{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T05:15:58Z","timestamp":1783055758392,"version":"3.54.6"},"reference-count":104,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The complement system is a central component of innate immunity that coordinates host defense, immune surveillance, and inflammatory responses through tightly regulated proteolytic cascades. Genetic variation within complement genes contributes substantially to interindividual differences in complement activity and disease susceptibility. While coding variants directly alter complement protein structure and function, the microRNA (miRNA)-mediated control and post-transcriptional regulation is not fully understood in shaping complement gene expression across immune and inflammatory mechanisms. Complement pathway genes exhibit extensive and heterogeneous 3\u2032-untranslated regions (3\u2032UTRs), which serve as primary platforms for miRNA binding and RNA-binding protein interactions. Both common and rare single-nucleotide polymorphisms within coding regions and 3\u2032UTRs can influence miRNA targeting efficiency, disrupt regulatory motifs, or alter mRNA turnover, thereby fine-tuning complement activity rather than causing complete loss of function. Here, we systematically analyzed miRNA binding sites and single-nucleotide polymorphisms (SNPs) within the 3\u2032UTRs of complement pathway genes spanning the classical, lectin, alternative, and terminal pathways. Our analysis uncovered heterogeneous patterns of miRNA-mediated regulation across the complement system. While core complement components showed relatively sparse conserved miRNA targeting, regulatory factors, receptors, and terminal pathway proteins emerged as densely regulated nodes, harboring multiple conserved binding sites. A broad repertoire of miRNAs was predicted to engage complement genes in a pathway-specific manner, implicating these interactions in inflammation, cancer progression, metabolic regulation, and immune signaling. SNPs within miRNA-binding regions are predicted to disrupt or create regulatory interactions, providing a mechanistic basis for how non-coding genetic variation can alter gene expression and modulate disease susceptibility. Our findings indicate miRNA-mediated post-transcriptional regulation as an important yet underappreciated layer of complement system control, providing a framework for understanding how regulatory genetic variation shapes complement-driven immune responses and disease risk.<\/jats:p>","DOI":"10.3390\/ijms27135877","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T08:26:15Z","timestamp":1782807975000},"page":"5877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive Prediction Analysis of Novel Noncoding Regulatory Variants Identified in the MicroRNA Binding Regions in Complement System Genes"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6282-1427","authenticated-orcid":false,"given":"Anthony","family":"Shadid","sequence":"first","affiliation":[{"name":"Institute of Molecular Medicine, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8360-293X","authenticated-orcid":false,"given":"Haydn E.","family":"Rich","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8335-7617","authenticated-orcid":false,"given":"Kathryn D.","family":"Hok","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Francoise","family":"Doursout","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9107-3405","authenticated-orcid":false,"given":"Marcos I.","family":"Restrepo","sequence":"additional","affiliation":[{"name":"VA-San Antonio Geriatric Research Education and Clinical Center (GRECC), South Texas Veterans Health Care System Audie L. Murphy Division, UTHealth San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirmal K.","family":"Banda","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6348-3359","authenticated-orcid":false,"given":"Lavanya","family":"Gunamalai","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5040-6805","authenticated-orcid":false,"given":"Pooja","family":"Shivshankar","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.gendis.2019.07.002","article-title":"An update on the genetics and pathogenesis of hereditary angioedema","volume":"7","author":"Banday","year":"2020","journal-title":"Genes Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bogdan, R.G., Anderco, P., Ichim, C., Cimpean, A.M., Todor, S.B., Glaja-Iliescu, M., Crainiceanu, Z.P., and Popa, M.L. (2025). Atypical Hemolytic Uremic Syndrome: A Review of Complement Dysregulation, Genetic Susceptibility and Multiorgan Involvement. J. Clin. Med., 14.","DOI":"10.3390\/jcm14072527"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Merle, N.S., Church, S.E., Fremeaux-Bacchi, V., and Roumenina, L.T. (2015). Complement System Part I\u2014Molecular Mechanisms of Activation and Regulation. