PMID- 33894768 OWN - NLM STAT- MEDLINE DCOM- 20220120 LR - 20220120 IS - 1755-8794 (Electronic) IS - 1755-8794 (Linking) VI - 14 IP - 1 DP - 2021 Apr 24 TI - Broadening our understanding of genetic risk for scleroderma/systemic sclerosis by querying the chromatin architecture surrounding the risk haplotypes. PG - 114 LID - 10.1186/s12920-021-00964-5 [doi] LID - 114 AB - BACKGROUND: Genetic variants in the human leukocyte antigen (HLA) locus contribute to the risk for developing scleroderma/systemic sclerosis (SSc). However, there are other replicated loci that also contribute to genetic risk for SSc, and it is unknown whether genetic risk in these non-HLA loci acts primarily on the vasculature, immune system, fibroblasts, or other relevant cell types. We used the Cistrome database to investigate the epigenetic landscapes surrounding 11 replicated SSc associated loci to determine whether SNPs in these loci may affect regulatory elements and whether they are likely to impact a specific cell type. METHODS: We mapped 11 replicated SNPs to haplotypes and sought to determine whether there was significant enrichment for H3K27ac and H3K4me1 marks, epigenetic signatures of enhancer function, on these haplotypes. We queried pathologically relevant cell types: B cells, endothelial cells, fibroblasts, monocytes, and T cells. We then identified the topologically associated domains (TADs) that encompass the SSc risk haplotypes in primary T cells to identify the full range of genes that may be influenced by SSc causal SNPs. We used gene ontology analyses of the genes within the TADs to gain insight into immunologic functions that might be affected by SSc causal SNPs. RESULTS: The SSc-associated haplotypes were enriched (p value < 0.01) for H3K4me1/H3K27ac marks in monocytes. Enrichment of one of the two histone marks was found in B cells, fibroblasts, and T cells. No enrichment was identified in endothelial cells. Ontological analyses of genes within the TADs encompassing the risk haplotypes showed enrichment for regulation of transcription, protein binding, activation of T lymphocytes, and proliferation of immune cells. CONCLUSIONS: The 11 non-HLA SSc risk haplotypes queried are highly enriched for H3K4me1/H3K27ac-marked regulatory elements in a broad range of immune cells and fibroblasts. Furthermore, in immune cells, the risk haplotypes belong to larger chromatin structures encompassing genes that regulate a wide array of immune processes associated with SSc pathogenesis. Though importance of the vasculature in the pathobiology of SSc is widely accepted, we were unable to find evidence for genetic influences on endothelial cell function in these regions. FAU - Poppenberg, Kerry E AU - Poppenberg KE AD - Canon Stroke and Vascular Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. AD - Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. FAU - Tutino, Vincent M AU - Tutino VM AD - Canon Stroke and Vascular Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. AD - Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. AD - Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. AD - Department of Biomedical Engineering, University at Buffalo, Buffalo, NY, USA. FAU - Tarbell, Evan AU - Tarbell E AD - Quantitative Systems Pharmacology, Enhanced Pharmacodynamics, LLC, Buffalo, NY, USA. FAU - Jarvis, James N AU - Jarvis JN AD - Quantitative Systems Pharmacology, Enhanced Pharmacodynamics, LLC, Buffalo, NY, USA. jamesjar@buffalo.edu. AD - Genetics, Genomics, and Bioinformatics Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. jamesjar@buffalo.edu. AD - Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. jamesjar@buffalo.edu. LA - eng GR - R21 AR071878/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210424 PL - England TA - BMC Med Genomics JT - BMC medical genomics JID - 101319628 SB - IM MH - Haplotypes MH - *Scleroderma, Systemic PMC - PMC8066847 OTO - NOTNLM OT - Genetic risk OT - Histone mark OT - Scleroderma OT - Systemic sclerosis OT - Topologically associated domain COIS- KEP-None. VMT-Principal investigator: National Science Foundation Award No. 1746694 and NIH NINDS award R43 NS115314-0. Awardee of the abovementioned Brain Aneurysm Foundation grant, Center for Advanced Technology grant, and Cummings Foundation grant. Co-founder: Neurovascular Diagnostics, Inc. ET-Assistant Director at Quantitative Systems Pharmacology, Enhanced Pharmacodynamics, LLC, JNJ-Principal Investigator: R21-AR071878. EDAT- 2021/04/26 06:00 MHDA- 2022/01/21 06:00 PMCR- 2021/04/24 CRDT- 2021/04/25 20:18 PHST- 2020/11/05 00:00 [received] PHST- 2021/04/14 00:00 [accepted] PHST- 2021/04/25 20:18 [entrez] PHST- 2021/04/26 06:00 [pubmed] PHST- 2022/01/21 06:00 [medline] PHST- 2021/04/24 00:00 [pmc-release] AID - 10.1186/s12920-021-00964-5 [pii] AID - 964 [pii] AID - 10.1186/s12920-021-00964-5 [doi] PST - epublish SO - BMC Med Genomics. 2021 Apr 24;14(1):114. doi: 10.1186/s12920-021-00964-5.