Mandi M Wiley, Marcin Radziszewski, Bhuwan Khatri, Michelle L Joachims, Kandice L Tessneer, Anna M Stolarczyk, Songyuan Yao, James Li, Cherilyn Pritchett-Frazee, Audrey A Johnston, Astrid Rasmussen, Juan-Manuel Anaya, Lara A Aqrawi, Sang-Cheol Bae, Eva Baecklund, Albin Björk, Johan G Brun, Sara Magnusson Bucher, Nick Dand, Maija-Leena Eloranta, Fiona Engelke, Helena Forsblad-d'Elia, Cecilia Fugmann, Stuart B Glenn, Chen Gong, Jacques-Eric Gottenberg, Daniel Hammenfors, Juliana Imgenberg-Kreuz, Janicke Liaaen Jensen, Svein Joar Auglænd Johnsen, Malin V Jonsson, Jennifer A Kelly, Sharmily Khanam, Kwangwoo Kim, Marika Kvarnström, Thomas Mandl, Javier Martín, David L Morris, Gaetane Nocturne, Katrine Brække Norheim, Peter Olsson, Øyvind Palm, Jacques-Olivier Pers, Nelson L Rhodus, Christopher Sjöwall, Kathrine Skarstein, Kimberly E Taylor, Phil Tombleson, Gudny Ella Thorlacius, Swamy R Venuturupalli, Edward M Vital, Daniel J Wallace, Lida Radfar, Michael T Brennan, Judith A James, R Hal Scofield, Patrick M Gaffney, Lindsey A Criswell, Roland Jonsson, Silke Appel, Per Eriksson, Simon J Bowman, Roald Omdal, Lars Rönnblom, Blake M Warner, Maureen Rischmueller, Torsten Witte, A Darise Farris, Xavier Mariette, Caroline H Shiboski, Marie Wahren-Herlenius, Marta E Alarcón-Riquelme, Wan-Fai Ng, Kathy L Sivils, Joel M Guthridge, Indra Adrianto, Timothy J Vyse, Betty P Tsao, Gunnel Nordmark, Christopher J Lessard
{"title":"DDX6-CXCR5自身免疫性疾病风险位点的变异影响免疫细胞和唾液腺的调节网络。","authors":"Mandi M Wiley, Marcin Radziszewski, Bhuwan Khatri, Michelle L Joachims, Kandice L Tessneer, Anna M Stolarczyk, Songyuan Yao, James Li, Cherilyn Pritchett-Frazee, Audrey A Johnston, Astrid Rasmussen, Juan-Manuel Anaya, Lara A Aqrawi, Sang-Cheol Bae, Eva Baecklund, Albin Björk, Johan G Brun, Sara Magnusson Bucher, Nick Dand, Maija-Leena Eloranta, Fiona Engelke, Helena Forsblad-d'Elia, Cecilia Fugmann, Stuart B Glenn, Chen Gong, Jacques-Eric Gottenberg, Daniel Hammenfors, Juliana Imgenberg-Kreuz, Janicke Liaaen Jensen, Svein Joar Auglænd Johnsen, Malin V Jonsson, Jennifer A Kelly, Sharmily Khanam, Kwangwoo Kim, Marika Kvarnström, Thomas Mandl, Javier Martín, David L Morris, Gaetane Nocturne, Katrine Brække Norheim, Peter Olsson, Øyvind Palm, Jacques-Olivier Pers, Nelson L Rhodus, Christopher Sjöwall, Kathrine Skarstein, Kimberly E Taylor, Phil Tombleson, Gudny Ella Thorlacius, Swamy R Venuturupalli, Edward M Vital, Daniel J Wallace, Lida Radfar, Michael T Brennan, Judith A James, R Hal Scofield, Patrick M Gaffney, Lindsey A Criswell, Roland Jonsson, Silke Appel, Per Eriksson, Simon J Bowman, Roald Omdal, Lars Rönnblom, Blake M Warner, Maureen Rischmueller, Torsten Witte, A Darise Farris, Xavier Mariette, Caroline H Shiboski, Marie Wahren-Herlenius, Marta E Alarcón-Riquelme, Wan-Fai Ng, Kathy L Sivils, Joel M Guthridge, Indra Adrianto, Timothy J Vyse, Betty P Tsao, Gunnel Nordmark, Christopher J Lessard","doi":"10.1016/j.ard.2025.04.023","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>Sjögren's disease (SjD) and systemic lupus erythematosus (SLE) share genetic risk at the DDX6-CXCR5 locus (11q23.3). Identifying and functionally characterising shared SNPs spanning this locus can provide new insights into common genetic mechanisms of autoimmunity.</p><p><strong>Methods: </strong>Transdisease meta-analyses, fine-mapping, and bioinformatic analyses prioritised shared likely functional single nucleotide polymorphisms (SNPs) for allele-specific and cell type-specific functional interrogation using electromobility shift, luciferase reporter, and quantitative chromatin conformation capture assays and clustered regularly interspaced short palindromic repeat (CRISPR) gene regulation.