PMID- 38145128 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240228 IS - 1664-2295 (Print) IS - 1664-2295 (Electronic) IS - 1664-2295 (Linking) VI - 14 DP - 2023 TI - High-resolution DNA methylation screening of the major histocompatibility complex in multiple sclerosis. PG - 1326738 LID - 10.3389/fneur.2023.1326738 [doi] LID - 1326738 AB - BACKGROUND: The HLA-DRB1 gene in the major histocompatibility complex (MHC) region in chromosome 6p21 is the strongest genetic factor identified as influencing multiple sclerosis (MS) susceptibility. DNA methylation changes associated with MS have been consistently detected at the MHC region. However, understanding the full scope of epigenetic regulations of the MHC remains incomplete, due in part to the limited coverage of this region by standard whole genome bisulfite sequencing or array-based methods. METHODS: We developed and validated an MHC capture protocol coupled with bisulfite sequencing and conducted a comprehensive analysis of the MHC methylation landscape in blood samples from 147 treatment naive MS study participants and 129 healthy controls. RESULTS: We identified 132 differentially methylated region (DMRs) within MHC region associated with disease status. The DMRs overlapped with established MS risk loci. Integration of the MHC methylome with human leukocyte antigen (HLA) genetic data indicate that the methylation changes are significantly associated with HLA genotypes. Using DNA methylation quantitative trait loci (mQTL) mapping and the causal inference test (CIT), we identified 643 cis-mQTL-DMRs paired associations, including 71 DMRs possibly mediating causal relationships between 55 single nucleotide polymorphisms (SNPs) and MS risk. RESULTS: The results describe MS-associated methylation changes in MHC region and highlight the association between HLA genotypes and methylation changes. Results from the mQTL and CIT analyses provide evidence linking MHC region variations, methylation changes, and disease risk for MS. CI - Copyright (c) 2023 Ma, Augusto, Montero-Martin, Caillier, Osoegawa, Cree, Hauser, Didonna, Hollenbach, Norman, Fernandez-Vina and Oksenberg. FAU - Ma, Qin AU - Ma Q AD - Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States. FAU - Augusto, Danillo G AU - Augusto DG AD - Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, United States. FAU - Montero-Martin, Gonzalo AU - Montero-Martin G AD - Histocompatibility and Immunogenetics Laboratory, Stanford Blood Center, Palo Alto, CA, United States. AD - Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, United States. AD - HLA Histocompatibility and Immunogenetics Laboratory, Vitalant, Phoenix, AZ, United States. FAU - Caillier, Stacy J AU - Caillier SJ AD - Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States. FAU - Osoegawa, Kazutoyo AU - Osoegawa K AD - Histocompatibility and Immunogenetics Laboratory, Stanford Blood Center, Palo Alto, CA, United States. FAU - Cree, Bruce A C AU - Cree BAC AD - Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States. FAU - Hauser, Stephen L AU - Hauser SL AD - Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States. FAU - Didonna, Alessandro AU - Didonna A AD - Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, United States. FAU - Hollenbach, Jill A AU - Hollenbach JA AD - Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States. FAU - Norman, Paul J AU - Norman PJ AD - Department of Biomedical Informatics and Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States. FAU - Fernandez-Vina, Marcelo AU - Fernandez-Vina M AD - Histocompatibility and Immunogenetics Laboratory, Stanford Blood Center, Palo Alto, CA, United States. AD - Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, United States. FAU - Oksenberg, Jorge R AU - Oksenberg JR AD - Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States. LA - eng GR - R01 AI169070/AI/NIAID NIH HHS/United States GR - R01 NS128277/NS/NINDS NIH HHS/United States GR - R35 NS111644/NS/NINDS NIH HHS/United States GR - U01 AI090905/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20231208 PL - Switzerland TA - Front Neurol JT - Frontiers in neurology JID - 101546899 PMC - PMC10739394 OTO - NOTNLM OT - DNA methylation OT - DNA methylation quantitative trait loci OT - differentially methylated regions OT - major histocompatibility complex OT - multiple sclerosis COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. EDAT- 2023/12/25 06:42 MHDA- 2023/12/25 06:43 PMCR- 2023/12/08 CRDT- 2023/12/25 04:52 PHST- 2023/10/23 00:00 [received] PHST- 2023/11/23 00:00 [accepted] PHST- 2023/12/25 06:43 [medline] PHST- 2023/12/25 06:42 [pubmed] PHST- 2023/12/25 04:52 [entrez] PHST- 2023/12/08 00:00 [pmc-release] AID - 10.3389/fneur.2023.1326738 [doi] PST - epublish SO - Front Neurol. 2023 Dec 8;14:1326738. doi: 10.3389/fneur.2023.1326738. eCollection 2023.