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New insights into relationships between genetic risk factors for type 2 diabetes and metabolic conditions

A new study found that groups of genetic variations that increase the risk of type 2 diabetes may also influence the risk of developing associated metabolic conditions. Type 2 diabetes increases people’s risk of developing serious and often life-threatening complications, such as cardiovascular disease and kidney failure. Because there is so much variability in whether or not individuals with type 2 diabetes develop these clinical outcomes, better understanding of genetic risk factors and the associated complications could help advance personalized patient care and improve prevention and treatment approaches.

In previous research, scientists used data from a large-scale cohort study to identify genetic variations that predispose an individual to type 2 diabetes and were able to group them into several subgroups based on the type of genetic mechanisms that led to the disease. For instance, within the group of genetic variations that affect the body’s glucose (sugar) uptake and increase insulin resistance, the scientists identified three subgroups, or “clusters,” that also increase people’s risk for obesity, lipodystrophy (a disorder that affects how the body accumulates and stores fat), and disrupted liver lipid metabolism. In this new study, the research team analyzed individual-level genetic data from a total of 454,193 participants, including 25,015 individuals with type 2 diabetes, in 13 cohort studies to determine whether these clusters were also associated with other clinical outcomes such as high blood pressure, coronary artery disease, and reduced kidney function. Even though all clusters included genetic variations that increase type 2 diabetes risk, there were differential associations with cardiovascular disease risk and kidney function. For example, coronary artery disease risk was decreased in the disrupted liver lipid metabolism cluster, whereas the risk was higher in the lipodystrophy cluster. Clusters for obesity and lipodystrophy were both associated with higher blood pressure, and the disrupted liver lipid metabolism cluster was associated with reduced kidney function.

Although not yet ready for use in a clinical setting, knowing whether and how someone with type 2 diabetes genetic risk factors could be predisposed to cardiovascular diseases or metabolic conditions could one day be a useful tool for not only predicting disease risk and informing patient management, but also classifying participants for clinical studies. Further research to clarify relationships between type 2 diabetes genetic risk, cardiovascular risk, and metabolic function will also provide insight into complex biological mechanisms underlying type 2 diabetes and may even lead to new targets for drug development.

DiCorpo D, LeClair J, Cole JB, …Udler MS. Type 2 diabetes partitioned polygenic scores associate with disease outcomes in 454,193 individuals across 13 cohorts. Diabetes Care 45: 674-683, 2022.

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