Towards precision medicine: insights into the molecular pathogenesis of early-onset type 2 diabetes.

Proponente Vincenzo Trischitta - Professore Ordinario
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Componente Categoria
Susanna Morano Componenti il gruppo di ricerca
Giuseppe Pugliese Componenti il gruppo di ricerca
Componente Qualifica Struttura Categoria
Serena Pezzilli Dottorando di Ricerca in Genetica Medica Dipartimento di Medicina Sperimentale, Università "Sapienza", Roma Altro personale Sapienza o esterni
Sabrina Prudente Dirigente Biologo IRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG) Altro personale Sapienza o esterni

Type 2 diabetes, T2D, is a complex disorder with heterogeneous backgrounds. Several disease forms could belong to a context named today as T2D, with a wide spectrum ranging from mono-and/or oligogenic forms, often with an early onset disease, to polygenic ones, due to environment and predisposing genetic background. Our aim is to verify, by a Next Generation Sequencing (NGS) approach, whether Italian patients with early-onset T2D are enriched for mutations in monogenic diabetes genes (MODY and Neonatal Diabetes, ND) than patients with late-onset disease. We will study 4730 T2D patients from 6 Italian T2D study-cohorts. Among these, 300 individuals with age at diagnosis 65 years (late-onset T2D, used as "super controls") will be screened. DNA will be subjected to NGS targeted of 27 MODY- and ND- genes by a custom panel (TSCA Illumina) on MiSeq-Illumina platform. All identified variants will be classified by a filtering/prioritization strategy, based on quality, allele frequency, predicted functional impact and absence in our in-house database. Statistical analyses by burden tests will be carried out to evaluate statistically significant differences in the distribution of MODY-/ND-genes mutations in two study-groups. While tailored, pharmacological treatment is a reality for monogenic diabetes, this is not the case in patients with T2D. Thus, defining the role of MODY and ND-gene mutations in patients with early-onset T2D will help: a) to guide most appropriate clinical and pharmacological treatment for their specific genetic subtype; b) to anticipate long-term clinical evolution and risk of complications; c) to perform genetic counseling in their families. This will be of importance both in children with incidental hyperglycemia and in undiagnosed patients; it could lead also to reclassifying diabetes in patients previously misdiagnosed as having "classical" T2D, with benefits on therapeutic options.


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