Mehmet Hocaoglu, Desiré Casares‐Marfil, Amr H. Sawalha
ObjectiveAntinuclear antibodies (ANA) are detected in up to 14% of the population, and the majority of individuals with ANA are asymptomatic. The literature on the genetic contribution to asymptomatic ANA positivity in the population is limited. In this study, we aimed to perform a genome‐wide association study (GWAS) of asymptomatic ANA positivity in multiple populations.MethodsAsymptomatic ANA positive and negative individuals from the All of Us Research Program were included in this study, selecting those with an ANA test by immunofluorescence and no evidence of autoimmune disease. Imputation was performed and a multi‐population meta‐analysis including approximately 6 million single‐nucleotide polymorphisms (SNPs) was conducted. Genome‐wide SNP based heritability was estimated using the GCTA software. A cumulative genetic risk score for lupus was constructed using previously reported genome‐wide significant loci.Results1,955 asymptomatic ANA positive and 3,634 asymptomatic ANA negative individuals were included across three genetic populations. The multi‐population meta‐analysis revealed SNPs with a suggestive association (p‐value < 1×10‐5) across 8 different loci, but no genome‐wide significant loci were identified. A gene variant upstream of HLA‐DQB1 (rs17211748, P = 1.4×10‐6, OR = 0.82, 95% CI 0.76‐0.89) showed the most significant association. The heritability of asymptomatic ANA positivity was estimated to be 24.9%. Asymptomatic ANA positive individuals did not exhibit increased cumulative genetic risk for lupus compared to ANA negative individuals.ConclusionANA production is not associated with significant genetic risk and is primarily determined by environmental factors.image
目的：多达 14% 的人群中可检测到抗核抗体 (ANA)，而大多数 ANA 患者是无症状的。有关人群中无症状 ANA 阳性的遗传贡献的文献十分有限。本研究旨在对多个人群中的无症状 ANA 阳性进行全基因组关联研究（GWAS）。研究方法纳入 "我们所有人研究计划 "中的无症状 ANA 阳性和阴性个体，选择那些通过免疫荧光法进行 ANA 检测且无自身免疫性疾病证据的个体。研究人员进行了估算，并进行了多人群荟萃分析，其中包括约 600 万个单核苷酸多态性 (SNP)。使用 GCTA 软件估算了基于 SNP 的全基因组遗传率。利用之前报告的全基因组重要基因位点，构建了狼疮累积遗传风险评分。多人群荟萃分析揭示了 8 个不同位点上具有提示性关联的 SNPs（p-value <1×10-5），但未发现具有全基因组意义的位点。HLA-DQB1上游的一个基因变异（rs17211748，P = 1.4×10-6，OR = 0.82，95% CI 0.76-0.89）显示了最显著的相关性。无症状 ANA 阳性的遗传率估计为 24.9%。与 ANA 阴性个体相比，无症状 ANA 阳性个体患红斑狼疮的累积遗传风险并没有增加。
{"title":"Genetic analysis of asymptomatic antinuclear antibody production","authors":"Mehmet Hocaoglu, Desiré Casares‐Marfil, Amr H. Sawalha","doi":"10.1002/art.43032","DOIUrl":"https://doi.org/10.1002/art.43032","url":null,"abstract":"ObjectiveAntinuclear antibodies (ANA) are detected in up to 14% of the population, and the majority of individuals with ANA are asymptomatic. The literature on the genetic contribution to asymptomatic ANA positivity in the population is limited. In this study, we aimed to perform a genome‐wide association study (GWAS) of asymptomatic ANA positivity in multiple populations.MethodsAsymptomatic ANA positive and negative individuals from the All of Us Research Program were included in this study, selecting those with an ANA test by immunofluorescence and no evidence of autoimmune disease. Imputation was performed and a multi‐population meta‐analysis including approximately 6 million single‐nucleotide polymorphisms (SNPs) was conducted. Genome‐wide SNP based heritability was estimated using the GCTA software. A cumulative genetic risk score for lupus was constructed using previously reported genome‐wide significant loci.Results1,955 asymptomatic ANA positive and 3,634 asymptomatic ANA negative individuals were included across three genetic populations. The multi‐population meta‐analysis revealed SNPs with a suggestive association (p‐value < 1×10<jats:sup>‐5</jats:sup>) across 8 different loci, but no genome‐wide significant loci were identified. A gene variant upstream of <jats:italic>HLA‐DQB1</jats:italic> (rs17211748, <jats:italic>P</jats:italic> = 1.4×10<jats:sup>‐6</jats:sup>, OR = 0.82, 95% CI 0.76‐0.89) showed the most significant association. The heritability of asymptomatic ANA positivity was estimated to be 24.9%. Asymptomatic ANA positive individuals did not exhibit increased cumulative genetic risk for lupus compared to ANA negative individuals.ConclusionANA production is not associated with significant genetic risk and is primarily determined by environmental factors.