Your browser doesn't support javascript.
loading
Genetic determinants of type 1 diabetes in individuals with weak evidence of islet autoimmunity at disease onset.
Carrera, Paola; Marzinotto, Ilaria; Bonfanti, Riccardo; Massimino, Luca; Calzavara, Silvia; Favellato, Μariagrazia; Jofra, Tatiana; De Giglio, Valeria; Bonura, Clara; Stabilini, Angela; Favalli, Valeria; Bondesan, Simone; Cicalese, Maria Pia; Laurenzi, Andrea; Caretto, Amelia; Frontino, Giulio; Rigamonti, Andrea; Molinari, Chiara; Scavini, Marina; Sandullo, Federica; Zapparoli, Ettore; Caridi, Nicoletta; Bonfiglio, Silvia; Castorani, Valeria; Ungaro, Federica; Petrelli, Alessandra; Barera, Graziano; Aiuti, Alessandro; Bosi, Emanuele; Battaglia, Manuela; Piemonti, Lorenzo; Lampasona, Vito; Fousteri, Georgia.
Afiliação
  • Carrera P; Unit of Genomics for Human Disease Diagnosis, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Marzinotto I; Laboratory of Clinical Molecular Biology, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Bonfanti R; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Massimino L; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Calzavara S; Vita-Salute San Raffaele University, Milan, Italy.
  • Favellato Μ; Department of Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele Hospital, Milan, Italy.
  • Jofra T; Laboratory of Clinical Molecular Biology, IRCCS Ospedale San Raffaele, Milan, Italy.
  • De Giglio V; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Bonura C; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Stabilini A; Pediatric Department, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Favalli V; Pediatric Department, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Bondesan S; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Cicalese MP; Pediatric Department, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Laurenzi A; Unit of Genomics for Human Disease Diagnosis, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Caretto A; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Frontino G; Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Rigamonti A; Department of Internal Medicine, Diabetology, Endocrinology and Metabolism, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Molinari C; Department of Internal Medicine, Diabetology, Endocrinology and Metabolism, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Scavini M; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Sandullo F; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Zapparoli E; Department of Internal Medicine, Diabetology, Endocrinology and Metabolism, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Caridi N; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Bonfiglio S; Department of Internal Medicine, Diabetology, Endocrinology and Metabolism, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Castorani V; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Ungaro F; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Petrelli A; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Barera G; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Aiuti A; Pediatric Department, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Bosi E; Department of Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele Hospital, Milan, Italy.
  • Battaglia M; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Piemonti L; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Lampasona V; Vita-Salute San Raffaele University, Milan, Italy.
  • Fousteri G; Pediatric Department, IRCCS Ospedale San Raffaele, Milan, Italy.
Diabetologia ; 66(4): 695-708, 2023 04.
Article em En | MEDLINE | ID: mdl-36692510
AIMS/HYPOTHESIS: Islet autoantibodies (AAbs) are detected in >90% of individuals with clinically suspected type 1 diabetes at disease onset. A single AAb, sometimes at low titre, is often detected in some individuals, making their diagnosis uncertain. Type 1 diabetes genetic risk scores (GRS) are a useful tool for discriminating polygenic autoimmune type 1 diabetes from other types of diabetes, particularly the monogenic forms, but testing is not routinely performed in the clinic. Here, we used a type 1 diabetes GRS to screen for monogenic diabetes in individuals with weak evidence of autoimmunity, i.e. with a single AAb at disease onset. METHODS: In a pilot study, we genetically screened 142 individuals with suspected type 1 diabetes, 42 of whom were AAb-negative, 27 of whom had a single AAb (single AAb-positive) and 73 of whom had multiple AAbs (multiple AAb-positive) at disease onset. Next-generation sequencing (NGS) was performed in 41 AAb-negative participants, 26 single AAb-positive participants and 60 multiple AAb-positive participants using an analysis pipeline of more than 200 diabetes-associated genes. RESULTS: The type 1 diabetes GRS was significantly lower in AAb-negative individuals than in those with a single and multiple AAbs. Pathogenetic class 4/5 variants in MODY or monogenic diabetes genes were identified in 15/41 (36.6%) AAb-negative individuals, while class 3 variants of unknown significance were identified in 17/41 (41.5%). Residual C-peptide levels at diagnosis were higher in individuals with mutations compared to those without pathogenetic variants. Class 3 variants of unknown significance were found in 11/26 (42.3%) single AAb-positive individuals, and pathogenetic class 4/5 variants were present in 2/26 (7.7%) single AAb-positive individuals. No pathogenetic class 4/5 variants were identified in multiple AAb-positive individuals, but class 3 variants of unknown significance were identified in 19/60 (31.7%) patients. Several patients across the three groups had more than one class 3 variant. CONCLUSIONS/INTERPRETATION: These findings provide insights into the genetic makeup of patients who show weak evidence of autoimmunity at disease onset. Absence of islet AAbs or the presence of a single AAb together with a low type 1 diabetes GRS may be indicative of a monogenic form of diabetes, and use of NGS may improve the accuracy of diagnosis.
Assuntos
Palavras-chave

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Diabetes Mellitus Tipo 1 Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Diabetes Mellitus Tipo 1 Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article