Type 2 diabetes (T2D) is a complex, widespread condition influenced by both lifestyle and genetic factors. While previous research has shed light on common genetic variants linked to T2D, rare genetic mutations, which may also play a crucial role, have been less explored. This article dives into a recent research conducted by Huerta-Chagoya et al., 2024, that analyzed a massive dataset of over 420,000 individuals to study the impact of rare genetic variants on T2D. The findings reveal new high-risk variants and offer insights into precision medicine, especially in identifying and managing monogenic diabetes, a rare form caused by single-gene mutations.
Understanding the Role of Rare Variants in T2D
While over 40 genes have been identified as causes of monogenic diabetes, reliably distinguishing between pathogenic and benign variants within these genes remains challenging. Resources like ClinVar provide classifications of variant pathogenicity, as reported by various laboratories and researchers. However, misclassifications are not uncommon, particularly for older entries predating current gold-standard curation methods, and for variants more prevalent in populations that are underrepresented in genetic studies.
What Are Rare Variants? Rare genetic variants have a low occurrence in the general population (typically less than 1%). However, some of these variants can drastically influence disease risk, including that of T2D.
Key Findings from the Study
Newly Discovered Variants Linked to T2D:
Through advanced genetic tools like TOPMed imputation and whole-genome sequencing (WGS), the researchers uncovered 12 new genetic variants associated with T2D.
One notable discovery is a variant near the LEP gene, found mainly in African and African American populations, which increases T2D risk fourfold. This variant affects a region that regulates LEP, known for its role in fat cell function and insulin regulation.
HNF4A Variant and Its Link to T2D:
The study found a rare missense variant (a type of mutation leading to amino acid changes) in the HNF4A gene, known to cause maturity-onset diabetes of the young (MODY). This variant was shown to increase T2D risk eightfold. Despite being historically linked to MODY, this variant was identified in the context of T2D, highlighting a potential overlap between monogenic diabetes and common forms of diabetes.
Pathogenicity of Known Monogenic Diabetes Genes:
Researchers investigated over 1,600 rare variants across 22 genes known to cause monogenic diabetes. This allowed them to classify variants based on risk, including “benign” (low risk) and “variants of intermediate penetrance” (VIPs), which convey moderate risk. For example, they discovered VIPs in the genes HNF1A and GCK, each associated with significant T2D risk.
Significance of Polygenic Risk Scores in Diabetes Risk
What Are Polygenic Risk Scores (PRS)? A PRS estimates an individual’s genetic predisposition to a disease based on the combined effects of multiple common genetic variants. By integrating PRS with rare variant data, the researchers observed that the effect of rare, high-risk variants could be influenced by an individual’s PRS. This means that a person carrying a VIP, such as the HNF4A variant, may experience varying diabetes risk depending on their PRS.
Implications for Precision Medicine in Diabetes
Using Genetics to Tailor Treatments:
Identifying specific genetic causes for T2D opens the door to personalized treatments. For example, individuals with HNF1A mutations might benefit from sulfonylurea medications, while those with GCK mutations may avoid medication altogether.
Enhancing Diagnostic Accuracy:
Misdiagnosis is common, especially in non-European populations with rare genetic variants not well-represented in existing databases. By analyzing a wide spectrum of genetic variants across diverse ancestries, this study provides new data that could improve diagnostic tools and reduce disparities in diabetes care.
Refining Genetic Variant Classifications:
Many variants are labeled as “uncertain significance” (VUSs) because it’s unclear whether they increase disease risk. The study’s framework for evaluating genetic variants could help reclassify these VUSs, enabling more accurate genetic counseling and treatment planning.
Challenges and Future Directions
Population-Specific Data Needs:
The accuracy of risk assessments relies on robust data from diverse populations. This study demonstrated the importance of including individuals of non-European descent to identify population-specific risks, like the LEP variant linked to higher T2D risk in African populations.
Limitations in Variant Validation:
Although the study identified several VIPs, not all findings could be replicated due to limited sample sizes in some populations. Future research with larger and more diverse samples will be essential to validate these variants' effects comprehensively.
Combining Rare and Common Variants for Better Predictions:
This study revealed that common variants can modulate the effects of rare mutations, a concept that could be expanded upon in future research. Developing models that combine both rare and common variants could refine PRSs for more precise diabetes risk prediction.
References:
Huerta-Chagoya, A., Schroeder, P., Mandla, R. et al. Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes. Nat Genet (2024). https://doi.org/10.1038/s41588-024-01947-9
-Written by Sohni Tagore
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