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" mimetype=\"image/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic/art43032-toc-0001-m.png\"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"40 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jessica Bryon, Christopher W Wasson, Katja Koeppen, Francesca Chandler, Leon F Willis, Stefano Di Donato, Elliott Klein, Elton Zeqiraj, Rebecca L Ross, Francesco Del Galdo
BackgroundActivation of Type I IFN response has been shown to correlates with disease activity in systemic sclerosis. It is currently unknown whether the tissue‐specific Type I IFN activation is a consequence of the response observed in blood or rather its source. Exosomes from SSc fibroblasts were recently shown to activate macrophages in vitro. Here, we aimed to determine the source of Type I IFN signature in SSc skin biopsies and the potential role of exosomes from SSc dermal fibroblasts in the process.MethodsSkin biopsies were obtained from healthy and SSc patients’ forearms and processed for dermal fibroblasts and keratinocytes. Exosomes were isolated from healthy and SSc dermal fibroblast supernatants by ultracentrifugation and added to human skin keratinocytes. Keratinocyte transcriptome was analysed by RNA‐seq analysis. TANK‐binding kinase (TBK) and JAK were inhibited using a small molecule inhibitor (GSK8612) and Tofacitinib, respectively.ResultsSSc skin biopsies showed highest levels of Type I IFN response in the epidermal layer. RNA‐seq analysis of keratinocytes transcriptome following exposure to dermal fibroblast exosomes showed strong upregulation of IFN signature genes induced by SSc exosomes compared to Healthy control. Inhibition of TBK or JAK activity suppressed the upregulation of the IFN signature induced by SSc exosomes.ConclusionIFN activation of SSc keratinocytes is dependent on their crosstalk with dermal fibroblasts and inducible by extracellular exosomes. Our data indicates that SSc fibroblasts exosomes contributes to theType I IFN activation in SSc skin through activation of pattern recognition receptors upstream of TBK.
背景I型IFN反应的激活已被证明与系统性硬化症的疾病活动有关。目前尚不清楚组织特异性 I 型 IFN 激活是血液中观察到的反应的结果还是其来源。最近有研究表明，来自 SSc 成纤维细胞的外泌体可在体外激活巨噬细胞。在此，我们旨在确定 SSc 皮肤活检组织中 I 型 IFN 特征的来源，以及 SSc 皮肤成纤维细胞的外泌体在这一过程中的潜在作用。通过超速离心从健康和 SSc 皮肤成纤维细胞上清液中分离出外泌体，并将其添加到人类皮肤角质细胞中。通过RNA-seq分析对角质细胞转录组进行了分析。分别使用小分子抑制剂（GSK8612）和托法替尼抑制 TANK 结合激酶（TBK）和 JAK。与健康对照组相比，暴露于真皮成纤维细胞外泌体后的角朊细胞转录组的RNA-seq分析表明，SSc外泌体诱导的IFN特征基因有很强的上调。结论IFN对SSc角质形成细胞的激活依赖于它们与真皮成纤维细胞的串联，并可由细胞外的外泌体诱导。我们的数据表明，SSc成纤维细胞外泌体通过激活TBK上游的模式识别受体，促进了SSc皮肤中I型IFN的激活。
{"title":"Systemic Sclerosis dermal fibroblast exosomes trigger a Type 1 interferon response in keratinocytes through the TBK/JAK/STAT signalling axis","authors":"Jessica Bryon, Christopher W Wasson, Katja Koeppen, Francesca Chandler, Leon F Willis, Stefano Di Donato, Elliott Klein, Elton Zeqiraj, Rebecca L Ross, Francesco Del Galdo","doi":"10.1002/art.43029","DOIUrl":"https://doi.org/10.1002/art.43029","url":null,"abstract":"BackgroundActivation of Type I IFN response has been shown to correlates with disease activity in systemic sclerosis. It is currently unknown whether the tissue‐specific Type I IFN activation is a consequence of the response observed in blood or rather its source. Exosomes from SSc fibroblasts were recently shown to activate macrophages <jats:italic>in vitro</jats:italic>. Here, we aimed to determine the source of Type I IFN signature in SSc skin biopsies and the potential role of exosomes from SSc dermal fibroblasts in the process.MethodsSkin biopsies were obtained from healthy and SSc patients’ forearms and processed for dermal fibroblasts and keratinocytes. Exosomes were isolated from healthy and SSc dermal fibroblast supernatants by ultracentrifugation and added to human skin keratinocytes. Keratinocyte transcriptome was analysed by RNA‐seq analysis. TANK‐binding kinase (TBK) and JAK were inhibited