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00262"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/imr.12500","article-title":"Complement component C3\u2014The \u201cSwiss Army Knife\u201d of innate immunity and host defense","volume":"274","author":"Ricklin","year":"2016","journal-title":"Immunol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"912","DOI":"10.4049\/jimmunol.0901702","article-title":"Factor H and factor H-related protein 1 bind to human neutrophils via complement receptor 3, mediate attachment to Candida albicans, and enhance neutrophil antimicrobial activity","volume":"184","author":"Losse","year":"2010","journal-title":"J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1093\/jimmun\/vkaf065","article-title":"The 4 functional segments of Factor H: Role in physiological target recognition and contribution to disease","volume":"214","author":"Zipfel","year":"2025","journal-title":"J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.molimm.2005.06.015","article-title":"Complement and diseases: Defective alternative pathway control results in kidney and eye diseases","volume":"43","author":"Zipfel","year":"2006","journal-title":"Mol. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.4049\/jimmunol.1203487","article-title":"Complement in immune and inflammatory disorders: Pathophysiological mechanisms","volume":"190","author":"Ricklin","year":"2013","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1007\/s10238-024-01334-y","article-title":"Exploring regulatory mechanisms on miRNAs and their implications in inflammation-related diseases","volume":"24","author":"Nalbant","year":"2024","journal-title":"Clin. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"138","DOI":"10.4110\/in.2014.14.3.138","article-title":"MicroRNA Regulation in Systemic Lupus Erythematosus Pathogenesis","volume":"14","author":"Yan","year":"2014","journal-title":"Immune Netw."},{"key":"ref_11","first-page":"970607","article-title":"Mechanisms of miRNA-Mediated Gene Regulation from Common Downregulation to mRNA-Specific Upregulation","volume":"2014","author":"Safaralizadeh","year":"2014","journal-title":"Int. J. Genom."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1146\/annurev-biochem-060308-103103","article-title":"Regulation of mRNA translation and stability by microRNAs","volume":"79","author":"Fabian","year":"2010","journal-title":"Annu. Rev. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Gaal, Z. (2024). Role of microRNAs in Immune Regulation with Translational and Clinical Applications. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031942"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Skerka, C., Cochlovius, B., H\u00fcllebrand, J.P., Goel, D., Sood, P., Pal, N., Chakravarti, A., Muth, D.R., Zeitz, O., and Zipfel, P.F. (2026). A new perspective on AMD pathogenesis: A sequential Factor H-centered view of complement dysregulation. Front. Immunol. Vol., 17.","DOI":"10.3389\/fimmu.2026.1814415"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41525-022-00327-8","article-title":"Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis","volume":"7","author":"Kerick","year":"2022","journal-title":"npj Genom. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1159\/000500545","article-title":"Common Genetic Variants in the Complement System and their Potential Link with Disease Susceptibility and Outcome of Invasive Bacterial Infection","volume":"12","author":"Langereis","year":"2020","journal-title":"J. Innate Immun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/imr.13131","article-title":"Genetic variability shapes the alternative pathway complement activity and predisposition to complement-related diseases","volume":"313","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/ajmg.a.30878","article-title":"Michels syndrome, Carnevale syndrome, OSA syndrome, Malpuech syndrome: Variable expression of a single disorder (3MC syndrome)?","volume":"137A","author":"Titomanlio","year":"2005","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/humu.23226","article-title":"Genetic variants in microRNAs and their binding sites within gene 3\u2019UTRs associate with susceptibility to age-related macular degeneration","volume":"38","author":"Ghanbari","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1167\/iovs.11-8468","article-title":"Significance of C2\/CFB variants in age-related macular degeneration and polypoidal choroidal vasculopathy in a Japanese population","volume":"53","author":"Nakata","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40246-015-0029-z","article-title":"Complement regulator CD46: Genetic variants and disease associations","volume":"9","author":"Liszewski","year":"2015","journal-title":"Hum. Genom."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.coi.2021.04.005","article-title":"Membrane cofactor protein (MCP.; CD46): Deficiency states and pathogen connections","volume":"72","author":"Liszewski","year":"2021","journal-title":"Curr. Opin. