and higher in the top tertile of total cholesterol/HDL-cholesterol ratio (HR 2.81 [95% CI 1.61, 5.04], p = 0.0002) and non-HDL-cholesterol (HR 1.80 [95% CI 1.06, 3.12], p = 0.03).We reported independent associations between HDL-cholesterol, ApoA-I, total cholesterol/HDL-cholesterol ratio or non-HDL-cholesterol and the prevalence or the incidence of major PAD in people with type 2 diabetes. Our findings provide a picture of lipoprotein profile in people with type 2 diabetes. Graphical abstract.

Published
2020

3. Correction to: Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study

Author

Coralie Amadou, Michael Joubert, Patrice Darmon, Samy Hadjadj, Amélie Ducet-Boiffard, Gwénaëlle Arnault, Pierre Jean Saulnier, Blandine Tramunt, Bertrand Cariou, Charles Thivolet, Abdallah Al-Salameh, Ingrid Allix, Emmanuel Cosson, Emmanuel Disse, Bruno Laviolle, Florence Baudoux, Matthieu Wargny, Véronique Kerlan, Muriel Bourgeon-Ghittori, Ariane Sultan, Bénédicte Gaborit, Olivier Bourron, Ronan Roussel, René Robert, Laurent Meyer, Camille Vatier, Sophie Borot, David Boutoille, Claude Chaumeil, Louis Potier, Jean François Gautier, Gaëtan Prévost, Jean-Pierre Riveline, Lucien Marchand, Bernard Bauduceau, Matthieu Pichelin, Jean François Thébaut, Pierre Gourdy, Sandrine Coudol, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service d'endocrinologie, nutrition et maladies métaboliques [Hôpital Nord - APHM], Hôpital Nord [CHU - APHM]-Assistance Publique - Hôpitaux de Marseille (APHM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM]

Subjects
2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, MEDLINE, Correction, 030209 endocrinology & metabolism, Human physiology, medicine.disease, Phenotype, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Diabetes mellitus, Internal Medicine, Medicine, business, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2020
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4. Prognostic value of plasma MR-proADM vs NT-proBNP for heart failure in people with type 2 diabetes: the SURDIAGENE prospective study

Author

Kamel Mohammedi, M. Fraty, David Montaigne, Gregory Ducrocq, Elise Gand, Philippe Sosner, Barnabas Gellen, Michel Marre, Ronan Roussel, Samy Hadjadj, Jean-Michel Halimi, Michaela Rehman, Stéphanie Ragot, Pierre-Jean Saulnier, Gilberto Velho, and Frédéric Fumeron

Subjects
Male, medicine.medical_specialty, medicine.drug_class, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, Adrenomedullin, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Natriuretic Peptide, Brain, Internal Medicine, medicine, Clinical endpoint, Natriuretic peptide, Humans, Prospective Studies, Prospective cohort study, Aged, Heart Failure, Proteinuria, Ejection fraction, business.industry, Neuropeptides, Middle Aged, Prognosis, medicine.disease, Peptide Fragments, Diabetes Mellitus, Type 2, Heart failure, Cohort, Cardiology, Female, medicine.symptom, business, Biomarkers
Abstract

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the gold standard prognostic biomarker for diagnosis and occurrence of heart failure. Here, we compared its prognostic value for the occurrence of congestive heart failure with that of plasma mid-region pro-adrenomedullin (MR-proADM), a surrogate for adrenomedullin, a vasoactive peptide with vasodilator and natriuretic properties, in people with type 2 diabetes. Plasma MR-proADM concentration was measured in baseline samples of a hospital-based cohort of consecutively recruited participants with type 2 diabetes. Our primary endpoint was heart failure requiring hospitalisation. We included 1438 participants (age 65 ± 11 years; 604 women and 834 men). Hospitalisation for heart failure occurred during follow-up (median 64 months) in 206 participants; the incidence rate of heart failure was 2.5 (95% CI 2.2, 2.9) per 100 person-years. Plasma concentrations of MR-proADM and NT-proBNP were significantly associated with heart failure in a Cox multivariable analysis model when adjusted for age, diabetes duration, history of coronary heart disease, proteinuria and baseline eGFR (adjHR [95%CI] 1.83 [1.51, 2.21] and 2.20 [1.86, 2.61], respectively, per 1 SD log10 increment, both p

