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Anguita-Ruiz, A.* ; Torres-Martos, A.* ; Bustos-Aibar, M.* ; Setó-Llorens, A.* ; Ruiz Ojeda, F.J. ; Moreno, L.A.* ; Gil, A.* ; Gil-Campos, M.* ; Bueno, G.* ; Leis, R.* ; Alcalá-Fdez, J.* ; Aguilera, C.M.*

Novel epigenetic marks of insulin resistance trajectories in a longitudinal study of childhood obesity.

Cardiovasc. Diabetol. 25:105 (2026)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Background Childhood obesity is a major global public-health challenge. Insulin resistance (IR) is a critical driver oflater cardiometabolic alterations. A comprehensive understanding of the molecular mechanisms underlying the initialdevelopment of childhood IR is essential for timely prevention and intervention. In this study, we aimed to assess theassociation between IR and blood DNA methylation in a longitudinal study from childhood into adolescence.Methods The PUBMEP study included a longitudinal core of 90 children with paired blood samples collected at bothpre-pubertal and pubertal stages. For cross-sectional analyses, this sample was expanded to 99 pre-pubertal and 129pubertal participants. IR status was defined according to clinically relevant sex- and pubertal stage specific HOMA-IRcut-offs, as recommended by pediatric expert clinicians. Genotype data was obtained with the Infinium GlobalScreening Array, and blood DNA methylation sites with the Infinium MethylationEPIC BeadChip. Epigenome-wideassociations with IR status and trajectories were tested using linear models in the longitudinal and cross-sectional sets.FDR-adjusted significant CpG sites were assessed with sex- and age-standardised cardiometabolic z-scores (adiposity,lipids, blood pressure, glycaemia and IR) at each stage. mQTL analyses were performed to identify genetic variantsthat drive IR-associated methylation signals.Results We identified 120 CpG sites related to obesity-associated IR in the context of pubertal transition thatremained significant after global FDR correction (FDR < 0.05). These CpG sites showed distinct methylation profilesthat tracked IR trajectories from prepuberty to puberty, with consistent differences across children whose IRimproved, worsened or remained stable, with several of them also related to cardiometabolic traits at pubertalstage, including adiposity measures, blood pressure and glycaemic indices. Among the FDR-significant CpG siteswith biological relevance for IR, methylation at CpG sites annotated to SLC2A9, PEPD, TSC2, EGLN3, EHD2 and VASNshowed consistent associations with pubertal HOMA-IR z-score and, for several loci, with adiposity and blood pressure.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cardiometabolic Risk Factors ; Dna Methylation ; Ewas ; Epigenetics ; Epigenome-wide Association Study ; Insulin Resistance ; Longitudinal Study ; Pediatric Obesity ; Puberty ; Whole-genome Genotype ; Mqtl; Body-mass Index; Genome-wide Association; Dna Methylation; Epigenome-wide; Homa-ir; Loci; Children; Growth; Gene; Identification
ISSN (print) / ISBN 1475-2840
e-ISSN 1475-2840
Zeitschrift Cardiovascular Diabetology
Quellenangaben Band: 25, Heft: 1, Seiten: , Artikelnummer: 105 Supplement: ,
Verlag Springer
Verlagsort Campus, 4 Crinan St, London N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) Adipocytes & Metabolism (ADM)
Förderungen 'la Caixa' Foundation
Instituto de Salud Carlos III
HORIZON EUROPE Framework Programme