Whole blood methylome-derived features to discriminate endocrine hypertension

Armignacco, R. et al. (2022) Whole blood methylome-derived features to discriminate endocrine hypertension. Clinical Epigenetics, 14, 142. (doi: 10.1186/s13148-022-01347-y) (PMID:36329530) (PMCID:PMC9635165)

Abstract

Background: Arterial hypertension represents a worldwide health burden and a major risk factor for cardiovascular morbidity and mortality. Hypertension can be primary (primary hypertension, PHT), or secondary to endocrine disorders (endocrine hypertension, EHT), such as Cushing's syndrome (CS), primary aldosteronism (PA), and pheochromocytoma/paraganglioma (PPGL). Diagnosis of EHT is currently based on hormone assays. Efficient detection remains challenging, but is crucial to properly orientate patients for diagnostic confirmation and specific treatment. More accurate biomarkers would help in the diagnostic pathway. We hypothesized that each type of endocrine hypertension could be associated with a specific blood DNA methylation signature, which could be used for disease discrimination. To identify such markers, we aimed at exploring the methylome profiles in a cohort of 255 patients with hypertension, either PHT (n = 42) or EHT (n = 213), and at identifying specific discriminating signatures using machine learning approaches. Results: Unsupervised classification of samples showed discrimination of PHT from EHT. CS patients clustered separately from all other patients, whereas PA and PPGL showed an overall overlap. Global methylation was decreased in the CS group compared to PHT. Supervised comparison with PHT identified differentially methylated CpG sites for each type of endocrine hypertension, showing a diffuse genomic location. Among the most differentially methylated genes, FKBP5 was identified in the CS group. Using four different machine learning methods—Lasso (Least Absolute Shrinkage and Selection Operator), Logistic Regression, Random Forest, and Support Vector Machine—predictive models for each type of endocrine hypertension were built on training cohorts (80% of samples for each hypertension type) and estimated on validation cohorts (20% of samples for each hypertension type). Balanced accuracies ranged from 0.55 to 0.74 for predicting EHT, 0.85 to 0.95 for predicting CS, 0.66 to 0.88 for predicting PA, and 0.70 to 0.83 for predicting PPGL. Conclusions: The blood DNA methylome can discriminate endocrine hypertension, with methylation signatures for each type of endocrine disorder.

• Item Type: Articles
• Additional Information: Funding This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633983, the Programme Hospitalier de Recherche Clinique “CompliCushing” (PHRC AOM 12-002-0064), the Agence Nationale pour la Recherche (ANR-18-CE14-0008-01), the Else Kröner-Fresenius Stiftung (2012_A103 and 2015_A228 to MR) and the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio 205/1 “The Adrenal: Central Relay in Health and Disease” (to MR, FB, AR). The work was further supported by the Clinical Research Priority Program of the University of Zurich for the CRPP HYRENE (to FB).
• Keywords: Research, Endocrine hypertension, Whole blood methylome, Circulating biomarker
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jefferson, Professor Emily and Davies, Professor Eleanor and MacKenzie, Dr Scott
• Authors: Armignacco, R., Reel, P. S., Reel, S., Jouinot, A., Septier, A., Gaspar, C., Perlemoine, K., Larsen, C. K., Bouys, L., Braun, L., Riester, A., Kroiss, M., Bonnet-Serrano, F., Amar, L., Blanchard, A., Gimenez-Roqueplo, A.-P., Prejbisz, A., Januszewicz, A., Dobrowolski, P., Davies, E., MacKenzie, S. M., Rossi, G. P., Lenzini, L., Ceccato, F., Scaroni, C., Mulatero, P., Williams, T. A., Pecori, A., Monticone, S., Beuschlein, F., Reincke, M., Zennaro, M.-C., Bertherat, J., Jefferson, E., and Assié, G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health
• Journal Name: Clinical Epigenetics
• Publisher: BioMed Central
• ISSN: 1868-7075
• ISSN (Online): 1868-7083
• Published Online: 03 November 2022
• Copyright Holders: Copyright © The Author(s) 2022
• First Published: First published in Clinical Epigenetics 14: 142
• Publisher Policy: Reproduced under a Creative Commons License