Published
2018

5. Plasma concentrations of 8-hydroxy-2′-deoxyguanosine and risk of kidney disease and death in individuals with type 1 diabetes

Author

Gilberto Velho, Ronan Roussel, Kamel Mohammedi, Manuel Sanchez, Samy Hadjadj, Michel Marre, and Abdul Moutairou

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Renal function, 030209 endocrinology & metabolism, Sensitivity and Specificity, Gastroenterology, End stage renal disease, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Internal Medicine, Humans, Medicine, Prospective Studies, Type 1 diabetes, business.industry, Confounding, Deoxyguanosine, Middle Aged, medicine.disease, Oxygen, Oxidative Stress, Cross-Sectional Studies, Diabetes Mellitus, Type 1, 030104 developmental biology, Increased risk, 8-Hydroxy-2'-Deoxyguanosine, Plasma concentration, Albuminuria, Kidney Failure, Chronic, Female, medicine.symptom, business, DNA Damage, Follow-Up Studies, Glomerular Filtration Rate, Kidney disease
Abstract

Oxidative stress is involved in the pathogenesis of diabetic kidney disease. We evaluated the association between 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of DNA oxidative damage, and end-stage renal disease (ESRD) or death in individuals with type 1 diabetes. Plasma 8-OHdG concentrations were measured at baseline in participants with type 1 diabetes from GENEDIAB (n = 348) and GENESIS (n = 571) cohorts. A follow-up was conducted in 205 and 499 participants for a mean ± SD duration of 8.9 ± 2.3 years and 5.2 ± 1.9 years, respectively. We tested associations between 8-OHdG concentrations and urinary albumin concentration (UAC) or eGFR at baseline, and the risk of ESRD or all-cause mortality during follow-up. Analyses were performed in pooled cohorts. The highest UAC (geometric mean [95% CI]) was observed in the third 8-OHdG tertile (tertile 1, 9 [6, 13] mg/l; tertile 2, 10 [7, 16] mg/l; tertile 3, 16 [10, 25] mg/l; p = 0.36 for tertile 1 vs tertile 2 and p = 0.003 for tertile 3 vs tertile 1) after adjustment for potential confounding covariates. The lowest eGFR (mean [95% CI]) was observed in the third tertile (tertile 1, 87 [82, 93] ml min−1 1.73 m−2; tertile 2, 88 [82, 94] ml min−1 1.73 m−2; tertile 3, 74 [68, 80] ml min−1 1.73 m−2; p = 0.61 for tertile 1 vs tertile 2; p

Published
2017

6. The relationship between eGFR slope and subsequent risk of vascular outcomes and all-cause mortality in type 2 diabetes: the ADVANCE-ON study

Author

Samy Hadjadj, Michel Marre, Min Jun, Pavel Hamet, Stephen B. Harrap, Mark Woodward, Tadashi Toyama, Toshiaki Ohkuma, Vlado Perkovic, Bryan Williams, Takashi Wada, Megumi Oshima, Giuseppe Mancia, John Chalmers, and Mark E. Cooper

Subjects
0301 basic medicine, Oncology, Male, Risk, medicine.medical_specialty, eGFR slope, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Type 2 diabetes, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Interquartile range, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Mortality, Renal Insufficiency, Chronic, Aged, Proportional Hazards Models, Creatinine, business.industry, Surrogate endpoint, Proportional hazards model, End-stage kidney disease, Middle Aged, medicine.disease, Cardiovascular disease, 3. Good health, 030104 developmental biology, Treatment Outcome, chemistry, Diabetes Mellitus, Type 2, Cohort, Chronic Disease, Linear Models, Kidney Failure, Chronic, Female, business, Biomarkers, Kidney disease, Glomerular Filtration Rate
Abstract

