Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes
2013
Bonnefond, A. | Yengo, L. | Philippe, J. | Dechaume, A. | Ezzidi, I. | Vaillant, E. | Gjesing, A. P. | Andersson, E. A. | Czernichow, S. | Hercberg, Serge | Hadjadj, S. | Charpentier, G. | Lantieri, O. | Balkau, B. | Marre, M. | Pedersen, O. | Hansen, T. | Froguel, P. | Vaxillaire, M. | Institut Pasteur de Lille ; Pasteur Network (Réseau International des Instituts Pasteur) | Université Lille Nord de France (COMUE) | جامعة المنستير - Université de Monastir - University of Monastir (UM) | 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 (UC)-University of California (UC) | 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) | Unité de Recherche en Epidémiologie Nutritionnelle (UREN) ; Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [Cnam] (Cnam)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM) | Hôpital Avicenne [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) | Centre hospitalier universitaire de Poitiers = Poitiers University Hospital (CHU de Poitiers [La Milétrie]) | INSERM CIC 0802 (INSERM - CHU de Poitiers) ; Université de Poitiers = University of Poitiers (UP)-Centre hospitalier universitaire de Poitiers = Poitiers University Hospital (CHU de Poitiers [La Milétrie])-Institut National de la Santé et de la Recherche Médicale (INSERM) | 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] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) | 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 | ANR-10-EQPX-0007,LIGAN PM,Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée(2010)
International audience
Mostrar más [+] Menos [-]Inglés. 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.
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