{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T07:17:09Z","timestamp":1781939829891,"version":"3.54.5"},"reference-count":40,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81901663"],"award-info":[{"award-number":["81901663"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82271851"],"award-info":[{"award-number":["82271851"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Young Backbone Teachers Training Program of Henan Province","award":["2023GGJS048"],"award-info":[{"award-number":["2023GGJS048"]}]},{"name":"Key Project of Medical Science and Technology Research Program of Henan Province","award":["SBGJ202002098"],"award-info":[{"award-number":["SBGJ202002098"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:sec>\n               <jats:title>Background<\/jats:title>\n               <jats:p>Variations in the TLR9 gene have been associated with several autoimmune disorders, but the relationship between TLR9 polymorphisms and systemic lupus erythematosus (SLE) remains controversial. This study aims to evaluate the potential association between three single-nucleotide polymorphisms (SNPs) within the TLR9 gene and susceptibility to SLE in the Han Chinese female population.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Methods<\/jats:title>\n               <jats:p>A total of 150 SLE patients and 151 healthy controls of Han Chinese ethnicity were enrolled. Genotyping of TLR9 was performed using sequence-specific primer (SSP) polymerase chain reaction and validated by Sanger sequencing. Associations between the SNPs and SLE susceptibility were analyzed using the chi-square test or Fisher\u2019s exact test. Additionally, correlations between the SNPs and clinical manifestations of SLE were assessed.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Results<\/jats:title>\n               <jats:p>The TLR9 <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.ncbi.nlm.nih.gov\/snp\/?term=rs352139\">rs352139<\/jats:ext-link> polymorphism was significantly associated with increased SLE susceptibility in heterozygous (AG <jats:italic>vs.<\/jats:italic> AA, OR = 1.79, 95% CI [1.07\u20132.99], <jats:italic>p<\/jats:italic>\u00a0=\u00a0 0.025), homozygous (GG <jats:italic>vs.<\/jats:italic> AA, OR = 2.11, 95% CI [1.06\u20134.19], <jats:italic>p<\/jats:italic>\u00a0=\u00a0 0.033), dominant (GG+AG <jats:italic>vs.<\/jats:italic> AA, OR = 1.86, 95% CI [1.15\u20133.03], <jats:italic>p<\/jats:italic>\u00a0=\u00a0 0.012), and allele (G <jats:italic>vs.<\/jats:italic> A, OR = 1.49, 95% CI [1.07\u20132.06], <jats:italic>p<\/jats:italic>\u00a0=\u00a0 0.017) models. Similarly, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.ncbi.nlm.nih.gov\/snp\/?term=rs352140\">rs352140<\/jats:ext-link> was significantly associated with SLE risk in homozygous (TT <jats:italic>vs.<\/jats:italic> CC, OR = 2.47, 95% CI [1.23\u20134.96], <jats:italic>p<\/jats:italic>\u00a0=\u00a0 0.010), recessive (TT <jats:italic>vs.<\/jats:italic> CC+CT, OR = 2.57, 95% CI [1.35\u20134.88], <jats:italic>p<\/jats:italic>\u00a0=\u00a0 0.003), and allele (T <jats:italic>vs.<\/jats:italic> C, OR = 1.43, 95% CI [1.03\u20131.99], <jats:italic>p<\/jats:italic>\u00a0=\u00a0 0.031) models. Haplotype analysis revealed that haplotype HT1 (C\/A\/T) had a protective effect against SLE (OR = 0.70, 95% CI [0.506\u20130.966], <jats:italic>p<\/jats:italic>\u00a0=\u00a0 0.030), while haplotype HT2 (T\/G\/T) was positively associated with increased susceptibility (OR = 1.505, 95% CI [1.068\u20132.121], <jats:italic>p<\/jats:italic>\u00a0=\u00a0 0.019).<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Conclusions<\/jats:title>\n               <jats:p>These findings suggest that the TLR9 <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.ncbi.nlm.nih.gov\/snp\/?term=rs352139\">rs352139<\/jats:ext-link> and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.ncbi.nlm.nih.gov\/snp\/?term=rs352140\">rs352140<\/jats:ext-link> polymorphisms are significantly associated with increased susceptibility to SLE in the Han Chinese population, indicating a potential role of TLR9 in the pathogenesis of SLE.