Aims/hypothesis Some studies have reported that annual change in eGFR (eGFR slope) is associated with the future risk of end-stage kidney disease, cardiovascular disease and death in general or chronic kidney disease cohorts. However, the benefits of using eGFR slopes for prediction of major clinical outcomes in diabetes are unclear. Methods We used data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial and the ADVANCE Post-Trial Observational Study (ADVANCE-ON). After excluding the first 4 months during which an acute fall in eGFR was induced by the initiation of an ACE inhibitor and diuretic combination agent, eGFR slopes were estimated by linear mixed models, using three measurements of eGFR at 4, 12 and 24 months after randomisation over 20 months, and categorised according to quartiles. Cox regression models were used to evaluate adjusted HRs for the study’s primary outcome, a composite of major renal events, major macrovascular events and all-cause mortality during the subsequent follow-up from 24 months after randomisation. Results A total of 8,879 participants (80%) were included in this cohort. The mean age was 65.6 years (SD 6.3), the mean eGFR was 75 ml min−1 (1.73 m)−2 (SD 17) and the median urinary albumin/creatinine ratio was 14 μg/mg (interquartile range 7–38). The mean eGFR slope was −0.63 ml min−1 (1.73 m)−2 year−1 (SD 1.75). Over a median follow-up of 7.6 years following the 20-month eGFR slope ascertainment period, 2,221 participants (25%) met the primary outcome. An annual substantial decrease in eGFR (lowest 25%, 0.33) had no significant association with the risk of the primary outcome (HR 0.96 [95% CI 0.86, 1.07]). Conclusions/interpretation Our study supports the utility of eGFR slope in type 2 diabetes as a surrogate endpoint for renal outcomes, as well as a prognostic factor for identifying individuals at high risk of cardiovascular disease and all-cause mortality. Trial registry number ClinicalTrials.gov registration no. NCT00145925 and no. NCT00949286 Electronic supplementary material The online version of this article (10.1007/s00125-019-4948-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Published
2019

7. A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

Author

Marju Orho-Melander, Tea Skaaby, Niina Sandholm, Mathilda Bedin, Marit E. Jørgensen, Per-Henrik Groop, Cramer Christensen, Allan Linneberg, Niels Grarup, Tarunveer S. Ahluwalia, Matias Simons, Natalie R. van Zuydam, Betina H. Thuesen, David-Alexandre Trégouët, Tuomas O. Kilpeläinen, Olle Melander, Mark I. McCarthy, Emma Ahlqvist, Ivan Brandslund, Jette Bork-Jensen, Johannes Waage, Torben Hansen, Christina-Alexandra Schulz, Oluf Pedersen, Peter Rossing, Samy Hadjadj, Peter Almgren, Leif Groop, Romain Charmet, IT University of Copenhagen, Lund University [Lund], University of Helsinki, Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford], The Wellcome Trust Centre for Human Genetics [Oxford], Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Monash University [Melbourne], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), University of Southern Denmark (SDU), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Clinicum, Research Programs Unit, Nefrologian yksikkö, Diabetes and Obesity Research Program, Department of Medicine, Per Henrik Groop / Principal Investigator, Centre of Excellence in Complex Disease Genetics, Institute for Molecular Medicine Finland, HUS Abdominal Center, Sorbonne Universités, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Endocrinology, Diabetes and Metabolism, LOCI, Genome-wide association study, Type 2 diabetes, DKD, 0302 clinical medicine, Gene Frequency, Medicine, GWAS, Diabetic Nephropathies, PROTECTION, Exome, RISK, Genetics, Diabetes, 1184 Genetics, developmental biology, physiology, Kidney disease, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, RECEPTORS, Medical genetics, medicine.symptom, medicine.medical_specialty, Genotype, Receptors, Cell Surface, 030209 endocrinology & metabolism, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, REVEALS, Diabetes Mellitus, Internal Medicine, Genetic predisposition, Humans, Albuminuria, Genetic Predisposition to Disease, Allele, METAANALYSIS, Alleles, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], business.industry, GENOME-WIDE, Rare variant, KIDNEY-DISEASE, FRAMEWORK, medicine.disease, SKAT, Exome chip, Minor allele frequency, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DISCOVERY, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, business
Abstract

