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1. The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

Author

Cédric Le May, Michel Marre, Loic Yengo, Beverley Balkau, Guillaume Charpentier, Frédéric Fumeron, Bertrand Cariou, Sylvia Franc, Philippe Froguel, Amélie Bonnefond, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), 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)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Paris Cite, Université Paris Diderot - Paris 7 (UPD7), Service d'endocrinologie, diabétologie et nutrition [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre de recherche en épidémiologie et santé des populations (CESP), 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), Centre d'études et de recherches pour l'intensification du traitement du diabète (CERITD), Centre Hospitalier Sud Francilien, CH Evry-Corbeil, Imperial College London, Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), 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), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Hôpital Paul Brousse-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Unité de recherche de l'institut du thorax (ITX-lab), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Blood Glucose, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, Body Mass Index, 0302 clinical medicine, Risk Factors, Homeostasis, Glucose homeostasis, Longitudinal Studies, humans, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, adult, Serine Endopeptidases, Age Factors, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, 3. Good health, Cholesterol, Regression Analysis, Kexin, Female, Proprotein Convertases, France, Proprotein Convertase 9, Type 2, medicine.medical_specialty, Genotype, Biology, 03 medical and health sciences, Sex Factors, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Diabetes mellitus, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Diabetes Mellitus, Internal Medicine, medicine, Loss function, 030304 developmental biology, PCSK9, Genetic Variation, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Proprotein convertase, medicine.disease, prospective studies, Endocrinology, Diabetes Mellitus, Type 2, Gene Expression Regulation
Abstract

International audience; AIMS/HYPOTHESIS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a critical regulator of cholesterol homeostasis. PCSK9 inhibitors are being actively developed to lower LDL-cholesterol levels. However, there are conflicting data regarding the consequences of Pcsk9 deficiency on glucose homeostasis in mouse models. Here, we analysed in humans the association between the PCSK9 p.R46L loss-of-function (LOF) variant and (1) glucose homeostasis variables; (2) type 2 diabetes status; and (3) the risk of 9 year incident type 2 diabetes in a prospective study. METHODS: PCSK9 p.R46L was genotyped in 4630 French participants from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study and in 1342 French participants with type 2 diabetes. The association between p.R46L and metabolic traits or type 2 diabetes risk was assessed through linear or logistic regression models adjusted for age, sex and BMI. The association between p.R46L and incident type 2 diabetes was assessed using a Cox regression model adjusted for sex, age and BMI at baseline. RESULTS: Significant associations (p \textless 10(-6)) were found between p.R46L and lower total cholesterol (-0.394 mmol/l), LDL-cholesterol (-0.393 mmol/l) and apolipoprotein B concentrations (-0.099 g/l). However, no significant association was observed between p.R46L and markers of glucose homeostasis (including fasting glucose, fasting insulin, HbA1c, HOMA-B, HOMA-IR) or type 2 diabetes risk. Furthermore, no significant association between p.R46L variant and risk of incident type 2 diabetes was observed in DESIR. CONCLUSIONS/INTERPRETATION: The PCSK9 p.R46L LOF variant was not associated with impaired glucose homeostasis in humans. These data are reassuring regarding the safety of PCSK9 inhibitors.

Published
2015
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2. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