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1056\/NEJMoa0900381","article-title":"Immunodeficiency associated with FCN3 mutation and ficolin-3 deficiency","volume":"360","author":"Hummelshoj","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.jaci.2018.01.048","article-title":"A type III complement factor D deficiency: Structural insights for inhibition of the alternative pathway","volume":"142","author":"Sng","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.clim.2015.05.004","article-title":"Novel CFI mutation in a patient with leukocytoclastic vasculitis may redefine the clinical spectrum of Complement Factor I deficiency","volume":"160","author":"Bay","year":"2015","journal-title":"Clin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.molimm.2009.08.028","article-title":"L-ficolin (ficolin-2) insufficiency is associated with combined allergic and infectious respiratory disease in children","volume":"47","author":"Cedzynski","year":"2009","journal-title":"Mol. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1086\/379324","article-title":"Impact of mannose-binding lectin on susceptibility to infectious diseases","volume":"37","author":"Eisen","year":"2003","journal-title":"Clin. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1056\/NEJMra0902814","article-title":"Atypical hemolytic-uremic syndrome","volume":"361","author":"Noris","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.it.2015.04.008","article-title":"Factor H-related proteins determine complement-activating surfaces","volume":"36","author":"Jozsi","year":"2015","journal-title":"Trends Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"104134","DOI":"10.1016\/j.drudis.2024.104134","article-title":"The efficacy and safety of eculizumab in patients and the role of C5 polymorphisms","volume":"29","author":"Bouwman","year":"2024","journal-title":"Drug Discov. Today"},{"key":"ref_31","first-page":"103","article-title":"The C5 gene polymorphism in patients with PNH","volume":"56","author":"Nishimura","year":"2015","journal-title":"Rinsho Ketsueki"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1056\/NEJMoa1311084","article-title":"Genetic variants in C5 and poor response to eculizumab","volume":"370","author":"Nishimura","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1078\/0171-2985-00141","article-title":"C1q, autoimmunity and apoptosis","volume":"205","author":"Botto","year":"2002","journal-title":"Immunobiology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1046\/j.0022-202x.2001.01381.x","article-title":"Ultraviolet-radiation-induced keratinocyte apoptosis in C1q-deficient mice","volume":"117","author":"Pickering","year":"2001","journal-title":"J. Investig. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3961","DOI":"10.1073\/pnas.0609101104","article-title":"Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus","volume":"104","author":"Wu","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.ejpn.2015.07.001","article-title":"Devastating recurrent brain ischemic infarctions and retinal disease in pediatric patients with CD59 deficiency","volume":"19","author":"Tabib","year":"2015","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.molimm.2007.05.004","article-title":"Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome","volume":"45","author":"Kavanagh","year":"2008","journal-title":"Mol. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1016\/j.cgh.2024.11.015","article-title":"A Pedigree with Complement Hyperactivation, Angiopathic Thrombosis, Severe Protein-losing Enteropathy (CHAPLE) Disease: Variable Penetrance and Treatment with Pozelimab","volume":"23","author":"Pouw","year":"2025","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1056\/NEJMoa1615887","article-title":"CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, Thrombosis","volume":"377","author":"Ozen","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1212\/WNL.0000000000001391","article-title":"Early-onset chronic axonal neuropathy, strokes, hemolysis: Inherited CD59 deficiency","volume":"84","author":"Haliloglu","year":"2015","journal-title":"Neurology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.3389\/fimmu.2019.02537","article-title":"C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers-Danlos Syndrome","volume":"10","author":"Grobner","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.ajhg.2016.08.019","article-title":"Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement","volume":"99","author":"Pepin","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1177\/0961203309358035","article-title":"Complete complement deficiency in a large cohort of familial systemic lupus erythematosus","volume":"24","author":"Aggarwal","year":"2015","journal-title":"Lupus"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cell.2009.01.002","article-title":"MicroRNAs: Target recognition and regulatory functions","volume":"136","author":"Bartel","year":"2009","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cell.2004.12.035","article-title":"Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets","volume":"120","author":"Lewis","year":"2005","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3246","DOI":"10.1002\/jcb.23251","article-title":"HDAC