Aims/hypothesis Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants. Methods We performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included. Results We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10−4, β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni

Published
2018

8. A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus

Author

Douwe Postmus, Lise Tarnow, Alaa Alkhalaf, Stephan J. L. Bakker, Peter Rossing, Nathalie Vionnet, H. H. Parving, P. H. Groop, Carol Forsblom, Michel Marre, Gerjan Navis, Henk J. G. Bilo, Samy Hadjadj, Reinold O. B. Gans, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Methods in Medicines evaluation & Outcomes research (M2O), and Life Course Epidemiology (LCE)

Subjects
Male, Dipeptidases, Endocrinology, Diabetes and Metabolism, Diabetic nephropathy, Type 2 diabetes, Disease, SUSCEPTIBILITY, Gastroenterology, End-stage renal disease, Medicine, Diabetic Nephropathies, AFRICAN-AMERICANS, RISK, COMPLICATIONS, Carnosinase gene, ASSOCIATION, Middle Aged, Prognosis, Type 1 diabetes, CNDP1, Disease Progression, SECRETION, Female, LEUCINE REPEAT, Adult, medicine.medical_specialty, Polymorphism, Single Nucleotide, White People, Article, Nephropathy, End stage renal disease, Internal medicine, Internal Medicine, Humans, Genetic Predisposition to Disease, In patient, Gene, business.industry, medicine.disease, Survival Analysis, TRENDS, Five leucine repeat, Diabetes Mellitus, Type 1, Endocrinology, Case-Control Studies, CELLS, Kidney Failure, Chronic, business, SYSTEM, Follow-Up Studies
Abstract

Aims/hypothesis Homozygosity for a five leucine repeat (5L–5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type 1 diabetes whether: (1) 5L–5L is associated with mortality; (2) there is an interaction of 5L–5L with DN or sex for prediction of mortality; and (3) 5L–5L is associated with progression to end-stage renal disease (ESRD). Methods In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria ≥300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria

Published
2010

9. Increased plasma adiponectin concentrations are associated with microangiopathy in type 1 diabetic subjects

Author

Frédéric Fumeron, Roberte Aubert, Michel Marre, Franck Péan, Desir study groups, Jean Tichet, Surgene, Samy Hadjadj, and Ronan Roussel

Subjects
Adult, Male, medicine.medical_specialty, Time Factors, Endocrinology, Diabetes and Metabolism, Blood Pressure, Diabetic nephropathy, Insulin resistance, Reference Values, Internal medicine, Internal Medicine, medicine, Albuminuria, Humans, Macrovascular disease, Type 1 diabetes, Diabetic Retinopathy, Proteinuria, Adiponectin, business.industry, Diabetic retinopathy, Middle Aged, medicine.disease, Diabetes Mellitus, Type 1, Endocrinology, Creatinine, Intercellular Signaling Peptides and Proteins, Female, Microalbuminuria, medicine.symptom, business, Biomarkers, Diabetic Angiopathies, Follow-Up Studies
Abstract