using a small molecule inhibitor (GSK8612) and Tofacitinib, respectively.ResultsSSc skin biopsies showed highest levels of Type I IFN response in the epidermal layer. RNA‐seq analysis of keratinocytes transcriptome following exposure to dermal fibroblast exosomes showed strong upregulation of IFN signature genes induced by SSc exosomes compared to Healthy control. Inhibition of TBK or JAK activity suppressed the upregulation of the IFN signature induced by SSc exosomes.ConclusionIFN activation of SSc keratinocytes is dependent on their crosstalk with dermal fibroblasts and inducible by extracellular exosomes. Our data indicates that SSc fibroblasts exosomes contributes to theType I IFN activation in SSc skin through activation of pattern recognition receptors upstream of TBK.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"13 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Role of Autoantibodies in Lupus Nephritis: reply.","authors":"Andrea Fava,Catriona A Wagner,Judith A James","doi":"10.1002/art.43033","DOIUrl":"https://doi.org/10.1002/art.43033","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"232 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Role of Autoantibodies in Lupus Nephritis: comment on the article by Fava et al.","authors":"Lingxiang Ran,Rui Zhao,Guangmo Hu","doi":"10.1002/art.43035","DOIUrl":"https://doi.org/10.1002/art.43035","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"68 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"JAK Inhibitors vs. Biologic DMARDs: Which is More Effective for Rheumatoid Arthritis Pain?","authors":"Abigail Weiland, Yvonne C. Lee","doi":"10.1002/art.43026","DOIUrl":"https://doi.org/10.1002/art.43026","url":null,"abstract":"Click on the article title to read more.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"193 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Osteoarthritis: MRI Definitions and Disease Progression","authors":"David T. Felson","doi":"10.1002/art.43022","DOIUrl":"https://doi.org/10.1002/art.43022","url":null,"abstract":"Click on the article title to read more.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"67 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sho Fukui, Masato Okada, Tomohiro Shinozaki, Takahiro Suzuki, Takehiro Nakai, Hiroki Ozawa, Hiromichi Tamaki, Mitsumasa Kishimoto, Hiroshi Hasegawa, Takeaki Matsuda, Javier Marrugo, Sara K Tedeschi, Hyon K Choi, Daniel H. Solomon
To evaluate associations of weight reduction with serum urate (SU) changes and achieving an SU <6 mg/dl in the real-world setting, outside of specific weight reduction interventions.
目的：在实际环境中，评估减轻体重与血清尿酸盐（SU）变化之间的关系，以及在不采取特定减轻体重干预措施的情况下，实现 SU <6 mg/dl 的目标。
{"title":"Weight Reduction and Target Serum Urate Level: A Longitudinal Study of Annual Medical Examination","authors":"Sho Fukui, Masato Okada, Tomohiro Shinozaki, Takahiro Suzuki, Takehiro Nakai, Hiroki Ozawa, Hiromichi Tamaki, Mitsumasa Kishimoto, Hiroshi Hasegawa, Takeaki Matsuda, Javier Marrugo, Sara K Tedeschi, Hyon K Choi, Daniel H. Solomon","doi":"10.1002/art.43027","DOIUrl":"https://doi.org/10.1002/art.43027","url":null,"abstract":"To evaluate associations of weight reduction with serum urate (SU) changes and achieving an SU <6 mg/dl in the real-world setting, outside of specific weight reduction interventions.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"9 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Enhancing Health Care Affordability: Strategies for Accelerating Biosimilar Uptake","authors":"Dongzhe Hong, Aaron S. Kesselheim","doi":"10.1002/art.43030","DOIUrl":"https://doi.org/10.1002/art.43030","url":null,"abstract":"Click on the article title to read more.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"229 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Incorrect about ICD coding for SLE","authors":"Johannes Nossent","doi":"10.1002/art.43025","DOIUrl":"https://doi.org/10.1002/art.43025","url":null,"abstract":"Click on the article title to read more.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"115 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：