Author

M. Tang, S. Y. Kim, Tom Forsén, Yun Li, Q. Li, Karina Banasik, J. M. Dekker, Leif Groop, B. Balkau, N. van Leeuwen, Jacek Mokrosinski, G. Tian, Alex S. F. Doney, Thue W. Schwartz, H. Jiang, Johanna Kuusisto, Thorfinn Sand Korneliussen, S. Huang, Guillaume Charpentier, Giel Nijpels, Daniel R. Witte, Maria Lajer, Alena Stančáková, F. Xi, Oluf Pedersen, Anders Albrechtsen, Torben Jørgensen, Mozhgan Dorkhan, Torben Hansen, Amanda J. Bennett, B. Wang, Gregers S. Andersen, Chang Yu, Aneta Aleksandra Nielsen, Mark I. McCarthy, Lise Tarnow, Markku Laakso, Timothy M. Frayling, P.E. Slagboom, Olov Rolandsson, Y. Wang, Torsten Lauritzen, Christopher J. Groves, Weihua Zhang, Peter M. Nilsson, T. Jiang, Loic Yengo, Leen M 't Hart, Y. Gui, Tiinamaija Tuomi, Chao Nie, Peter Rossing, J. Zhang, Frida Renström, Andrew D. Morris, Cramer Christensen, Graham A. Hitman, Neil Robertson, H. Cao, Göran Hallmans, Allan Linneberg, Niels Grarup, Line Skotte, H. Wu, Colin N. A. Palmer, M. P. Manijak, Q. Zhang, Andrew P. Morris, Rasmus Ribel-Madsen, Yi Chen, Arne Astrup, Tibor V. Varga, Mark Walker, Y. Zhou, Jun Wang, Maria Sterner, Paul W. Franks, Lars Bolund, Andrew T. Hattersley, Johan Holmkvist, Karsten Kristiansen, David Altshuler, E. van 't Riet, Philippe Froguel, Stéphane Cauchi, R. Wu, Kunlun He, B. Mu, X. Ma, X. Liu, Weijing Li, H. Liang, Rasmus Nielsen, Olivier Lantieri, T. Ma, Xin Jin, Claes Ladenvall, Michel Marre, Nigel W. Rayner, Thomas Sparsø, Marie A. Vestmar, Johanne Marie Justesen, Ivan Brandslund, Q. Liao, Xiaoming Zhang, H. Zheng, Epidemiology and Data Science, General practice, EMGO - Lifestyle, overweight and diabetes, Massachusetts Institute of Technology. Department of Biology, and Altshuler, David

Subjects
Exome/genetics, Exome sequencing, Endocrinology, Diabetes and Metabolism, IDENTIFIES 6, EFFICIENT, Genome-wide association study, VARIANTS, 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Genetic epidemiology, Exome, Polymorphism, Genetic/genetics, RISK, Genetics, 0303 health sciences, High-Throughput Nucleotide Sequencing, Type 2 diabetes, Polymorphism, Single Nucleotide/genetics, Lipids, Gene Frequency/genetics, Hypertension, Diabetes Mellitus, Type 2/genetics, Genotype, 030209 endocrinology & metabolism, Biology, Polymorphism, Single Nucleotide, DNA sequencing, Article, 03 medical and health sciences, Internal Medicine, Humans, Obesity, GENOME-WIDE ASSOCIATION, Allele frequency, METAANALYSIS, 030304 developmental biology, Polymorphism, Genetic, DIABETES SUSCEPTIBILITY LOCI, Minor allele frequency, INDIVIDUALS, Diabetes Mellitus, Type 2, DE-NOVO MUTATIONS, Next-generation sequencing, GLUCOSE-HOMEOSTASIS, Hypertension/genetics
Abstract

Aims/hypothesis Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. Methods The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m2 and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10−14), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10−11) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10−10). Conclusions/interpretation We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits. Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2756-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Published
2012
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3. Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3,243 (maternally inherited diabetes and deafness). A case–control study

Author

Marie Laloi-Michelin, S. Casanova, J. Cahen-Varsaux, José Timsit, O. Dupuy, E. Kaloustian, Guillaume Charpentier, F. Olivier, A. Lecleire-Collet, T. Meas, Eric Bertin, Pascale Massin, Bernard Vialettes, F. Lorenzini, Bruno Guerci, M. Virally, A. Grimaldi, P. Chedin, Danièle Dubois-Laforgue, H. Gin, Béatrice Bouhanick, C. Bellanné-Chantelot, A. Murat, Pierre-Jean Guillausseau, M Vincenot, Véronique Paquis-Flucklinger, J.-F. Blickle, H. Narbonne, and Bernard Bauduceau

Subjects
medicine.medical_specialty, Mitochondrial Diseases, Endocrinology, Diabetes and Metabolism, Blood Pressure, DNA, Mitochondrial, Gastroenterology, Nephropathy, Diabetic nephropathy, Retinal Diseases, Internal medicine, Diabetes mellitus, Internal Medicine, Humans, Medicine, Diabetic Nephropathies, Glycated Hemoglobin, Diabetic Retinopathy, business.industry, Diabetic retinopathy, medicine.disease, Diabetes Mellitus, Type 1, Phenotype, Endocrinology, Blood pressure, Diabetes Mellitus, Type 2, Mutation, ACE inhibitor, Female, Kidney Diseases, business, Diabetic Angiopathies, Glomerular Filtration Rate, medicine.drug, Kidney disease, Retinopathy
Abstract