<\/jats:p>\n            <\/jats:sec>","DOI":"10.7717\/peerj.19847","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T08:42:22Z","timestamp":1755074542000},"page":"e19847","source":"Crossref","is-referenced-by-count":2,"title":["Genetic variants of Toll-like receptor 9 are associated with susceptibility to systemic lupus erythematosus in Han Chinese female patients"],"prefix":"10.7717","volume":"13","author":[{"given":"Lili","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Immunology, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shushu","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Immunology, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, China"},{"name":"Qingpu Traditional Chinese Medicine Hospital, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Immunology, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang,  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongzeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Immunology, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4443","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"10.7717\/peerj.19847\/ref-1","doi-asserted-by":"publisher","first-page":"665","DOI":"10.2147\/JIR.S394927","article-title":"Impact of toll-like receptor 2 and 9 gene polymorphisms on COVID-19: susceptibility, severity, and thrombosis","volume":"16","author":"Alhabibi","year":"2023","journal-title":"Journal of Inflammation Research"},{"key":"10.7717\/peerj.19847\/ref-2","doi-asserted-by":"publisher","first-page":"e244123","DOI":"10.1590\/1519-6984.244123","article-title":"Toll-like receptor 9 polymorphisms in Brazilian patients with systemic lupus erythematosus: a pilot study","volume":"83","author":"Barbosa","year":"2021","journal-title":"Brazilian Journal of Biology"},{"key":"10.7717\/peerj.19847\/ref-3","doi-asserted-by":"publisher","first-page":"2355","DOI":"10.3899\/jrheum.080175","article-title":"Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): LXI, Value of C-reactive protein as a marker of disease activity and damage","volume":"35","author":"Bertoli","year":"2008","journal-title":"The Journal of Rheumatology"},{"key":"10.7717\/peerj.19847\/ref-4","doi-asserted-by":"publisher","first-page":"e28256","DOI":"10.1371\/journal.pone.0028256","article-title":"The C allele of rs5743836 polymorphism in the human TLR9 promoter links IL-6 and TLR9 up-regulation and confers increased B-cell proliferation","volume":"6","author":"Carvalho","year":"2011","journal-title":"PLOS ONE"},{"key":"10.7717\/peerj.19847\/ref-5","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1007\/s10875-013-9887-0","article-title":"Distinct autoantibody profiles in systemic lupus erythematosus patients are selectively associated with TLR7 and TLR9 upregulation","volume":"33","author":"Chauhan","year":"2013","journal-title":"Journal of Clinical Immunology"},{"key":"10.7717\/peerj.19847\/ref-6","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1111\/cei.13022","article-title":"Relevant genetic polymorphisms and kidney expression of Toll-like receptor (TLR)-5 and TLR-9 in lupus nephritis","volume":"190","author":"Elloumi","year":"2017","journal-title":"Clinical and Experimental Immunology"},{"key":"10.7717\/peerj.19847\/ref-7","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1038\/s41584-020-00544-4","article-title":"Toll-like receptor signalling in B cells during systemic lupus erythematosus","volume":"17","author":"Fillatreau","year":"2021","journal-title":"Nature Reviews Rheumatology"},{"key":"10.7717\/peerj.19847\/ref-8","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1016\/j.cell.2020.02.041","article-title":"Toll-like receptors and the control of immunity","volume":"180","author":"Fitzgerald","year":"2020","journal-title":"Cell"},{"key":"10.7717\/peerj.19847\/ref-9","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.3390\/ijms18071432","article-title":"Polymorphisms within genes involved in regulation of the NF-kappaB pathway in patients with rheumatoid arthritis","volume":"18","author":"Gebura","year":"2017","journal-title":"International Journal of Molecular Sciences"},{"key":"10.7717\/peerj.19847\/ref-10","doi-asserted-by":"publisher","first-page":"10556","DOI":"10.3390\/ijms241310556","article-title":"Synonymous variants of uncertain silence","volume":"24","author":"Giacoletto","year":"2023","journal-title":"International Journal of Molecular Sciences"},{"key":"10.7717\/peerj.19847\/ref-11","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1136\/annrheumdis-2017-212794","article-title":"The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-\u03b3 production in T cells from patients with SLE","volume":"77","author":"Hagberg","year":"2018","journal-title":"Annals of the Rheumatic Diseases"},{"key":"10.7717\/peerj.19847\/ref-12","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1002\/art.1780400928","article-title":"Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus","volume":"40","author":"Hochberg","year":"1997","journal-title":"Arthritis & Rheumatology"},{"key":"10.7717\/peerj.19847\/ref-13","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/978-1-60327-411-1_2","article-title":"Silent (synonymous) SNPs: should we care about them?","volume":"578","author":"Hunt","year":"2009","journal-title":"Methods in Molecular Biology"},{"key":"10.7717\/peerj.19847\/ref-14","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1111\/j.1399-0039.2005.00374.x","article-title":"Association