</p><p><strong>Results: </strong>Five shared SNPs were identified as likely functional in primary human immune cells, salivary gland and kidney tissues: rs57494551, rs4936443, rs4938572, rs7117261, and rs4938573. All 5 SNPs exhibited cell type-specific and allele-specific effects on nuclear protein binding affinity and enhancer/promoter regulatory activity in immune, salivary gland epithelial, and kidney epithelial cell models. Mapping of chromatin-chromatin interactions revealed a chromatin regulatory network that expanded beyond DDX6 and CXCR5 to include PHLDB1, lnc-PHLDB1-1, BCL9L, TRAPPC4, among others. Coalescence of functional assays and multiomic data analyses indicated that these SNPs likely modulate the activity of 3 regulatory regions: intronic rs57494551 regulatory region, intergenic SNP haplotype (rs4938572, rs4936443, and rs7117261) regulatory region, and rs4938573 regulatory region upstream of the CXCR5 promoter.</p><p><strong>Conclusions: </strong>Shared genetic susceptibly at the DDX6-CXCR5 locus in SjD and SLE likely alters common mechanisms of autoimmunity, including interferon signalling (DDX6), autophagy (TRAPPC4), and lymphocytic infiltration of disease-target tissues (CXCR5). Further, using multiomic data from patients with SjD, combined with bioinformatic and in vitro functional studies, can provide mechanistic insights into how genetic risk influences the biological pathways that drive complex autoimmunity.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3000,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236377/pdf/","citationCount":"0","resultStr":"{\"title\":\"Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland.\",\"authors\":\"Mandi M Wiley, Marcin Radziszewski, Bhuwan Khatri, Michelle L Joachims, Kandice L Tessneer, Anna M Stolarczyk, Songyuan Yao, James Li, Cherilyn Pritchett-Frazee, Audrey A Johnston, Astrid Rasmussen, Juan-Manuel Anaya, Lara A Aqrawi, Sang-Cheol Bae, Eva Baecklund, Albin Björk, Johan G Brun, Sara Magnusson Bucher, Nick Dand, Maija-Leena Eloranta, Fiona Engelke, Helena Forsblad-d'Elia, Cecilia Fugmann, Stuart B Glenn, Chen Gong, Jacques-Eric Gottenberg, Daniel Hammenfors, Juliana Imgenberg-Kreuz, Janicke Liaaen Jensen, Svein Joar Auglænd Johnsen, Malin V Jonsson, Jennifer A Kelly, Sharmily Khanam, Kwangwoo Kim, Marika Kvarnström, Thomas Mandl, Javier Martín, David L Morris, Gaetane Nocturne, Katrine Brække Norheim, Peter Olsson, Øyvind Palm, Jacques-Olivier Pers, Nelson L Rhodus, Christopher Sjöwall, Kathrine Skarstein, Kimberly E Taylor, Phil Tombleson, Gudny Ella Thorlacius, Swamy R Venuturupalli, Edward M Vital, Daniel J Wallace, Lida Radfar, Michael T Brennan, Judith A James, R Hal Scofield, Patrick M Gaffney, Lindsey A Criswell, Roland Jonsson, Silke Appel, Per Eriksson, Simon J Bowman, Roald Omdal, Lars Rönnblom, Blake M Warner, Maureen Rischmueller, Torsten Witte, A Darise Farris, Xavier Mariette, Caroline H Shiboski, Marie Wahren-Herlenius, Marta E Alarcón-Riquelme, Wan-Fai Ng, Kathy L Sivils, Joel M Guthridge, Indra Adrianto, Timothy J Vyse, Betty P Tsao, Gunnel Nordmark, Christopher J Lessard\",\"doi\":\"10.1016/j.ard.2025.04.023\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>Sjögren's disease (SjD) and systemic lupus erythematosus (SLE) share genetic risk at the DDX6-CXCR5 locus (11q23.3). Identifying and functionally characterising shared SNPs spanning this locus can provide new insights into common genetic mechanisms of autoimmunity.</p><p><strong>Methods: </strong>Transdisease meta-analyses, fine-mapping, and bioinformatic analyses prioritised shared likely functional single nucleotide polymorphisms (SNPs) for allele-specific and cell type-specific functional interrogation using electromobility shift, luciferase reporter, and quantitative chromatin conformation capture assays and clustered regularly interspaced short palindromic repeat (CRISPR) gene regulation.</p><p><strong>Results: </strong>Five shared SNPs were identified as likely functional in primary human immune cells, salivary gland and kidney tissues: rs57494551, rs4936443, rs4938572, rs7117261, and rs4938573. All 5 SNPs exhibited cell type-specific and allele-specific effects on nuclear protein binding affinity and enhancer/promoter regulatory activity in immune, salivary gland epithelial, and kidney epithelial cell models. Mapping of chromatin-chromatin interactions revealed a chromatin regulatory network that expanded beyond DDX6 and CXCR5 to include PHLDB1, lnc-PHLDB1-1, BCL9L, TRAPPC4, among others. Coalescence of functional assays and multiomic data analyses indicated that these SNPs likely modulate the activity of 3 regulatory regions: intronic rs57494551 regulatory region, intergenic SNP haplotype (rs4938572, rs4936443, and rs7117261) regulatory region, and rs4938573 regulatory region upstream of the CXCR5 promoter.