Insulin resistance is related to an increased risk of diabetic retinopathy and nephropathy in type 1 diabetes. Patients with insulin resistance and/or macrovascular disease have abnormally low levels of adiponectin. The aim of this study was to investigate the relationships between adiponectin and renal and retinal diabetic complications in type 1 diabetic patients.In this 6-year prospective follow-up observational study, we evaluated the severity of retinopathy at baseline and determined the incident risk of microalbuminuria in 126 normoalbuminuric patients with type 1 diabetes. Each patient was age- and sex-matched to two non-diabetic control subjects.Plasma adiponectin concentrations were significantly higher in diabetic subjects than in control subjects (p0.0001). The adiponectin concentration was significantly higher in patients with severe diabetic retinopathy than in those without (39.1+/-14.0 vs 29.0+/-13.0 microg/ml, p = 0.0005). The 18 patients who developed persistent microalbuminuria had higher adiponectin concentrations than the other patients (35.8+/-14.5 vs 30.6+/-13.7 microg/ml). Increased adiponectin concentrations were independently associated with the occurrence of microalbuminuria (p = 0.0158) after adjustment for baseline urinary albumin concentration (p = 0.004), sex (p = 0.0054), blood pressure (NS) and metabolic control (NS).The elevated adiponectin concentrations observed in subjects with microvascular disease may indicate an altered regulation of this adipocytokine in patients with complications associated with type 1 diabetes.

Published
2005

10. Catalase activity, allelic variations in the catalase gene and risk of kidney complications in patients with type 1 diabetes

Author

Frédéric Fumeron, Mirela Jobim de Azevedo, Elizabeth João Pavin, Nathalie Seta, Luis Henrique Santos Canani, Michel Marre, Thiago A. Patente, Gilberto Velho, Ronan Roussel, Fathi Driss, Kamel Mohammedi, Maria Lúcia Corrêa-Giannella, Maria Beatriz Monteiro, Samy Hadjadj, and Naiema Bellili-Munoz

Subjects
Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Gastroenterology, Polymorphism, Single Nucleotide, Risk Assessment, End stage renal disease, Nephropathy, Diabetic nephropathy, Belgium, Gene Frequency, Risk Factors, Internal medicine, Internal Medicine, medicine, Prevalence, Humans, Diabetic Nephropathies, Risk factor, Allele frequency, Type 1 diabetes, business.industry, Incidence, ANTIOXIDANTES, Genetic Variation, medicine.disease, Catalase, Oxidative Stress, Endocrinology, Cross-Sectional Studies, Kidney Failure, Chronic, Microalbuminuria, Female, France, business, Brazil, Kidney disease, Follow-Up Studies, Glomerular Filtration Rate
Abstract

Oxidative stress is involved in the pathogenesis of diabetic nephropathy. The antioxidant enzyme catalase plays a key role in redox regulation in the kidney. We investigated associations of catalase gene (CAT) polymorphisms and plasma catalase activity with diabetic nephropathy in type 1 diabetic patients. We genotyped nine single nucleotide polymorphisms (SNPs) in the CAT region in participants from the Survival Genetic Nephropathy (SURGENE) (340 French participants, 10 year follow-up) and the Genetique de la Nephropathie Diabetique (GENEDIAB) (444 Belgian and French participants, 8 year follow-up) study cohorts. Replication was performed in a Brazilian cross-sectional cohort (n = 451). Baseline plasma catalase activity was measured in SURGENE (n = 120) and GENEDIAB (n = 391) participants. The A allele of rs7947841 was associated with the prevalence of incipient (OR 2.79, 95% CI 1.21, 6.24, p = 0.01) and established or advanced nephropathy (OR 5.72, 95% CI 1.62, 22.03, p = 0.007), and with the incidence of renal events, which were defined as new cases of microalbuminuria or progression to a more severe stage of nephropathy during follow-up (HR 1.82, 95% CI 1.13, 2.81, p = 0.01) in SURGENE participants. The same risk allele was associated with incipient nephropathy (OR 3.13, 95% CI 1.42, 7.24, p = 0.004) and with the incidence of end-stage renal disease (ESRD) (HR 2.11, 95% CI 1.23, 3.60, p = 0.008) in GENEDIAB participants. In both cohorts, the risk allele was associated with lower catalase activity. Associations with incipient and established or advanced nephropathy were confirmed in the replication cohort. CAT variants were associated with the prevalence and incidence of diabetic nephropathy and ESRD in type 1 diabetic patients. Our results confirm the protective role of catalase against oxidative stress in the kidney.