inhibition promotes cardiogenesis and the survival of embryonic stem cells through proteasome-dependent pathway","volume":"112","author":"Chen","year":"2011","journal-title":"J. Cell. Biochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/ni.f.209","article-title":"MicroRNAs: New regulators of immune cell development and function","volume":"9","author":"Baltimore","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1146\/annurev-immunol-020711-075013","article-title":"microRNA regulation of inflammatory responses","volume":"30","author":"Rao","year":"2012","journal-title":"Annu. Rev. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"706","DOI":"10.4161\/rna.8.5.16154","article-title":"Regulation and function of miRNA-21 in health and disease","volume":"8","author":"Kumarswamy","year":"2011","journal-title":"RNA Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"12481","DOI":"10.1073\/pnas.0605298103","article-title":"NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses","volume":"103","author":"Taganov","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1146\/annurev-genet-120116-024704","article-title":"Regulation by 3\u2019-Untranslated Regions","volume":"51","author":"Mayr","year":"2017","journal-title":"Annu. Rev. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/nrm.2016.116","article-title":"Alternative polyadenylation of mRNA precursors","volume":"18","author":"Tian","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41413-022-00236-7","article-title":"Transcript shortening via alternative polyadenylation promotes gene expression during fracture healing","volume":"11","author":"Khajuria","year":"2023","journal-title":"Bone Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.matbio.2022.06.001","article-title":"3\u2019UTR shortening of HAS2 promotes hyaluronan hyper-synthesis and bioenergetic dysfunction in pulmonary hypertension","volume":"111","author":"Tseng","year":"2022","journal-title":"Matrix Biol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Cihan, M., Anyaegbunam, U.A., Albrecht, S., rade-Navarro, M.A., and Sprang, M. (2025). Evaluating Genetic Regulators of MicroRNAs Using Machine Learning Models. Int. J. Mol. Sci., 26.","DOI":"10.1101\/2025.01.09.632215"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Shivshankar, P., Fekry, B., Eckel-Mahan, K., and Wetsel, R.A. (2020). Circadian Clock and Complement Immune System-Complementary Control of Physiology and Pathology?. Front. Cell. Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.00418"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s12931-025-03152-6","article-title":"Complement activity and autophagy are dysregulated in the lungs of patients with nonresolvable COVID-19 requiring lung transplantation","volume":"26","author":"Shivshankar","year":"2025","journal-title":"Respir. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1002\/JLB.3MIR0220-270R","article-title":"Complement: Bridging the innate and adaptive immune systems in sterile inflammation","volume":"108","author":"Lo","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e05005","DOI":"10.7554\/eLife.05005","article-title":"Predicting effective microRNA target sites in mammalian mRNAs","volume":"4","author":"Agarwal","year":"2015","journal-title":"Elife"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.molcel.2007.06.017","article-title":"MicroRNA targeting specificity in mammals: Determinants beyond seed pairing","volume":"27","author":"Grimson","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_61","first-page":"83","article-title":"MicroRNAs: Processing, Maturation, Target Recognition and Regulatory Functions","volume":"3","author":"Shukla","year":"2011","journal-title":"Mol. Cell. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"eaav1741","DOI":"10.1126\/science.aav1741","article-title":"The biochemical basis of microRNA targeting efficacy","volume":"366","author":"McGeary","year":"2019","journal-title":"Science"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"W191","DOI":"10.1093\/nar\/gkz369","article-title":"g:Profiler: A web server for functional enrichment analysis and conversions of gene lists (2019 update)","volume":"47","author":"Raudvere","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/cr.2009.139","article-title":"Complement and its role in innate and adaptive immune responses","volume":"20","author":"Dunkelberger","year":"2010","journal-title":"Cell Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1056\/NEJM200104053441406","article-title":"Complement. First of two parts","volume":"344","author":"Walport","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1056\/NEJM200104123441506","article-title":"Complement. Second of two parts","volume":"344","author":"Walport","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/ng1750","article-title":"Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration","volume":"38","author":"Gold","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1093\/hmg\/ddm146","article-title":"Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration","volume":"16","author":"Spencer","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0161-5890(03)00104-4","article-title":"Mannose-binding lectin deficiency\u2014Revisited","volume":"40","author":"Garred","year":"2003","journal-title":"Mol. