{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T04:09:46Z","timestamp":1772683786234,"version":"3.50.1"},"reference-count":45,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T00:00:00Z","timestamp":1635465600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["NRF\u20102017M3A9B4050335"],"award-info":[{"award-number":["NRF\u20102017M3A9B4050335"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI132532"],"award-info":[{"award-number":["R01AI132532"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI144829"],"award-info":[{"award-number":["R21AI144829"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["P30AR073750"],"award-info":[{"award-number":["P30AR073750"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR060366"],"award-info":[{"award-number":["R01AR060366"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>In a recent genome\u2010wide association study, a significant genetic association between rs34330 of <jats:italic>CDKN1B<\/jats:italic> and risk of systemic lupus erythematosus (SLE) in Han Chinese was identified. This study was undertaken to validate the reported association and elucidate the biochemical mechanisms underlying the effect of the variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed an allelic association analysis in patients with SLE, followed by a meta\u2010analysis assessing genome\u2010wide association data across 11 independent cohorts (n = 28,872). In silico bioinformatics analysis and experimental validation in SLE\u2010relevant cell lines were applied to determine the functional consequences of rs34330.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We replicated a genetic association between SLE and rs34330 (meta\u2010analysis <jats:italic>P<\/jats:italic> = 5.29 \u00d7 10<jats:sup>\u221222<\/jats:sup>, odds ratio 0.84 [95% confidence interval 0.81\u20130.87]). Follow\u2010up bioinformatics and expression quantitative trait locus analysis suggested that rs34330 is located in active chromatin and potentially regulates several target genes. Using luciferase and chromatin immunoprecipitation\u2013real\u2010time quantitative polymerase chain reaction, we demonstrated substantial allele\u2010specific promoter and enhancer activity, and allele\u2010specific binding of 3 histone marks (H3K27ac, H3K4me3, and H3K4me1), RNA polymerase II (Pol II), CCCTC\u2010binding factor, and a critical immune transcription factor (interferon regulatory factor 1 [IRF\u20101]). Chromosome conformation capture revealed long\u2010range chromatin interactions between rs34330 and the promoters of neighboring genes <jats:italic>APOLD1<\/jats:italic> and <jats:italic>DDX47<\/jats:italic>, and effects on <jats:italic>CDKN1B<\/jats:italic> and the other target genes were directly validated by clustered regularly interspaced short palindromic repeat (CRISPR)\u2013based genome editing. Finally, CRISPR\/dead CRISPR\u2010associated protein 9\u2013based epigenetic activation\/silencing confirmed these results. Gene\u2010edited cell lines also showed higher levels of proliferation and apoptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Collectively, these findings suggest a mechanism whereby the rs34330 risk allele (C) influences the presence of histone marks, RNA Pol II, and IRF\u20101 transcription factor to regulate expression of several target genes linked to proliferation and apoptosis. This process could potentially underlie the association of rs34330 with SLE.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41799","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T07:09:11Z","timestamp":1620889751000},"page":"2303-2313","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Lupus Susceptibility Region Containing <i>CDKN1B<\/i> rs34330 Mechanistically Influences Expression and Function of Multiple Target Genes, Also Linked to Proliferation and Apoptosis"],"prefix":"10.1002","volume":"73","author":[{"given":"Bhupinder","family":"Singh","sequence":"first","affiliation":[{"name":"Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guru P.","family":"Maiti","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xujie","family":"Zhou","sequence":"additional","affiliation":[{"name":"Peking University First Hospital Peking University Ministry of Health of China  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7979-758X","authenticated-orcid":false,"given":"Mehdi","family":"Fazel\u2010Najafabadi","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4658-1093","authenticated-orcid":false,"given":"Sang\u2010Cheol","family":"Bae","sequence":"additional","affiliation":[{"name":"Hanyang University Hospital for Rheumatic Diseases  Seoul Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celi","family":"Sun","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chikashi","family":"Terao","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences RIKEN Yokohama Campus, Yokohama, Japan, and University of Shizuoka  Shizuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0311-8472","authenticated-orcid":false,"given":"Yukinori","family":"Okada","sequence":"additional","affiliation":[{"name":"Osaka University  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kek","family":"Heng Chua","sequence":"additional","affiliation":[{"name":"University of Malaya  Kuala Lumpur Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuta","family":"Kochi","sequence":"additional","affiliation":[{"name":"Tokyo Medical and Dental University RIKEN Center for Integrative Medical Sciences RIKEN Yokohama Campus  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel M.","family":"Guthridge","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Peking University First Hospital Peking University Ministry of Health of China  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Weirauch","sequence":"additional","affiliation":[{"name":"Cincinnati Children\u2019s Hospital Medical Center University of Cincinnati, and Cincinnati VA Medical Center  Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9574-7355","authenticated-orcid":false,"given":"Judith A.","family":"James","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John B.","family":"Harley","sequence":"additional","affiliation":[{"name":"Cincinnati Children\u2019s Hospital Medical Center University of Cincinnati, and Cincinnati VA Medical Center  Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaurav K.","family":"Varshney","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loren L.","family":"Looger","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Janelia Research Campus  Ashburn Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6013-9328","authenticated-orcid":false,"given":"Swapan K.","family":"Nath","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,10,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39504"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000654"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.11.018"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2017.06.031"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.12.1501"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0805057106"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.17140\/CSMMOJ-4-e006"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1110666"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep44871"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.25112"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq340"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3496"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-214116"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr917"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1022"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.137323.112"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2394"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1089\/bio.2015.29031.hmm"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2756"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0100924"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.00486"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx043"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01066"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3312"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3199"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0048-5"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11101"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.13226"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkh372"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2011.01.001"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1232033"},{"key":"e_1_2_7_34_1","first-page":"2266","article-title":"Molecular analysis of the cyclin\u2010dependent kinase inhibitor gene p27\/Kip1 in human malignancies","volume":"55","author":"Kawamata N","year":"1995","journal-title":"Cancer Res"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1879-7"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2018.10.048"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2009.5"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.6.6.4088"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003222"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23191"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02026"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00179793"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-12-0139"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/iub.2187"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2014.00418"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.37778"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.41799","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/art.41799","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.41799","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T12:55:18Z","timestamp":1759928118000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.41799"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,29]]},"references-count":45,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["10.1002\/art.41799"],"URL":"https:\/\/doi.org\/10.1002\/art.41799","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,29]]},"assertion":[{"value":"2020-08-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-10-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}