Blood epigenetic remodeling in asthma associated with biologic therapy
- 1Genomics and Health Group, University of La Laguna, Spain; Instituto de Tecnologias Biomedicas (ITB), Spain; CIBER de Enfermedades Respiratorias (CIBERES), Insi
Abstract
BackgroundPolygenic risk scores (PRS) capture inherited susceptibility to asthma, whereas methylation risk scores (MRS) may reflect disease-associated epigenetic variation. We assessed whether these scores differ in patients requiring biologic therapy and whether MRS change after mepolizumab initiation.
MethodsCross-sectional analyses in the GEMAS study included 699 participants with genotype data (428 with asthma, 271 controls) and 668 with blood DNA methylation data (408 with asthma, 260 controls). We evaluated 35 existing asthma PRS and derived six MRS from published epigenomic asthma studies. Longitudinal MRS changes after mepolizumab initiation were assessed in 16 GEMAS patients and were replicated in 20 patients from the MEGA study.
ResultsTwenty-eight PRS differentiated biologic-treated patients from controls (areas under the curve [AUC], 0.68-0.75), but none distinguished biologic-treated and non-treated patients after multiple-testing correction. MRS was higher in asthma without biologic than in controls (odds ratio [OR], 1.64; 95% CI, 1.34-1.99) and lower in biologic-treated than in asthma without biologic patients (OR, 0.54; 95% CI, 0.35-0.81). MRS did not differ significantly between biologic-treated patients and controls. Following mepolizumab initiation, MRS decreased at 6 and 12 months in GEMAS (p=4.81x10-5 and p=2.40x10-5, respectively). The 6-month decrease was also observed in MEGA (p=3.25x10-9). MRS epigenetic markers were predominantly hypermethylated, opposite to their described pattern in asthma risk.
ConclusionsAsthma PRS did not differ significantly between biologic-treated and non-biologic-treated patients, but asthma MRS were lower in biologic-treated patients. The MRS decreased after mepolizumab initiation in two independent cohorts, consistent with a reversal of asthma-associated epigenetic patterns.
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BibTeX
@misc{martinalmeida2026blood,
title = {{Blood epigenetic remodeling in asthma associated with biologic therapy}},
author = {M. Martin-Almeida and J. Perez-Garcia and E. Martin-Gonzalez and P. Poza-Guedes and J. Antonio-Canas and I. Sanchez-Machin and J. M. Hernandez-Perez and D. Gonzalez-Garcia and E. Mederos-Luis and B. Roman-Bernal and J. Villar and M. Valverde-Monge and D. Betancor and M. J. Rodriguez-Nieto and F. Lorenzo-Diaz and V. del Pozo and R. Gonzalez-Perez and M. Pino-Yanes},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.26363868},
url = {https://www.medrxiv.org/content/10.64898/2026.09.24.26363868v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Blood epigenetic remodeling in asthma associated with biologic therapy
AU - M. Martin-Almeida
AU - J. Perez-Garcia
AU - E. Martin-Gonzalez
AU - P. Poza-Guedes
AU - J. Antonio-Canas
AU - I. Sanchez-Machin
AU - J. M. Hernandez-Perez
AU - D. Gonzalez-Garcia
AU - E. Mederos-Luis
AU - B. Roman-Bernal
AU - J. Villar
AU - M. Valverde-Monge
AU - D. Betancor
AU - M. J. Rodriguez-Nieto
AU - F. Lorenzo-Diaz
AU - V. del Pozo
AU - R. Gonzalez-Perez
AU - M. Pino-Yanes
PY - 2026
DA - 2026/09/24
PB - medRxiv
DO - 10.64898/2026.09.24.26363868
UR - https://www.medrxiv.org/content/10.64898/2026.09.24.26363868v1
AB - BackgroundPolygenic risk scores (PRS) capture inherited susceptibility to asthma, whereas methylation risk scores (MRS) may reflect disease-associated epigenetic variation. We assessed whether these scores differ in patients requiring biologic therapy and whether MRS change after mepolizumab initiation. MethodsCross-sectional analyses in the GEMAS study included 699 participants with genotype data (428 with asthma, 271 controls) and 668 with blood DNA methylation data (408 with asthma, 260 controls). We evaluated 35 existing asthma PRS and derived six MRS from published epigenomic asthma studies. Longitudinal MRS changes after mepolizumab initiation were assessed in 16 GEMAS patients and were replicated in 20 patients from the MEGA study. ResultsTwenty-eight PRS differentiated biologic-treated patients from controls (areas under the curve [AUC], 0.68-0.75), but none distinguished biologic-treated and non-treated patients after multiple-testing correction. MRS was higher in asthma without biologic than in controls (odds ratio [OR], 1.64; 95% CI, 1.34-1.99) and lower in biologic-treated than in asthma without biologic patients (OR, 0.54; 95% CI, 0.35-0.81). MRS did not differ significantly between biologic-treated patients and controls. Following mepolizumab initiation, MRS decreased at 6 and 12 months in GEMAS (p=4.81x10-5 and p=2.40x10-5, respectively). The 6-month decrease was also observed in MEGA (p=3.25x10-9). MRS epigenetic markers were predominantly hypermethylated, opposite to their described pattern in asthma risk. ConclusionsAsthma PRS did not differ significantly between biologic-treated and non-biologic-treated patients, but asthma MRS were lower in biologic-treated patients. The MRS decreased after mepolizumab initiation in two independent cohorts, consistent with a reversal of asthma-associated epigenetic patterns.
ER -