{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:05:23Z","timestamp":1791644723607,"version":"4.3.4"},"reference-count":82,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,10,14]],"date-time":"2020-10-14T00:00:00Z","timestamp":1602633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015902","name":"European Orthodontic Society","doi-asserted-by":"publisher","award":["2016"],"award-info":[{"award-number":["2016"]}],"id":[{"id":"10.13039\/100015902","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Personalized dental medicine requires from precise and customized genomic diagnostic. To conduct an association analysis over multiple putative loci and genes located at chromosomes 2, 4, 8, 12, 18, X, and Y, potentially implicated in an extreme type of external apical root resorption secondary to orthodontic forces (aEARR). A genome-wide association study of aEARR was conducted with 480 patients [ratio~1:3 case\/control]. Genomic DNA was extracted and analyzed using the high-throughput Axiom platform with the GeneTitan\u00ae MC Instrument. Up to 14,377 single nucleotide polymorphisms (SNPs) were selected at candidate regions and clinical\/diagnostic data were recorded. A descriptive analysis of the data along with a backward conditional binary logistic regression was used to calculate odds ratios, with 95% confidence intervals [p &lt; 0.05]. To select the best SNP candidates, a logistic regression model was fitted assuming a log-additive genetic model using R software [p &lt; 0.0001]. In this sample the top lead genetic variants associated with aEARR were two novel putative genes located in the X chromosome, specifically, STAG 2 gene, rs151184635 and RP1-30E17.2 gene, rs55839915. These variants were found to be associated with an increased risk of aEARR, particularly restricted to men [OR: 6.09; 95%CI: 2.6\u201314.23 and OR: 6.86; 95%CI: 2.65\u201317.81, respectively]. Marginal associations were found at previously studied variants such as SSP1: rs11730582 [OR: 0.54; 95%CI: 0.34\u20130.86; p = 0.008], P2RX7: rs1718119 [OR: 0.6; 95%CI: 0.36\u20131.01; p = 0.047], and TNFRSF11A: rs8086340 [OR: 0.6; 95%CI: 0.38\u20130.95; p = 0.024]), found solely in females. Multiple putative genetic variants located at chromosomes X and Y are potentially implicated in an extreme phenotype of aEARR. A gender-linked association was noted.<\/jats:p>","DOI":"10.3390\/jpm10040169","type":"journal-article","created":{"date-parts":[[2020,10,14]],"date-time":"2020-10-14T08:59:22Z","timestamp":1602665962000},"page":"169","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["GWAS of Post-Orthodontic Aggressive External Apical Root Resorption Identified Multiple Putative Loci at X-Y Chromosomes"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5666-7598","authenticated-orcid":false,"given":"Paula","family":"Iber-D\u00edaz","sequence":"first","affiliation":[{"name":"Section of Orthodontics, School of Dentistry, Complutense University, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Senen-Carramolino","sequence":"additional","affiliation":[{"name":"Section of Orthodontics, School of Dentistry, Complutense University, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9063-1612","authenticated-orcid":false,"given":"Alejandro","family":"Iglesias-Linares","sequence":"additional","affiliation":[{"name":"Section of Orthodontics, School of Dentistry, Complutense University, 28040 Madrid, Spain"},{"name":"BIOCRAN Craniofacial Biology Research Group, Complutense University, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Fern\u00e1ndez-Navarro","sequence":"additional","affiliation":[{"name":"Cancer and Environmental Epidemiology Unit, National Center for Epidemiology, Carlos III Institute of Health, 28029 Madrid, Spain"},{"name":"Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Flores-Mir","sequence":"additional","affiliation":[{"name":"Professor and Interim Graduate Orthodontic Program Director, School of Dentistry, University of Alberta, Edmonton, AB T6G 1C9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Ya\u00f1ez-Vico","sequence":"additional","affiliation":[{"name":"Section of Orthodontics, School of Dentistry, Complutense University, 28040 Madrid, Spain"},{"name":"BIOCRAN Craniofacial Biology Research Group, Complutense University, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1093\/ejo\/cjz034","article-title":"Development of a clinical practice guideline for orthodontically induced external apical root resorption","volume":"42","author":"Sondeijker","year":"2020","journal-title":"Eur. J. Orthod."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s40510-017-0177-x","article-title":"A preliminary investigation of short-term cytokine expression in gingival crevicular fluid secondary to high-level orthodontic forces and the associated root resorption: Case series analytical study","volume":"18","author":"Ahuja","year":"2017","journal-title":"Prog. Orthod."