DNA methylation profiling of CD04+/CD08+ T cells reveals pathogenic mechanisms in increasing hyperglycemia: PIRAMIDE pilot study

Giuditta Benincasa; Monica Franzese; Concetta Schiano; Raffaele Marfella; Marco Miceli; Teresa Infante; Celestino Sardu; Mario Zanfardino; Ornella Affinito; Gelsomina Mansueto; Linda Sommese; Giovanni Francesco Nicoletti; Marco Salvatore; Giuseppe Paolisso; Claudio Napoli

doi:10.1016/j.amsu.2020.10.016

DNA methylation profiling of CD04⁺/CD08⁺ T cells reveals pathogenic mechanisms in increasing hyperglycemia: PIRAMIDE pilot study

Ann Med Surg (Lond). 2020 Oct 20:60:218-226. doi: 10.1016/j.amsu.2020.10.016. eCollection 2020 Dec.

Authors

Giuditta Benincasa¹, Monica Franzese², Concetta Schiano¹, Raffaele Marfella¹, Marco Miceli², Teresa Infante¹, Celestino Sardu¹, Mario Zanfardino², Ornella Affinito², Gelsomina Mansueto³, Linda Sommese¹, Giovanni Francesco Nicoletti⁴, Marco Salvatore², Giuseppe Paolisso¹, Claudio Napoli^{1

2

3}

Affiliations

¹ Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", 80138, Naples, Italy.
² IRCCS SDN, 80143, Naples, Italy.
³ Clinical Department of Internal Medicine and Specialistics, Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", 80138, Naples, Italy.
⁴ Multidisciplinary Department of Medical, Surgical and Dental Sciences, Plastic Surgery Unit University of Campania "Luigi Vanvitelli", 80138, Naples, Italy.

Abstract

Background: DNA methylation can play a pathogenic role in the early stages of hyperglycemia linking homeostasis imbalance and vascular damage.

Material and methods: We investigated DNA methylome by RRBS in CD04⁺ and CD08⁺ T cells from healthy subjects (HS) to pre-diabetics (Pre-Diab) and type 2 diabetic (T2D) patients to identify early biomarkers of glucose impairment and vascular damage. Our cross-sectional study enrolled 14 individuals from HS state to increasing hyperglycemia (pilot study, PIRAMIDE trial, NCT03792607).

Results: Globally, differentially methylated regions (DMRs) were mostly annotated to promoter regions. Hypermethylated DMRs were greater than hypomethylated in CD04⁺ T cells whereas CD08⁺ T showed an opposite trend. Moreover, DMRs overlapping between Pre-Diab and T2D patients were mostly hypermethylated in both T cells. Interestingly, SPARC was the most hypomethylated gene in Pre-Diab and its methylation level gradually decreased in T2D patients. Besides, SPARC showed a significant positive correlation with DBP (+0.76), HDL (+0.54), Creatinine (+0.83), LVDd (+0.98), LVSD (+0.98), LAD (+0.98), LVPWd (+0.84), AODd (+0.81), HR (+0.72), Triglycerides (+0.83), LAD (+0.69) and AODd (+0.52) whereas a negative correlation with Cholesterol (-0.52) and LDL (-0.71) in T2D.

Conclusion: SPARC hypomethylation in CD08⁺ T cells may be a useful biomarker of vascular complications in Pre-Diab with a possible role for primary prevention warranting further multicenter clinical trials to validate our findings.

Keywords: Cardiovascular complications; DNA methylation; Prediabetes; T cells; Type 2 diabetes.

Associated data

ClinicalTrials.gov/NCT03792607