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/ng.757","article-title":"Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome","volume":"43","author":"Rooryck","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.ajhg.2010.09.018","article-title":"MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes","volume":"87","author":"Sirmaci","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1056\/NEJMoa022836","article-title":"Inherited deficiency of mannan-binding lectin-associated serine protease 2","volume":"349","author":"Thiel","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1093\/hmg\/ddi173","article-title":"Polymorphisms in the FCN2 gene determine serum variation and function of Ficolin-2","volume":"14","author":"Hummelshoj","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Munye, M.M., Diaz-Font, A., Ocaka, L., Henriksen, M.L., Lees, M., Brady, A., Jenkins, D., Morton, J., Hansen, S.W., and Bacchelli, C. (2017). COLEC10 is mutated in 3MC patients and regulates early craniofacial development. PLoS Genet., 13.","DOI":"10.1371\/journal.pgen.1006679"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Hok, K.D., Rich, H.E., Shadid, A., Gunamalai, L., Weng-Mills, T., Thandavarayan, R.A., Banda, N.K., Doursout, M.F., Restrepo, M.I., and Shivshankar, P. (2025). Functional Roles of the Complement Immune System in Cardiac Inflammation and Hypertrophy. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26209931"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1126\/science.1110189","article-title":"Complement factor H polymorphism and age-related macular degeneration","volume":"308","author":"Edwards","year":"2005","journal-title":"Science"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1126\/science.1110359","article-title":"Complement factor H variant increases the risk of age-related macular degeneration","volume":"308","author":"Haines","year":"2005","journal-title":"Science"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1097\/IAE.0b013e318184661d","article-title":"Complement factor H variant increases the risk for early age-related macular degeneration","volume":"28","author":"Lin","year":"2008","journal-title":"Retina"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/gim.2015.70","article-title":"Age-related macular degeneration: Genome-wide association studies to translation","volume":"18","author":"Black","year":"2016","journal-title":"Genet. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e936565","DOI":"10.12659\/AJCR.936565","article-title":"Novel Complement Factor B Gene Mutation Identified in a Kidney Transplant Recipient with a Shiga Toxin-Triggered Episode of Thrombotic Microangiopathy","volume":"23","author":"Korzycka","year":"2022","journal-title":"Am. J. Case Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1172\/JCI200112023","article-title":"A family with complement factor D deficiency","volume":"108","author":"Biesma","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4865","DOI":"10.1182\/blood-2005-07-2820","article-title":"Deficient alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the complement factor D gene in a family with meningococcal infections","volume":"107","author":"Sprong","year":"2006","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1016\/j.ekir.2019.05.1156","article-title":"Glomerulonephritis with Isolated C3 Deposits as a Manifestation of Subtotal Factor I Deficiency","volume":"4","author":"Boudhabhay","year":"2019","journal-title":"Kidney Int. Rep."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41435-024-00310-6","article-title":"Understanding rare genetic variants within the terminal pathway of complement system in preeclampsia","volume":"26","author":"Lokki","year":"2025","journal-title":"Genes Immun."