DDX6 - CXCR5自身免疫性疾病风险基因座中的变异影响免疫细胞和唾液腺中的调控网络。
Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland.
作者信息
Wiley Mandi M, Radziszewski Marcin, Khatri Bhuwan, Joachims Michelle L, Tessneer Kandice L, Stolarczyk Anna M, Yao Songyuan, Li James, Pritchett-Frazee Cherilyn, Johnston Audrey A, Rasmussen Astrid, Anaya Juan-Manuel, Aqrawi Lara A, Bae Sang-Cheol, Baecklund Eva, Björk Albin, Brun Johan G, Bucher Sara Magnusson, Dand Nick, Eloranta Maija-Leena, Engelke Fiona, Forsblad-d'Elia Helena, Fugmann Cecilia, Glenn Stuart B, Gong Chen, Gottenberg Jacques-Eric, Hammenfors Daniel, Imgenberg-Kreuz Juliana, Jensen Janicke Liaaen, Johnsen Svein Joar Auglænd, Jonsson Malin V, Kelly Jennifer A, Khanam Sharmily, Kim Kwangwoo, Kvarnström Marika, Mandl Thomas, Martín Javier, Morris David L, Nocturne Gaetane, Norheim Katrine Brække, Olsson Peter, Palm Øyvind, Pers Jacques-Olivier, Rhodus Nelson L, Sjöwall Christopher, Skarstein Kathrine, Taylor Kimberly E, Tombleson Phil, Thorlacius Gudny Ella, Venuturupalli Swamy R, Vital Edward M, Wallace Daniel J, Radfar Lida, Brennan Michael T, James Judith A, Scofield R Hal, Gaffney Patrick M, Criswell Lindsey A, Jonsson Roland, Appel Silke, Eriksson Per, Bowman Simon J, Omdal Roald, Rönnblom Lars, Warner Blake M, Rischmueller Maureen, Witte Torsten, Farris A Darise, Mariette Xavier, Shiboski Caroline H, Wahren-Herlenius Marie, Alarcón-Riquelme Marta E, Ng Wan-Fai, Sivils Kathy L, Guthridge Joel M, Adrianto Indra, Vyse Timothy J, Tsao Betty P, Nordmark Gunnel, Lessard Christopher J
机构信息
Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, OK, USA.
Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, OK, USA; University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
出版信息
Ann Rheum Dis. 2025 May 29. doi: 10.1016/j.ard.2025.04.023.
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.
目的
干燥综合征（SjD）和系统性红斑狼疮（SLE）在DDX6 - CXCR5基因座（11q23.3）存在共同的遗传风险。鉴定该基因座上的共享单核苷酸多态性（SNP）并对其进行功能表征，可为自身免疫的共同遗传机制提供新的见解。
方法
跨疾病荟萃分析、精细定位和生物信息学分析，优先选择共享的可能具有功能的单核苷酸多态性（SNP），使用电泳迁移率变动分析、荧光素酶报告基因分析、定量染色质构象捕获分析以及成簇规律间隔短回文重复序列（CRISPR）基因调控技术，进行等位基因特异性和细胞类型特异性的功能研究。
结果
在原代人免疫细胞、唾液腺和肾脏组织中，鉴定出5个共享的可能具有功能的SNP：rs57494551、rs4936443、rs4938572、rs7117261和rs4938573。在免疫、唾液腺上皮和肾脏上皮细胞模型中，所有这5个SNP对核蛋白结合亲和力和增强子/启动子调控活性均表现出细胞类型特异性和等位基因特异性效应。染色质 - 染色质相互作用图谱揭示了一个染色质调控网络延伸至DDX6和CXCR5之外，还包括PHLDB1、lnc - PHLDB1 - 1、BCL9L、TRAPPC4等。功能分析和多组学数据分析表明，这些SNP可能调节3个调控区域的活性：内含子rs57494551调控区域、基因间SNP单倍型（rs4938572、rs4936443和rs7117261）调控区域以及CXCR5启动子上游的rs4938573调控区域。
结论
SjD和SLE在DDX6 - CXCR5基因座上的共同遗传易感性可能改变自身免疫的共同机制，包括干扰素信号传导（DDX6）、自噬（TRAPPC4）以及疾病靶组织的淋巴细胞浸润（CXCR5）。此外，利用SjD患者的多组学数据，结合生物信息学和体外功能研究，可为遗传风险如何影响驱动复杂自身免疫的生物学途径提供机制性见解。
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