We assessed the prevalence and determinants of retinal and renal complications in patients with maternally inherited diabetes and deafness (MIDD).This was a multicentre prospective study comparing the prevalence of retinopathy and renal disease in 74 patients with MIDD and 134 control patients matched for sex, age and clinical presentation at onset of diabetes, duration of diabetes and current treatment. Comparisons were adjusted for HbA(1c) and hypertension.In MIDD patients, HbA(1c) (7.6 +/- 1.6 vs 8.5 +/- 2.0%, p0.002), systolic blood pressure (126.6 +/- 16.2 vs 133.1 +/- 17.3 mmHg, p0.007) and prevalence of hypertension (33.8 vs 64.2%, p0.0001) were lower than in control patients. Prevalence of diabetic retinopathy was 3.7-fold lower in MIDD patients (6/74, 8 vs 40/134, 29.6%, p0.0001). Differences between groups remained significant after adjustment for hypertension, systolic blood pressure and HbA(1c). In MIDD, urinary albumin excretion (314.8 vs 80.1 mg/24 h, p = 0.035) and creatinine plasma levels (103.5 vs 82.2 micromol/l, p = 0.0178) were higher and GFR was lower. Impaired renal function (GFR60 ml/min) was four- to sixfold more frequent in MIDD. Differences between MIDD and control diabetic patients further increased when adjusted for HbA(1c) and systolic blood pressure (p0.0001). Adjustment for treatment with an ACE inhibitor or angiotensin II receptor antagonist did not modify the results.This study indicates that diabetic retinopathy is less prevalent in MIDD than in control diabetes. This suggests that retinal alterations due to mitochondrial disease may have a protective role. By contrast, nephropathy is far more frequent in MIDD, suggesting the presence of a specific renal disease independent of diabetic nephropathy.

Published
2008
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4. Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

Author

Nicole Helbecque, Aurélie Dechaume, Philippe Froguel, Guillaume Charpentier, Martine Vaxillaire, Christian Dina, Valérie Vasseur-Delannoy, and Stéphane Lobbens

Subjects
Male, Linkage disequilibrium, Diabetes risk, Genotype, Endocrinology, Diabetes and Metabolism, Single-nucleotide polymorphism, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, Gene Frequency, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, Allele frequency, Finland, Genetic association, Genetics, Polymorphism, Genetic, Haplotype, Middle Aged, Phosphoproteins, medicine.disease, DNA-Binding Proteins, Minor allele frequency, Diabetes Mellitus, Type 2, Hepatocyte Nuclear Factor 4, Case-Control Studies, Female, France, Transcription Factors
Abstract

The gene encoding HNF-4alpha, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the HNF-4alpha P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population.Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a case-control study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the HNF4alpha region had been shown.The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNF-4alpha was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected p=0.022 for rs2144908; OR 0.82 uncorrected p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage.None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of HNF-4alpha and type 2 diabetes in several ethnic groups.

Published
2005
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5. 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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6. Strong association of common variants in the CDKN2A/CDKN2B region with type 2 diabetes in French Europids

Author

Jean Tichet, Philippe Froguel, Guillaume Charpentier, Fernando Gibson, Serge Hercberg, Michel Marre, Konsta Duesing, Beverley Balkau, and Ghazaleh Fatemifar

Subjects
Linkage disequilibrium, Endocrinology, Diabetes and Metabolism, Population, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, Internal Medicine, SNP, Humans, Genetic Predisposition to Disease, education, Cyclin-Dependent Kinase Inhibitor p16, Genetic association, Cyclin-Dependent Kinase Inhibitor p15, Genetics, education.field_of_study, Genetic Variation, Exons, Tag SNP, Introns, Diabetes Mellitus, Type 2, France, 5' Untranslated Regions
Abstract

