{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T12:46:55Z","timestamp":1782737215865,"version":"3.54.5"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2021,1,31]],"date-time":"2021-01-31T00:00:00Z","timestamp":1612051200000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000964","name":"Arthritis National Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000964","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000890","name":"National Multiple Sclerosis Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000890","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Health","award":["R21 NS096443"],"award-info":[{"award-number":["R21 NS096443"]}]},{"name":"National Institute of Health","award":["R21 AR070378"],"award-info":[{"award-number":["R21 AR070378"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,28]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Currently, it remains difficult to identify which single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) are functional and how various functional SNPs (fSNPs) interact and contribute to disease susceptibility. GWAS have identified a CD40 locus that is associated with rheumatoid arthritis (RA). We previously used two techniques developed in our laboratory, single nucleotide polymorphism-next-generation sequencing (SNP-seq) and flanking restriction enhanced DNA pulldown-mass spectrometry (FREP-MS), to determine that the RA risk gene RBPJ regulates CD40 expression via a fSNP at the RA-associated CD40 locus. In the present work, by applying the same approach, we report the identification of six proteins that regulate RBPJ expression via binding to two fSNPs on the RA-associated RBPJ locus. Using these findings, together with the published data, we constructed an RA-associated signal transduction and transcriptional regulation network (STTRN) that functionally connects multiple RA-associated risk genes via transcriptional regulation networks (TRNs) linked by CD40-induced nuclear factor kappa B (NF-kB) signaling. Remarkably, this STTRN provides insight into the potential mechanism of action for the histone deacetylase inhibitor givinostat, an approved therapy for systemic juvenile idiopathic arthritis. Thus, the generation of disease-associated STTRNs based on post-GWAS functional studies is demonstrated as a novel and effective approach to apply GWAS for mechanistic studies and target identification.<\/jats:p>","DOI":"10.1093\/hmg\/ddab032","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T20:17:15Z","timestamp":1611260235000},"page":"823-835","source":"Crossref","is-referenced-by-count":11,"title":["Post-GWAS functional studies reveal an RA-associated<i>CD40<\/i>-induced NF-kB signal transduction and transcriptional regulation network targeted by class II HDAC inhibitors"],"prefix":"10.1093","volume":"30","author":[{"given":"Meijuan","family":"Zou","sequence":"first","affiliation":[{"name":"Aging Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA"},{"name":"Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danli","family":"Jiang","sequence":"additional","affiliation":[{"name":"Aging Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Wu","sequence":"additional","affiliation":[{"name":"Aging Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA"},{"name":"Department of Medicine, Xiangya School of Medicine, Central South University, Changsha 410083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Aging Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Aging Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Periodontology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry","family":"Moreland","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1725-6611","authenticated-orcid":false,"given":"Gang","family":"Li","sequence":"additional","affiliation":[{"name":"Aging Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA"},{"name":"Department of Medicine, Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,30]]},"reference":[{"key":"2021052810104187400_ref1","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1016\/S0140-6736(10)60826-4","article-title":"Rheumatoid arthritis","volume":"376","author":"Scott","year":"2010","journal-title":"Lancet"},{"key":"2021052810104187400_ref2","doi-asserted-by":"crossref","first-page":"e87645","DOI":"10.1371\/journal.pone.0087645","article-title":"Integration of sequence data from a consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene","volume":"9","author":"Okada","year":"2014","journal-title":"PLoS One"},{"key":"2021052810104187400_ref3","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/ng.3028","article-title":"Little boxes","volume":"46","year":"2014","journal-title":"Nat. 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