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Hypertension is common in youth with type 2 diabetes (T2D), increasing risk of cardiovascular disease. The mechanisms underlying the high burden of hypertension in youth with T2D remains incompletely understood.
We conducted an in-depth analysis of 7604 Aptamers in 374 baseline and 10-year follow-up plasma samples from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study using the SomaScan 7K Proteomic platform. Blood pressure was obtained at every visit, with hypertension defined as systolic blood pressure ≥ 130mmHg, and/or diastolic blood pressure ≥ 80mmHg, or blood pressure ≥ 95th percentile for age, sex, and height on three consecutive occasions or elevated blood pressure followed by initiation of anti-hypertensive therapy. To substantiate our findings, we analyzed top proteins in an independent cohort of youth with T2D (n=19), including both SomaScan and Olink proteomic data (Figure 1).
Figure 1. Consort figure.
In the TODAY study (mean age 14±2 years, 63% female, average diabetes duration 7±6 months), 61% of the participants developed hypertension over 15 years. Incident hypertension was associated with upregulation of pathways related to metabolism of amino acid and carbohydrates, biological and ethanol oxidations, and downregulation of pathways involved in extracellular matrix organization and glycosaminoglycan metabolism, and regulation of insulin-like growth factor transport and uptake (Figure 2). In our analysis of proteomic pathways comparing baseline and 10-year samples, we identified both shared and unique enriched pathways. Pathways related to inflammation and oxidative stress were upregulated in the 10-year follow-up samples, whereas those associated with perturbed metabolism were upregulated in the baseline samples (Figure 3). Next, we assessed the top proteins identified as predictors of hypertension onset in the TODAY study for their correlation with mean arterial pressure (MAP) in an independent cross-sectional cohort of youth with T2D. The top 5 proteins, Seizure 6-like protein (SEZ6L), Whey acidic protein, Kazal, immunoglobulin, Kunitz and Netrin domain-containing protein 2 (WFKN2), Secretogranin-3 (SCG3), Heparan-sulfate 6-O-sulfotransferase 3 (H6ST3), and Neuronal cell adhesion molecule (Nr-CAM), exhibited strong correlation with MAP in this cohort (Table 1).
Figure 2. Upregulated and downregulated pathways in the TODAY study, based on over-representation analysis using results of the adjusted Cox proportional hazards models and the Reactome database.
Figure 3.Baseline FU
Our findings reveal novel proteomic pathways and proteins associated with hypertension in youth with T2D, offering potential avenues for early detection and targeted therapeutic development.