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.ajodo.2012.04.013","article-title":"Association analysis of clinical aspects and vitamin D receptor gene polymorphism with external apical root resorption in orthodontic patients","volume":"142","author":"Fontana","year":"2012","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1067\/mod.2003.42","article-title":"Genetic predisposition to external apical root resorption","volume":"123","author":"Hartsfield","year":"2003","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0889-5406(97)70189-6","article-title":"A heritable component for external apical root resorption in patients treated orthodontically","volume":"111","author":"Harris","year":"1997","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1177\/0022034519833353","article-title":"Impact of Dental Diseases on Quality-Adjusted Life Expectancy in US Adults","volume":"98","author":"Matsuyama","year":"2019","journal-title":"J. Dent. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.ajodo.2007.06.012","article-title":"Identification of orthodontic patients at risk of severe apical root resorption","volume":"135","author":"Artun","year":"2009","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/S0889-5406(95)70065-X","article-title":"Risk factors for apical root resorption of maxillary anterior teeth in adult orthodontic patients","volume":"108","author":"Mirabella","year":"1995","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.ajodo.2018.10.015","article-title":"Orthodontic mechanotherapies and their influence on external root resorption: A systematic review","volume":"155","author":"Currell","year":"2019","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.ajodo.2015.12.028","article-title":"Genetic and clinical risk factors of root resorption associated with orthodontic treatment","volume":"150","author":"Guo","year":"2016","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1093\/ejo\/cjl090","article-title":"A radiographic analysis of external apical root resorption of maxillary incisors during active orthodontic treatment","volume":"29","author":"Mohandesan","year":"2007","journal-title":"Eur. J. Orthod."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.ajodo.2017.10.026","article-title":"Apical root resorption during orthodontic treatment with clear aligners: A retrospective study using cone-beam computed tomography","volume":"153","author":"Aman","year":"2018","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"395","DOI":"10.4041\/kjod.2018.48.6.395","article-title":"Association between genetic polymorphisms and external apical root resorption: A systematic review and meta-analysis","volume":"48","author":"Nowrin","year":"2018","journal-title":"Korean J. Orthod."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1111\/ocr.12329","article-title":"Biomarkers in the gingival crevicular fluid used to detect root resorption in patients undergoing orthodontic treatment: A systematic review","volume":"22","author":"Tarallo","year":"2019","journal-title":"Orthod. Craniofac. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1177\/154405910308200506","article-title":"Genetic predisposition to external apical root resorption in orthodontic patients: Linkage of chromosome-18 marker","volume":"82","author":"Hartsfield","year":"2003","journal-title":"J. Dent. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.ajodo.2018.05.016","article-title":"Association of clinical variables and polymorphisms in RANKL, RANK, and OPG genes with external apical root resorption","volume":"155","author":"Pereira","year":"2019","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1111\/odi.12185","article-title":"Polymorphisms of genes encoding P2X7R, IL-1B, OPG and RANK in orthodontic-induced apical root resorption","volume":"20","author":"Pereira","year":"2014","journal-title":"Oral Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/ocr.12078","article-title":"Genetic and treatment-related risk factors associated with external apical root resorption (EARR) concurrent with orthodontia","volume":"18","author":"Sharab","year":"2015","journal-title":"Orthod. Craniofac. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/odi.12114","article-title":"Osteopontin gene SNPs (rs9138, rs11730582) mediate susceptibility to external root resorption in orthodontic patients","volume":"20","year":"2014","journal-title":"Oral Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.joen.2011.12.022","article-title":"Postorthodontic external root resorption in root-filled teeth is influenced by interleukin-1beta polymorphism","volume":"38","author":"Ballesta","year":"2012","journal-title":"J. Endod."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1089\/thy.2009.0099","article-title":"Association of polymorphisms in genes of the homologous recombination DNA repair pathway and thyroid cancer risk","volume":"19","author":"Bastos","year":"2009","journal-title":"Thyroid"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/s00056-009-8808-6","article-title":"Interleukin-1 polymorphisms in relation to external apical root resorption (EARR)","volume":"70","author":"Gulden","year":"2009","journal-title":"J. Orofac. Orthop."