Underestimated risk of secondary complications in pathogenic and glucose-elevating GCK variant carriers with type 2 diabetes
Abstract Background 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 patient...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-11-01
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| Series: | Communications Medicine |
| Online Access: | https://doi.org/10.1038/s43856-024-00663-z |
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| Summary: | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
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| ISSN: | 2730-664X |