study of Toll-like receptor 9 gene polymorphism in Korean patients with systemic lupus erythematosus","volume":"65","author":"Hur","year":"2005","journal-title":"Tissue Antigens"},{"key":"10.7717\/peerj.19847\/ref-15","doi-asserted-by":"publisher","first-page":"123","DOI":"10.5808\/gi.2017.15.4.123","article-title":"Synonymous codon usage controls various molecular aspects","volume":"15","author":"Im","year":"2017","journal-title":"Genomics & Informatics"},{"key":"10.7717\/peerj.19847\/ref-16","doi-asserted-by":"publisher","first-page":"20169","DOI":"10.1038\/s41598-021-99625-x","article-title":"Association of TLR 9 gene polymorphisms with remission in patients with rheumatoid arthritis receiving TNF-\u03b1 inhibitors and development of machine learning models","volume":"11","author":"Kim","year":"2021","journal-title":"Scientific Reports"},{"key":"10.7717\/peerj.19847\/ref-17","doi-asserted-by":"publisher","first-page":"Itc81","DOI":"10.7326\/aitc202006020","article-title":"Systemic lupus erythematosus","volume":"172","author":"Kiriakidou","year":"2020","journal-title":"Annals of Internal Medicine"},{"key":"10.7717\/peerj.19847\/ref-18","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1089\/gtmb.2021.0288","article-title":"TLR9 2848 G\/A gene polymorphism in HCV+, HIV+, and HCV+\/HIV+ individuals","volume":"26","author":"Kulmann-Leal","year":"2022","journal-title":"Genetic Testing and Molecular Biomarkers"},{"key":"10.7717\/peerj.19847\/ref-19","doi-asserted-by":"publisher","first-page":"e124020","DOI":"10.1172\/jci.insight.124020","article-title":"IRF5 genetic risk variants drive myeloid-specific IRF5 hyperactivation and presymptomatic SLE","volume":"5","author":"Li","year":"2020","journal-title":"JCI Insight"},{"key":"10.7717\/peerj.19847\/ref-20","doi-asserted-by":"publisher","first-page":"1878","DOI":"10.1016\/s0140-6736(14)60128-8","article-title":"Systemic lupus erythematosus","volume":"384","author":"Lisnevskaia","year":"2014","journal-title":"Lancet"},{"key":"10.7717\/peerj.19847\/ref-21","doi-asserted-by":"publisher","first-page":"55","DOI":"10.3389\/fimmu.2016.00055","article-title":"Systemic lupus erythematosus and deficiencies of early components of the complement classical pathway","volume":"7","author":"Macedo","year":"2016","journal-title":"Frontiers in Immunology"},{"key":"10.7717\/peerj.19847\/ref-22","doi-asserted-by":"publisher","first-page":"e1008092","DOI":"10.1371\/journal.pgen.1008092","article-title":"Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians","volume":"15","author":"Molineros","year":"2019","journal-title":"PLOS Genetics"},{"key":"10.7717\/peerj.19847\/ref-23","first-page":"695","article-title":"Prevalence and clinico-serological correlations of anti-alpha-enolase, anti-C1q, and anti-dsDNA antibodies in patients with systemic lupus erythematosus","volume":"33","author":"Mosca","year":"2006","journal-title":"The Journal of Rheumatology"},{"key":"10.7717\/peerj.19847\/ref-24","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1128\/IAI.01226-09","article-title":"Increase in NF-kappaB binding affinity of the variant C allele of the toll-like receptor 9-1237T\/C polymorphism is associated with Helicobacter pylori-induced gastric disease","volume":"78","author":"Ng","year":"2010","journal-title":"Infection and Immunity"},{"key":"10.7717\/peerj.19847\/ref-25","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/j.immuni.2018.03.013","article-title":"Toll-like receptor 9 contains two DNA binding sites that function cooperatively to promote receptor dimerization and activation","volume":"48","author":"Ohto","year":"2018","journal-title":"Immunity"},{"key":"10.7717\/peerj.19847\/ref-26","doi-asserted-by":"publisher","first-page":"1492092","DOI":"10.1155\/2019\/1492092","article-title":"Genetic polymorphisms of toll-like receptors 2 and 9 as susceptibility factors for the development of ankylosing spondylitis and psoriatic arthritis","volume":"2019","author":"Oliveira-Tor\u00e9","year":"2019","journal-title":"Journal of Immunology Research"},{"key":"10.7717\/peerj.19847\/ref-27","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1186\/1475-2875-11-168","article-title":"Toll-like receptor 9 (TLR9) polymorphism associated with symptomatic malaria: a cohort study","volume":"11","author":"Omar","year":"2012","journal-title":"Malaria Journal"},{"key":"10.7717\/peerj.19847\/ref-28","doi-asserted-by":"publisher","first-page":"929995","DOI":"10.3389\/fimmu.2022.929995","article-title":"Influence of single-nucleotide polymorphisms in TLR3 (rs3775291) and TLR9 (rs352139) on the risk of CMV infection in kidney transplant recipients","volume":"13","author":"Redondo","year":"2022","journal-title":"Frontiers