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1111\/j.1601-0825.2012.01973.x","article-title":"IL1 gene polymorphisms in relation to external apical root resorption concurrent with orthodontia","volume":"19","author":"Linhartova","year":"2013","journal-title":"Oral Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1111\/j.1365-2591.2012.02065.x","article-title":"Interleukin 1 gene cluster SNPs (rs1800587, rs1143634) influences post-orthodontic root resorption in endodontic and their contralateral vital control teeth differently","volume":"45","author":"Ballesta","year":"2012","journal-title":"Int. Endod. J."},{"key":"ref_25","first-page":"abstract-1922","article-title":"Evaluation of SNPs in orthodontic patients with root resorption","volume":"86(Spec Iss A)","author":"Shank","year":"2007","journal-title":"J. Dent Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2592","DOI":"10.1002\/jbmr.162","article-title":"Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget\u2019s disease of bone","volume":"25","author":"Chung","year":"2010","journal-title":"J. Bone Miner. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1111\/odi.12514","article-title":"IRAK1 variant is protective for orthodontic-induced external apical root resorption","volume":"22","author":"Pereira","year":"2016","journal-title":"Oral Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/ng1706","article-title":"Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies","volume":"38","author":"Skol","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1001\/jama.2013.281053","article-title":"World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects","volume":"310","year":"2013","journal-title":"JAMA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0889-5406(05)81678-6","article-title":"Patient characteristics and treatment variables associated with apical root resorption during orthodontic treatment","volume":"99","author":"Linge","year":"1991","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_31","first-page":"780","article-title":"The use of an individual jig in measuring tooth length changes","volume":"74","author":"Brezniak","year":"2004","journal-title":"Angle Orthod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0889-5406(98)70306-3","article-title":"Skeletal effects of early treatment of Class III malocclusion with maxillary expansion and face-mask therapy","volume":"113","author":"Baccetti","year":"1998","journal-title":"Am. J. Orthod. Dentofac. Orthop"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/nature09534","article-title":"A map of human genome variation from population-scale sequencing","volume":"467","author":"Abecasis","year":"2010","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ygeno.2011.04.005","article-title":"Next generation genome-wide association tool: Design and coverage of a high-throughput European-optimized SNP array","volume":"98","author":"Hoffmann","year":"2011","journal-title":"Genomics"},{"key":"ref_35","unstructured":"R Core Team (2014). R: A language and environment for statistical computing. R Foundation for Statistical Computing, R Core Team. Available online: http:\/\/www.R-project.org\/."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/0002-9416(83)90322-6","article-title":"The analysis of errors in orthodontic measurements","volume":"83","author":"Houston","year":"1983","journal-title":"Am. J. Orthod."},{"key":"ref_37","unstructured":"Siegel, S., and Castellan, N.J. (1998). Non Parametric Statistics for the Behavioural Sciences, McGraw-Hill."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.ajodo.2015.09.020","article-title":"How long does treatment with fixed orthodontic appliances last? A systematic review","volume":"149","author":"Tsichlaki","year":"2016","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1177\/0022034517750572","article-title":"Global-, Regional-, and Country-Level Economic Impacts of Dental Diseases in 2015","volume":"97","author":"Righolt","year":"2018","journal-title":"J. Dent. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.ajodo.2014.12.026","article-title":"Association of orthodontic force system and root resorption: A systematic review","volume":"147","author":"Roscoe","year":"2015","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Qin, F., and Zhou, Y. (2019). The influence of bracket type on the external apical root resorption in class I extraction patients\u2014A retrospective study. BMC Oral Health, 19.","DOI":"10.1186\/s12903-019-0743-3"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1034\/j.1600-9657.2003.00205.x","article-title":"Root resorption in dental trauma: 45 cases followed for 5 years","volume":"19","author":"Majorana","year":"2003","journal-title":"Dent. Traumatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1093\/ejo\/cjs064","article-title":"Association between root resorption incident to orthodontic treatment and treatment factors","volume":"35","author":"Celikoglu","year":"2013","journal-title":"Eur. J. Orthod."