</p><p><strong>Conclusions: </strong>Shared genetic susceptibly at the DDX6-CXCR5 locus in SjD and SLE likely alters common mechanisms of autoimmunity, including interferon signalling (DDX6), autophagy (TRAPPC4), and lymphocytic infiltration of disease-target tissues (CXCR5). Further, using multiomic data from patients with SjD, combined with bioinformatic and in vitro functional studies, can provide mechanistic insights into how genetic risk influences the biological pathways that drive complex autoimmunity.</p>\",\"PeriodicalId\":8087,\"journal\":{\"name\":\"Annals of the Rheumatic Diseases\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":20.3000,\"publicationDate\":\"2025-05-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236377/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of the Rheumatic Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ard.2025.04.023\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of the Rheumatic Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ard.2025.04.023","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland.
Objectives: Sjögren's disease (SjD) and systemic lupus erythematosus (SLE) share genetic risk at the DDX6-CXCR5 locus (11q23.3). Identifying and functionally characterising shared SNPs spanning this locus can provide new insights into common genetic mechanisms of autoimmunity.
Methods: Transdisease meta-analyses, fine-mapping, and bioinformatic analyses prioritised shared likely functional single nucleotide polymorphisms (SNPs) for allele-specific and cell type-specific functional interrogation using electromobility shift, luciferase reporter, and quantitative chromatin conformation capture assays and clustered regularly interspaced short palindromic repeat (CRISPR) gene regulation.
Results: Five shared SNPs were identified as likely functional in primary human immune cells, salivary gland and kidney tissues: rs57494551, rs4936443, rs4938572, rs7117261, and rs4938573. All 5 SNPs exhibited cell type-specific and allele-specific effects on nuclear protein binding affinity and enhancer/promoter regulatory activity in immune, salivary gland epithelial, and kidney epithelial cell models. Mapping of chromatin-chromatin interactions revealed a chromatin regulatory network that expanded beyond DDX6 and CXCR5 to include PHLDB1, lnc-PHLDB1-1, BCL9L, TRAPPC4, among others. Coalescence of functional assays and multiomic data analyses indicated that these SNPs likely modulate the activity of 3 regulatory regions: intronic rs57494551 regulatory region, intergenic SNP haplotype (rs4938572, rs4936443, and rs7117261) regulatory region, and rs4938573 regulatory region upstream of the CXCR5 promoter.
Conclusions: Shared genetic susceptibly at the DDX6-CXCR5 locus in SjD and SLE likely alters common mechanisms of autoimmunity, including interferon signalling (DDX6), autophagy (TRAPPC4), and lymphocytic infiltration of disease-target tissues (CXCR5). Further, using multiomic data from patients with SjD, combined with bioinformatic and in vitro functional studies, can provide mechanistic insights into how genetic risk influences the biological pathways that drive complex autoimmunity.
期刊介绍：
Annals of the Rheumatic Diseases (ARD) is an international peer-reviewed journal covering all aspects of rheumatology, which includes the full spectrum of musculoskeletal conditions, arthritic disease, and connective tissue disorders. ARD publishes basic, clinical, and translational scientific research, including the most important recommendations for the management of various conditions.
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