Underestimated risk of secondary complications in pathogenic and glucose-elevating GCK variant carriers with type 2 diabetes

Abstract

Natural HbA1c levels in GCK Maturity-onset diabetes of the young (GCK-MODY) patients often sit above the diagnostic threshold for type 2 diabetes (T2D). Treatments to lower HbA1c levels show reduced effectiveness in these individuals, yet in case studies to date, GCK-MODY patients often evade secondary T2D complications. Given these deviations, genetic screening of GCK may be clinically useful, but population studies are needed to more broadly understand T2D-related complications in GCK variant carriers. To identify GCK variant carriers at the population level, we used both ACMG/AMP variant interpretation for GCK-MODY pathogenicity and a state-of-the-art variant interpretation strategy based on functional and statistical evidence to predict glucose elevations. Presence of pathogenic and glucose-elevating GCK variants was assessed in two cohorts (n~535,000). We identified 442 individuals with GCK variants predicted to increase glucose (~1/1200), with 150 (34%) of these individuals harboring variants reaching a pathogenic interpretation. In a retrospective analysis, we show that in addition to elevated HbA1c, pathogenic variant carriers are 10x as likely, and all other glucose-elevating GCK variant carriers are 3x as likely, to receive a T2D diagnosis compared to non-GCK carriers. Surprisingly, carriers of pathogenic and glucose-elevating GCK variants with T2D develop T2D-related complications at rates more than double that of individuals without T2D, comparable to non-GCK individuals with T2D. This population-level assessment shows secondary complications in individuals with pathogenic and glucose-elevating GCK variants and T2D and suggests that genotyping for these variants should be considered in a precision medicine approach for T2D treatment and prevention. This study investigates the role of the GCK gene in Type 2 Diabetes (T2D). Variations in the GCK gene are known to cause a form of diabetes that is characterized by early onset and stable blood sugar levels, with a low risk of the type of complications often experienced by people with other causes of T2D. However, our study of a large number of people living in both the United Kingdom and the United States shows that some specific variations in the GCK gene give people a higher risk of developing T2D with the typical secondary complications. This suggests that knowledge of GCK variation in a person should be considered when optimizing T2D prevention and treatment strategies. Schiabor Barrett et al evaluate variants in GCK, a gene associated with Monogenic Diabetes of the Young (MODY), in two population cohorts with healthcare records. They find that participants with pathogenic MODY and other glucose-elevating variants are at risk for Type 2 Diabetes (T2D) and those with T2D show secondary complications of T2D.