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Ferreira, C.S., Francisco Junior, R.D.S., Gerber, A.L., Guimaraes, A.P.C., de Carvalho, F.A.A., Dos Reis, B.C.S., Pinto-Mariz, F., de Souza, M.S., de Vasconcelos, Z.F.M., and Goudouris, E.S. (2023). Genetic screening in a Brazilian cohort with inborn errors of immunity. BMC Genom. Data, 24.","DOI":"10.1186\/s12863-023-01148-z"},{"key":"ref_87","first-page":"1","article-title":"A Novel Mutation Identified in Complement C6 Deficiency","volume":"6","author":"Rizvi","year":"2023","journal-title":"J. Clin. Med. Images"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e25265","DOI":"10.1097\/MD.0000000000025265","article-title":"Disseminated gonococcal infection in a Japanese man with complement 7 deficiency with compound heterozygous variants: A case report","volume":"100","author":"Kageyama","year":"2021","journal-title":"Medicine"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1002\/eji.200636812","article-title":"Hereditary complement C7 deficiency in nine families: Subtotal C7 deficiency revisited","volume":"37","author":"Regnier","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.jmb.2010.10.031","article-title":"Structure of human complement C8, a precursor to membrane attack","volume":"405","author":"Bubeck","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"5290","DOI":"10.1021\/bi0601860","article-title":"Functional studies of the MACPF domain of human complement protein C8alpha reveal sites for simultaneous binding of C8beta, C8gamma, and C9","volume":"45","author":"Slade","year":"2006","journal-title":"Biochemistry"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Bettoni, S., Maziarz, K., Stone, M.R.L., Blaskovich, M.A.T., Potempa, J., Bazzo, M.L., Unemo, M., Ram, S., and Blom, A.M. (2021). Serum Complement Activation by C4BP-IgM Fusion Protein Can Restore Susceptibility to Antibiotics in Neisseria gonorrhoeae. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.726801"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e0014125","DOI":"10.1128\/mbio.00141-25","article-title":"Terminal complement complexes with or without C9 potentiate antimicrobial activity against Neisseria gonorrhoeae","volume":"16","author":"Lamb","year":"2025","journal-title":"mBio"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1080\/07853890510007278","article-title":"C5b-9 complement complex in autoimmune demyelination and multiple sclerosis: Dual role in neuroinflammation and neuroprotection","volume":"37","author":"Rus","year":"2005","journal-title":"Ann. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1080\/14656566.2024.2388267","article-title":"Pharmacotherapy for CD55 deficiency with CHAPLE disease: How close are we to a cure?","volume":"25","author":"Can","year":"2024","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1093\/cei\/uxac120","article-title":"miR-132-3p regulates antibody-mediated complement-dependent cytotoxicity in colon cancer cells by directly targeting CD55","volume":"211","author":"Fan","year":"2023","journal-title":"Clin. Exp. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s00277-007-0420-5","article-title":"Detection of CD55- and CD59-deficient granulocytic populations in patients with myelodysplastic syndrome","volume":"87","author":"Kaiafa","year":"2008","journal-title":"Ann. Hematol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1182\/blood-2012-07-441857","article-title":"CD59 deficiency is associated with chronic hemolysis and childhood relapsing immune-mediated polyneuropathy","volume":"121","author":"Nevo","year":"2013","journal-title":"Blood"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1055\/s-0039-3399583","article-title":"Recurrent Demyelinating Episodes as Sole Manifestation of Inherited CD59 Deficiency","volume":"51","author":"Solmaz","year":"2020","journal-title":"Neuropediatrics"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1212\/CPJ.0000000000000511","article-title":"Uncontrolled inflammation of the nervous system: Inherited CD59 deficiency","volume":"8","author":"Yuksel","year":"2018","journal-title":"Neurol. Clin. Pract."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Lorenzini, P.A., Gusareva, E.S., Ghosh, A.G., Ramli, N.A.B., Preiser, P.R., and Kim, H.L. (2023). Population-specific positive selection on low CR1 expression in malaria-endemic regions. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0280282"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"566","DOI":"10.46497\/ArchRheumatol.2022.9167","article-title":"Identification of a novel mutation in complement receptor 2 in Chinese familial systemic lupus erythematosus","volume":"37","author":"Tang","year":"2022","journal-title":"Arch. Rheumatol."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Christiansen, M., Offersen, R., Jensen, J.M.B., Petersen, M.S., Larsen, C.S., and Mogensen, T.H. (2019). Identification of Novel Genetic Variants in CVID Patients with Autoimmunity, Autoinflammation, or Malignancy. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.03022"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.4049\/jimmunol.2200423","article-title":"Identification and Characterization of chCR2, a Protein That Binds Chicken Complement Component 3d","volume":"210","author":"Jin","year":"2023","journal-title":"J. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5877\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T04:20:37Z","timestamp":1783052437000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":104,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135877"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135877","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]}}}