Genome-wide association studies (GWASs) recently identified common variants in the CDKN2A/CDKN2B region on chromosome 9p as being strongly associated with type 2 diabetes. Since these association signals were not picked up by the French-Canadian GWAS, we sought to replicate these findings in the French Europid population and to further characterise the susceptibility variants at this novel locus.We genotyped 20 single nucleotide polymorphisms (SNPs) spanning the CDKN2A/CDKN2B locus in our type 2 diabetes case-control cohort. The association between CDKN2A/CDKN2B SNPs and quantitative metabolic traits was also examined in the normoglycaemic participants comprising the control cohort.We report replication of the strong association of rs10811661 with type 2 diabetes found in the GWASs (P= 3.8 X 10(-7); OR 1.43 [95% CI 1.24-1.64]). The other CDKN2A/CDKN2B susceptibility variant, rs564398, did not attain statistical significance (p = 0.053; OR 1.11 [95% CI 1.00-1.24]) in the present study. We also obtained several additional nominal association signals (p0.05) at the CDKN2A/CDKN2B locus; however, only the rs3218018 result (p = 0.002) survived Bonferroni correction for multiple testing (adjusted p = 0.04).Our comprehensive association study of common variation spanning the CDKN2A/CDKN2B locus confirms the strong association between the distal susceptibility variant rs10811661 and type 2 diabetes in the French population. Further genetic and functional studies are required to identify the aetiological variants at this locus and determine the cellular and physiological mechanisms by which they act to modulate type 2 diabetes susceptibility.

Published
2008

7. Mutation screening in 18 Caucasian families suggest the existence of other MODY genes

Author

Dominique Beckers, El Habib Hani, Etienne Larger, Marc Maes, José Timsit, Philippe Boutin, Guillaume Charpentier, Philippe Froguel, Gilberto Velho, Jean-Claude Chèvre, Nathalie Vionnet, Hélène Blanché, Martine Vaxillaire, C. Bellanné-Chantelot, V. C. Pardini, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition, and UCL - (MGD) Service de pédiatrie

Subjects
Adult, Male, Genetic Linkage, Endocrinology, Diabetes and Metabolism, European Continental Ancestry Group, DNA Mutational Analysis, Chromosomes, Human, Pair 20, Locus (genetics), Biology, digestive system, White People, Internal Medicine, Missense mutation, Humans, Genetic Testing, Hepatocyte Nuclear Factor 1-alpha, Promoter Regions, Genetic, Gene, Chromosome 12, Chromosome 13, Hepatocyte Nuclear Factor 1-beta, Genetics, Chromosome 7 (human), Chromosomes, Human, Pair 12, Polymorphism, Genetic, Chromosomes, Human, Pair 13, Glucokinase, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Nuclear Proteins, Exons, Phosphoproteins, Pedigree, DNA-Binding Proteins, Diabetes Mellitus, Type 2, Hepatocyte Nuclear Factor 4, embryonic structures, Hepatocyte Nuclear Factor 1, Female, Chromosome 20, Chromosomes, Human, Pair 7, Transcription Factors
Abstract

Maturity-onset diabetes of the young (MODY) is a heterogeneous subtype of non-insulin-dependent diabetes mellitus characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date five MODY genes have been identified: hepatocyte nuclear factor-4 alpha (HNF-4 α/MODY1/TCF14) on chromosome 20 q, glucokinase (GCK/MODY2) on chromosome 7 p, hepatocyte nuclear factor-1 alpha (HNF-1 α/MODY3/TCF1) on chromosome 12 q, insulin promoter factor-1 (IPF1/MODY4) on chromosome 13 q and hepatocyte nuclear factor-1 beta (HNF-1 β/MODY5/TCF2) on chromosome 17cen-q. We have screened the HNF-4 α, HNF-1 α and HNF-1 β genes in members of 18 MODY kindreds who tested negative for glucokinase mutations. Five missense (G31D, R159W, A161T, R200W, R271W), one substitution at the splice donor site of intron 5 (IVS5nt + 2T→A) and one deletion mutation (P379fsdelT) were found in the HNF-1 α gene, but no MODY-associated mutations were found in the HNF-4 α and HNF-1 β genes. Of 67 French MODY families that we have now studied, 42 (63 %) have mutations in the glucokinase gene, 14 (21 %) have mutations in the HNF-1 α gene, and 11 (16 %) have no mutations in the HNF-4 α, IPF1 and HNF-1 β genes. Eleven families do not have mutations in the five known MODY genes suggesting that there is at least one additionnal locus that can cause MODY. [Diabetologia (1998) 41: 1017–1023]

Published
1998

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