in Immunology"},{"key":"10.7717\/peerj.19847\/ref-29","doi-asserted-by":"publisher","first-page":"504","DOI":"10.2337\/db20-0373","article-title":"TLR9 deficiency in B cells promotes immune tolerance via interleukin-10 in a type 1 diabetes mouse model","volume":"70","author":"Sha","year":"2021","journal-title":"Diabetes"},{"key":"10.7717\/peerj.19847\/ref-30","doi-asserted-by":"publisher","first-page":"235","DOI":"10.3109\/08820139.2015.1137934","article-title":"Contribution of Toll-like receptor 9 gene single-nucleotide polymorphism to systemic lupus erythematosus in Egyptian patients","volume":"45","author":"Shahin","year":"2016","journal-title":"Immunological Investigations"},{"key":"10.7717\/peerj.19847\/ref-31","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1136\/jmedgenet-2016-104072","article-title":"Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B","volume":"54","author":"Simhadri","year":"2017","journal-title":"Journal of Medical Genetics"},{"key":"10.7717\/peerj.19847\/ref-32","doi-asserted-by":"publisher","first-page":"3231","DOI":"10.1093\/nar\/gkx001","article-title":"Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage","volume":"45","author":"Suspene","year":"2017","journal-title":"Nucleic Acids Research"},{"key":"10.7717\/peerj.19847\/ref-33","doi-asserted-by":"publisher","first-page":"102615","DOI":"10.1016\/j.jaut.2021.102615","article-title":"Clinical disease activity and flare in SLE: current concepts and novel biomarkers","volume":"119","author":"Thanou","year":"2021","journal-title":"Journal of Autoimmunity"},{"key":"10.7717\/peerj.19847\/ref-34","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1136\/ard-2022-223035","article-title":"Global epidemiology of systemic lupus erythematosus: a comprehensive systematic analysis and modelling study","volume":"82","author":"Tian","year":"2023","journal-title":"Annals of the Rheumatic Diseases"},{"key":"10.7717\/peerj.19847\/ref-35","doi-asserted-by":"publisher","first-page":"3172","DOI":"10.1172\/JCI132328","article-title":"B cell-intrinsic TLR9 expression is protective in murine lupus","volume":"130","author":"Tilstra","year":"2020","journal-title":"Journal of Clinical Investigation"},{"key":"10.7717\/peerj.19847\/ref-36","doi-asserted-by":"publisher","first-page":"1030736","DOI":"10.3389\/fendo.2023.1030736","article-title":"Association analysis between the TLR9 gene polymorphism rs352140 and type 1 diabetes","volume":"14","author":"Wang","year":"2023","journal-title":"Frontiers in Endocrinology"},{"key":"10.7717\/peerj.19847\/ref-37","first-page":"7872","article-title":"Associations of genetic polymorphisms of TLR5, TLR9 and transduction molecules in MyD88 signaling pathway with systemic lupus erythematosus in Zhuang and Han ethnics of Guangxi province, China","volume":"8","author":"Wen","year":"2015","journal-title":"International Journal of Clinical and Experimental Medicine"},{"key":"10.7717\/peerj.19847\/ref-38","doi-asserted-by":"publisher","first-page":"2245","DOI":"10.1007\/s11033-008-9440-z","article-title":"Association study of a single nucleotide polymorphism in the exon 2 region of toll-like receptor 9 (TLR9) gene with susceptibility to systemic lupus erythematosus among Chinese","volume":"36","author":"Xu","year":"2009","journal-title":"Molecular Biology Reports"},{"key":"10.7717\/peerj.19847\/ref-39","doi-asserted-by":"publisher","first-page":"1049340","DOI":"10.3389\/fimmu.2022.1049340","article-title":"Toll-like receptor-targeted anti-tumor therapies: advances and challenges","volume":"13","author":"Yang","year":"2022","journal-title":"Frontiers in Immunology"},{"key":"10.7717\/peerj.19847\/ref-40","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/j.gene.2013.08.051","article-title":"Association study of TLR-9 polymorphisms and systemic lupus erythematosus in northern Chinese Han population","volume":"533","author":"Zhang","year":"2014","journal-title":"Gene"}],"container-title":["PeerJ"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/peerj.com\/articles\/19847.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/19847.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/19847.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/19847.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T08:42:28Z","timestamp":1755074548000},"score":1,"resource":{"primary":{"URL":"https:\/\/peerj.com\/articles\/19847"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,13]]},"references-count":40,"alternative-id":["10.7717\/peerj.19847"],"URL":"https:\/\/doi.org\/10.7717\/peerj.19847","archive":["CLOCKSS","LOCKSS","Portico"],"relation":{},"ISSN":["2167-8359"],"issn-type":[{"value":"2167-8359","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,13]]},"article-number":"e19847"}}