Title of project

Genetic and metabolic modifiers of hyperglycemia: Functional and clinical evaluation of HNF1A A98V in Danish and Norwegian cohorts

Abstract

This application seeks support for a sabbatical research stay in Professor Torben Hansen’s group at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen. The visit will strengthen ongoing collaboration between Danish and Norwegian diabetes researchers as part of the Bergenhagen Initiative and will focus on understanding genetic and metabolic modifiers of hyperglycemia. The primary project investigates the functional and clinical impact of the missense variant HNF1A A98V. Since it is common in the population, our findings might affect diagnosis and treatment of thousands of people making the variant of special interest. We will use data from well-characterized cohorts: The Inter99 and the DD2 (Denmark), and Norwegian and Danish MODY cohorts as well as the UKBB. These resources span both polygenic type 2 diabetes (T2) and monogenic diabetes contexts, offering a unique opportunity to assess the context-dependent effects of A98V on glycemia and treatment response.

The study combines statistical genetics, polygenic risk modeling, and functional assays to determine whether A98V acts as an intermediate-effect variant and whether it interacts with polygenic background to modulate disease risk or sulfonylurea sensitivity. Preliminary analyses suggest a non-additive, exponential increase in diabetes risk among A98V carriers with high T2D polygenic risk scores, which may also point towards enhanced therapeutic responsiveness. The one-year sabbatical stay will enable deep integration with Danish expertise in genomics, proteomics, and cohort-based translational research. It will also contribute to DDEA education and networking activities, foster knowledge exchange between institutions, and lay the foundation for future joint projects, including a Center of Excellence proposal and international grant applications.