Published
2013

11. Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes

Author

Philippe Froguel, Anette P. Gjesing, Torben Hansen, Emmanuel Vaillant, J. Philippe, Aurélie Dechaume, B. Balkau, Amélie Bonnefond, Olivier Lantieri, Guillaume Charpentier, Serge Hercberg, Sébastien Czernichow, Oluf Pedersen, Loic Yengo, Ehm A. Andersson, Samy Hadjadj, Martine Vaxillaire, Michel Marre, Intissar Ezzidi, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Université Lille Nord de France (COMUE), Université de Monastir (Université de Monastir), Fac Hlth Sci, Aarhus University [Aarhus], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Dept Nutr, University of California [Davis] (UC Davis), University of California-University of California, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre d' investigation clinique-plurithématique du CHU de Poitiers, Centre Hospitalier Sud Francilien, Institut inter-Régional pour la SAnté (IRSA), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11), AP-HP - Hôpital Bichat - Claude Bernard [Paris], INSERM U695, Université Paris Diderot - Paris 7 (UPD7), Steno Diabet Ctr, Partenaires INRAE, Hagedorn Research Institute, Imperial College London, French Agence Nationale de la Recherche (EuroGeBeta) [ERANET-09 RARE-005], Contrat de Projets Etat-Region Nord-Pas-De-Calais, Danish Diabetes Association, Danish Council for Independent Research (Medical Sciences), AFD-Association Francaise des Diabetiques [2003], GEMMS-Poitiers, University of Poitiers, French Ministry of Health, CNAMTS, Lilly, Novartis Pharma, Sanofi-aventis, Inserm (Reseaux en Sante Publique, Interactions entre les determinants de la sante, Cohortes Sante TGIR), Association Diabete Risque Vasculaire, Federation Francaise de Cardiologie, La Fondation de France, ALFE-DIAM, ONIVINS, Societe Francophone du Diabete, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Sante, Novo Nordisk, Pierre Fabre, Roche, Topcon, University of California (UC)-University of California (UC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM CIC 0802 (INSERM - CHU de Poitiers), Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ProdInra, Migration

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, Locus (genetics), Type 2 diabetes, Biology, SUSCEPTIBILITY, Maturity onset diabetes of the young, Maturity-onset diabetes of the young, Loss of function mutation, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Low-frequency variant, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Genetics, Humans, Genetic Predisposition to Disease, Child, Gene, 030304 developmental biology, 0303 health sciences, Insulin, Diabesity, ASSOCIATION, medicine.disease, POLYMORPHISM, 3. Good health, [SDV] Life Sciences [q-bio], Endocrinology, src-Family Kinases, YOUNG MODY, Diabetes Mellitus, Type 2, OBESITY, MODY, Mutation, Female, Beta cell, BLK
Abstract

International audience; MODY is believed to be caused by at least 13 different genes. Five rare mutations at the BLK locus, including only one non-synonymous p.A71T variant, were reported to segregate with diabetes in three MODY families. The p.A71T mutation was shown to abolish the enhancing effect of BLK on insulin content and secretion from pancreatic beta cell lines. Here, we reassessed the contribution of BLK to MODY and tested the effect of BLK-p.A71T on type 2 diabetes risk and variations in related traits. BLK was sequenced in 64 unelucidated MODY samples. The BLK-p.A71T variant was genotyped in a French type 2 diabetes case-control study including 4,901 cases and 4,280 controls, and in the DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) and SUVIMAX (Supplementation en Vitamines et Mineraux Antioxydants) population-based cohorts (n = 6,905). The variant effects were assessed by logistic and linear regression models. No rare non-synonymous BLK mutations were found in the MODY patients. The BLK p.A71T mutation was present in 52 normoglycaemic individuals, making it very unlikely that this loss-of-function mutation causes highly penetrant MODY. We found a nominal association between this variant and increased type 2 diabetes risk, with an enrichment of the mutation in the obese diabetic patients, although no significant association with BMI was identified. No mutation in BLK was found in our MODY cohort. From our findings, the BLK-p.A71T mutation may weakly influence type 2 diabetes risk in the context of obesity; however, this will require further validation.

Published
2012

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