Inflammation, Global DNA Methylation and Telomeres in Healthy Adolescents
Authors: Dong Yutong , Huang Ying , Gutin Bernard , Dong Yanbin , Zhu Haidong 
Published: November 2023

IntroductionLeukocyte telomere length (LTL) is a biomarker for cellular aging and diseases. Its shortening increases genome instability, encouraging susceptibility to various diseases, including cancer. Likewise, global DNA hypomethylation, an epigenetic mechanism, increases genome instability and disease susceptibility. Inflammation is a risk factor for both LTL shortening and global DNA hypomethylation as well as various diseases. Limited studies have suggested that global DNA methylation is an epigenetic mechanism in regulating LTL in adult patient populations. However, the relationships among global DNA methylation, LTL and the influence of inflammation have not been investigated in healthy and young populations.HypothesisOur three hypothese were: (1) that global DNA methylation level would be positively associated with LTL; (2) that higher levels of inflammation would be associated with lower global DNA methylation level and shorter LTL; and (3) that global DNA methylation level might mediate the relationship between inflammation and LTL.MethodsSix hundred and seventeen apparently healthy, Southeastern US adolescents from age 14 to 18 years old were previously recruited (50.3% females; 49.2% African‐Americans). BMI was calculated from recordings of height and weight. Physical activity (PA) was determined via accelerometry. Fasting blood samples were measured for C‐reactive protein, resistin, tumor necrosis factor‐alpha, and intercellular adhesion molecular‐1 (ICAM‐1). LTL (T/S ratio) was measured by quantitative polymerase chain reaction. Global DNA methylation level (percentage of 5‐methylcytosine, %5‐mC) was quantified using leukocyte DNA with MethylflashTM Methylated DNA Quantification Kit (Epigentek).ResultsMultiple linear regressions, adjusting for age, sex, race, Tanner stage, BMI, PA, and batch effect revealed that %5mC was positively associated with LTL (standardized β = 0.147, p = 0.00). Additionally, resistin was found to be negatively associated with %5mC and with LTL (β = −0.210, β = −0.099, all p ≤0.03). ICAM‐1 was also found to be inversely associated with %5mC (β = −0.134, p = 0.01), but not with LTL (β = −0.065, p = 0.22). Resistin was positively associated with ICAM‐1 (β = 0.120, p < 0.01). To explore the potential underlying mechanism, a mediation test was conducted, which identified %5mC as a mediator between resistin and LTL (indirect effect = −0.015; 95% CI: −0.032, −0.004) but not between ICAM‐1 and LTL (indirect effect = −0.004; 95% CI: −0.002, 0.000).ConclusionsOur study was the first to show that global DNA methylation level was positively associated with LTL in healthy adolescents. Moreover, inflammatory biomarkers were inversely associated with global DNA methylation level and LTL, potentially increasing genome instability and disease susceptibility. Global DNA methylation, an epigenetic mechanism, may mediate the relationship between inflammation and LTL. Future studies, in particular longitudinal studies, are warranted to establish the effects of global DNA methylation on LTL maintenance over time and the influence of inflammation on DNA methylation and LTL.Support or Funding InformationThe study was supported by National Institute of Health (HL064157).