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"310","DOI":"10.4041\/kjod.2019.49.5.310","article-title":"Predisposing factors for external apical root resorption associated with orthodontic treatment","volume":"49","author":"Fernandes","year":"2019","journal-title":"Korean J. Orthod."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.ajodo.2019.05.011","article-title":"Optimal force magnitude for bodily orthodontic tooth movement with fixed appliances: A systematic review","volume":"156","author":"Theodorou","year":"2019","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"740","DOI":"10.2319\/111417-777.1","article-title":"Apical root displacement is a critical risk factor for apical root resorption after orthodontic treatment","volume":"88","author":"Kim","year":"2018","journal-title":"Angle Orthod."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1093\/ejo\/cjp165","article-title":"Root resorption before and after orthodontic treatment: A clinical study of contributory factors","volume":"32","author":"Jiang","year":"2010","journal-title":"Eur. J. Orthod."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1007\/s11914-016-0340-1","article-title":"Bone Density and Dental External Apical Root Resorption","volume":"14","author":"Morford","year":"2016","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1093\/ejo\/cjz063","article-title":"Does medication administration affect the rate of orthodontic tooth movement and root resorption development in humans? A systematic review","volume":"42","author":"Kaklamanos","year":"2020","journal-title":"Eur. J. Orthod."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1093\/ejo\/cjz021","article-title":"Effects of systematic bisphosphonate use in patients under orthodontic treatment: A systematic review","volume":"42","author":"Zymperdikas","year":"2020","journal-title":"Eur. J. Orthod."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"570","DOI":"10.2319\/101710-607.1","article-title":"Tooth movement and root resorption; the effect of ovariectomy on orthodontic force application in rats","volume":"81","author":"Sirisoontorn","year":"2011","journal-title":"Angle Orthod."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/ocr.12288","article-title":"Ethnic differences in the root to crown ratios of the permanent dentition","volume":"22","author":"Wang","year":"2019","journal-title":"Orthod. Craniofac. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1177\/154411130401500205","article-title":"Genetic Factors in External Apical Root Resorption and Orthodontic Treatment","volume":"15","author":"Hartsfield","year":"2004","journal-title":"Crit. Rev. Oral Biol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1177\/0022034516682017","article-title":"Bone Density and Clinical Periodontal Attachment in Postmenopausal Women: A Systematic Review and Meta-Analysis","volume":"96","author":"Penoni","year":"2017","journal-title":"J. Dent. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1111\/jre.12656","article-title":"Loss of alveolar bone density in postmenopausal, osteopenic women is associated with circulating levels of gelatinases","volume":"54","author":"Thompson","year":"2019","journal-title":"J. Periodontal Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1158\/1055-9965.EPI-11-0246","article-title":"Sex disparities in cancer mortality and survival","volume":"20","author":"Cook","year":"2011","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Wang, Y., Freemantle, N., Nazareth, I., and Hunt, K. (2014). Gender differences in survival and the use of primary care prior to diagnosis of three cancers: An analysis of routinely collected UK general practice data. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101562"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1136\/bmj.332.7545.808","article-title":"Life expectancy: Women now on top everywhere","volume":"332","author":"Barford","year":"2006","journal-title":"BMJ"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"34006","DOI":"10.1038\/srep34006","article-title":"Gender effects of single nucleotide polymorphisms and miRNAs targeting clock-genes in metastatic colorectal cancer patients (mCRC)","volume":"6","author":"Garufi","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1002\/jbmr.1679","article-title":"Assessment of gene-by-sex interaction effect on bone mineral density","volume":"27","author":"Liu","year":"2012","journal-title":"J. Bone Miner. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/nrg2415","article-title":"Sex-specific genetic architecture of human disease","volume":"9","author":"Ober","year":"2008","journal-title":"Nat. Rev. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Winkler, T.W., Justice, A.E., Graff, M., Barata, L., Feitosa, M.F., Chu, S., Czajkowski, J., Esko, T., Fall, T., and Kilpelainen, T.O. (2015). The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005378"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"16012","DOI":"10.1038\/s41598-018-34394-8","article-title":"NF-kappaB p65 directs sex-specific neuroprotection in human neurons","volume":"8","author":"Schneider","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41586-019-1657-6","article-title":"Sex and gender analysis improves science and engineering","volume":"575","author":"Tannenbaum","year":"2019","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/nature20149","article-title":"Local regulation of gene expression by lncRNA promoters, transcription and splicing","volume":"539","author":"Engreitz","year":"2016","journal-title":"Nature"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s10142-016-0524-x","article-title":"Long noncoding RNA (lincRNA), a new paradigm in gene expression control","volume":"17","author":"Deniz","year":"2017","journal-title":"Funct. Integr. Genom."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1186\/s13287-019-1458-8","article-title":"lncRNAs: Function and mechanism in cartilage development, degeneration, and regeneration","volume":"10","author":"Zhu","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1038\/s41467-019-09659-z","article-title":"A requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant cancers","volume":"10","author":"Mondal","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"6131","DOI":"10.1073\/pnas.1318948111","article-title":"Defining functional DNA elements in the human genome","volume":"111","author":"Kellis","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","first-page":"5556","article-title":"Downregulation of long noncoding RNA ZMAT1 transcript variant 2 predicts a poor prognosis in patients with gastric cancer","volume":"8","author":"Lai","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s11033-015-3939-x","article-title":"Identification of new SOX2OT transcript variants highly expressed in human cancer cell lines and down regulated in stem cell differentiation","volume":"43","author":"Samaei","year":"2016","journal-title":"Mol. Biol. Rep."},{"key":"ref_72","unstructured":"(2019, December 10). Available online: https:\/\/www.ncbi.nlm.nih.gov\/snp\/rs151184635."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3793","DOI":"10.1002\/art.22981","article-title":"Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome","volume":"56","author":"Fall","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/nrrheum.2015.179","article-title":"Macrophage activation syndrome in the era of biologic therapy","volume":"12","author":"Grom","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1177\/0022034514553817","article-title":"Enhanced M1\/M2 macrophage ratio promotes orthodontic root resorption","volume":"94","author":"He","year":"2015","journal-title":"J. Dent. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1177\/0022034516677539","article-title":"Cellular and Molecular Pathways Leading to External Root Resorption","volume":"96","author":"Hartsfield","year":"2017","journal-title":"J. Dent. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"891","DOI":"10.3389\/fgene.2019.00891","article-title":"Novel Y-Chromosome Long Non-Coding RNAs Expressed in Human Male CNS During Early Development","volume":"10","author":"Johansson","year":"2019","journal-title":"Front. Genet."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Reinius, B., Shi, C., Hengshuo, L., Sandhu, K.S., Radomska, K.J., Rosen, G.D., Lu, L., Kullander, K., Williams, R.W., and Jazin, E. (2010). Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse. BMC Genom., 11.","DOI":"10.1186\/1471-2164-11-614"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1007\/s10875-015-0144-6","article-title":"A female patient with incomplete hemophagocytic lymphohistiocytosis caused by a heterozygous XIAP mutation associated with non-random X-chromosome inactivation skewed towards the wild-type XIAP allele","volume":"35","author":"Yang","year":"2015","journal-title":"J. Clin. Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.ajodo.2008.10.014","article-title":"Detection of apical root resorption after orthodontic treatment by using panoramic radiography and cone-beam computed tomography of super-high resolution","volume":"135","author":"Dudic","year":"2009","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/496007a","article-title":"If a job is worth doing, it is worth doing twice","volume":"496","author":"Russell","year":"2013","journal-title":"Nature"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"9","DOI":"10.2105\/AJPH.2007.126847","article-title":"The importance of external validity","volume":"98","author":"Steckler","year":"2008","journal-title":"Am. J. Public Health"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/10\/4\/169\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:20:55Z","timestamp":1760178055000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/10\/4\/169"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,14]]},"references-count":82,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["jpm10040169"],"URL":"https:\/\/doi.org\/10.3390\/jpm10040169","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,14]]}}}