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O5 Exploring the impact of genome-wide DNA methylation alterations on chromosome X inactivation and female lupus
  1. Olivia Castellini-Pérez1,
  2. Elena Povedano-Espejo1,2,
  3. Guillermo Barturen1,3,
  4. Abir Azri1,4,
  5. Ruth Dominguez1,
  6. Marta E Alarcón-Riquelme1 and
  7. Elena Carnero-Montoro1,3
  1. *Shared first authors, ** Shared last senior authors
  2. 1Pfizer – University of Granada – Andalusian Government Center for Genomics and Oncological Research (GENYO), Granada, Spain
  3. 2Spanish National Research Council (CSIC), Institute of Economy, Geography and Demography, Madrid (IEGD), Madrid, Spain
  4. 3University of Granada (UGR), Granada, Spain
  5. 4Research unit of Genomics, Biotechnology and Antiviral Strategies, Higher institute of biotechnology of Monastir, Tunisia

Abstract

Objective Lupus, an autoimmune disease primarily affecting women, is influenced by genetics and the environment. Recent research suggests that epigenetic changes play a role in connecting these factors. In females, a process called X chromosome inactivation (XCI) helps balance X chromosome dosage. However, some X-linked genes escape this process, which is associated with aging and immune-related conditions. This study proposes that DNA methylation changes on the X chromosome may disrupt XCI control, leading to lupus in women by affecting the regulation of immune genes and accelerating aging.

Methods We used DNAm data obtained from Illumina EPIC and 450K arrays on 310 SLE and 358 CTRLS. Firstly, we ran epigenome-wide association studies separately on females (N=556) and males (N= 112) to identify lupus associated DNAm differential positions on chrX (lupus chrX-DMPs). Secondly, we estimated epigenetic age acceleration using machine-learning algorithms such as Horvath, Hannum, and Levine’s epigenetic clocks and studied their associations with DNAm. Finally, we ran trans methylation quantitative methylation loci mapping to identify genetic variants influencing lupus DNAm at lupus chrX-DMP.

Results Our preliminary results show vast alteration of chrX DNAm in lupus females (N=298 DMPs at FDR < 5%), many of them were not present in men (P > 0.05) and were enriched in genes known to escape XCI (Chi-square, P = 5x10E-5). Some of the greatest DNAm changes were observed in relevant genes such as BCOR, AP1S2 and IQSEC2. Although we discovered fewer alterations in males, DNAm differences were greater between cases and controls, probably due to men only carrying one chromosome X. Interestingly, a high proportion of female lupus chrX DMPs do also show strong associations with epigenetic age acceleration measurements and a strong autosomic genetic control.

Conclusion Most EWAS ignore chrX DNAm changes between sexes, leaving the genetic and epigenetic factors of diseases like lupus in women unexplored. Our findings show that chrX epigenetic alterations contribute to aging and female lupus by impacting X chromosome inactivation and immune-related gene dysregulation.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/lupus-2024-el.15

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