系统性红斑狼疮易感区域FAM167A-BLK遗传变异的调控机制研究
收稿日期: 2025-02-26
修回日期: 2025-05-09
网络出版日期: 2025-05-12
基金资助
国家自然科学基金项目(82170896);西安交通大学高性能计算平台和仪器分析中心资助
Exploration of the regulatory function of genetic variants at FAM167A-BLK locus in systemic lupus erythematosus
Received date: 2025-02-26
Revised date: 2025-05-09
Online published: 2025-05-12
Supported by
National Natural Science Foundation of China(82170896);High-Performance Computing Platform and Instrument Analysis Center of Xi’an Jiaotong University
系统性红斑狼疮(systemic lupus erythematosus，SLE)是一种累及多器官的自身免疫性疾病。8p23区域的FAM167A-BLK基因座是SLE既往全基因组关联研究(genome-wide association study，GWAS)报道的热点区域。为探索该区域内功能SNP(single-nucleotide polymorphism)对其相关基因BLK和FAM167A调控的作用，本研究利用GCTA软件和fnGWAS进行一系列功能注释，筛选出潜在的功能SNP，并通过双荧光素酶报告基因实验、shRNA敲低和CRISPR/dCas9敲低等功能实验进行验证。结果显示，该区域有4个功能SNP对BLK表达具有等位基因特异性增强效应，但对FAM167A无显著影响。同时，BLK可调控FAM167A表达。FAM167A可能是SLE的潜在致病基因。本研究深化了对FAM167A-BLK区域的遗传变异调控机制的理解，为解析SLE的发生机制研究提供了新视角。
关键词： 系统性红斑狼疮; FAM167A-BLK基因座; SNP; 增强子
李轲, 周晓蓉, 朱东丽, 陈晓峰, 郭燕 . 系统性红斑狼疮易感区域FAM167A-BLK遗传变异的调控机制研究[J]. 遗传, 2025 , 47(11) : 1244 -1255 . DOI: 10.16288/j.yczz.25-064
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with multi-organ involvement. The FAM167A-BLK locus at 8p23 has been identified as a genetic susceptibility locus for SLE by previous genome-wide association studies (GWAS). To explore the role of functional single-nucleotide polymorphisms (SNPs) within this locus on the regulation of BLK and FAM167A genes, we perform comprehensive functional annotation using GCTA and fnGWAS approaches to identify candidate functional SNPs，and verify them through dual-luciferase reporter assays, shRNA knockdown experiments, and CRISPR/dCas9 knockdown experiments. The results show that four functional SNPs exhibit allele-specific enhancing effect on BLK expression, while showing no discernible regulatory influence on FAM167A expression. Importantly, BLK is shown to regulate the expression of FAM167A. These findings highlight FAM167A as a potential pathogenic gene contributing to SLE. This study expands the mechanistic understanding of genetic regulation at the FAM167A-BLK locus and provides new insights into SLE development.
Key words： SLE; FAM167A-BLK locus; SNP; enhancer
| [1] | Jiang N, Bai W, Zhao JL, Zhang SZ, Wu CY, Wang L, Zhao LD, Li J, Hu CJ, Wang Q, Xu D, Leng XM, Zhang W, Li MT, Tian XP, Zeng XF. Diagnosis and treatment directions and research frontiers of systemic lupus erythematosu. Sci Sin(Vitae), 2021, 51(8): 887-900. |
| 姜楠, 白炜, 赵久良, 张上珠, 吴婵媛, 王立, 赵丽丹, 李菁, 胡朝军, 王迁, 徐东, 冷晓梅, 张文, 李梦涛, 田新平, 曾小峰. 系统性红斑狼疮的诊治方向与研究前沿. 中国科学: 生命科学, 2021, 51(8): 887-900. | |
| [2] | Tsokos GC, Lo MS, Reis PC, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol, 2016, 12(12): 716-730. |
| [3] | Catalina MD, Owen KA, Labonte AC, Grammer AC, Lipsky PE. The pathogenesis of systemic lupus erythematosus: harnessing big data to understand the molecular basis of lupus. J Autoimmun, 2020, 110: 102359. |
| [4] | Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, Lee AT, Chung SA, Ferreira RC, Pant PVK, Ballinger DG, Kosoy R, Demirci FY, Kamboh MI, Kao AH, Tian C, Gunnarsson I, Bengtsson AA, Rantapää-Dahlqvist S, Petri M, Manzi S, Seldin MF, Rönnblom L, Syvänen AC, Criswell LA, Gregersen PK, Behrens TW. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med, 2008, 358(9): 900-909. |
| [5] | Simpfendorfer KR, Olsson LM, Manjarrez Orduño N, Khalili H, Simeone AM, Katz MS, Lee AT, Diamond B, Gregersen PK. The autoimmunity-associated BLK haplotype exhibits cis-regulatory effects on mRNA and protein expression that are prominently observed in B cells early in development. Hum Mol Genet, 2012, 21(17): 3918-3925. |
| [6] | Ni JL, Hou YY, Dou H. Research progress on the B lymphoid tyrosine kinase. Chin Bull Life Sci, 2021, 33(2): 176-183. |
| 倪佳俐, 侯亚义, 窦环. B淋巴酪氨酸激酶的研究进展. 生命科学, 2021, 33(2): 176-183. | |
| [7] | Mohammed RA, Elhadad SM, Tawfeik AM, El-Dydamoni OA, Attia AA, Seliem N, Kassem IA, Anani HA. Association of BLK and BANK1 gene polymorphisms with systemic lupus erythematous in Egyptian patients. Egypt J Immunol, 2024, 31(4): 36-45. |
| [8] | Zhang XZ, Mei D, Zhang LL, Wei W. Src family protein kinase controls the fate of B cells in autoimmune diseases. Inflammation, 2021, 44(2): 423-433. |
| [9] | Mentlein L, Thorlacius GE, Meneghel L, Aqrawi LA, Ramírez Sepúlveda JI, Grunewald J, Espinosa A, Wahren-Herlenius M. The rheumatic disease-associated FAM167A-BLK locus encodes DIORA-1, a novel disordered protein expressed highly in bronchial epithelium and alveolar macrophages. Clin Exp Immunol, 2018, 193(2): 167-177. |
| [10] | Yang J, Ferreira T, Morris AP, Medland SE, Genetic Investigation of ANthropometric Traits (GIANT) Consortium, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Madden PAF, Heath AC, Martin NG, Montgomery GW, Weedon MN, Loos RJ, Frayling TM, McCarthy MI, Hirschhorn JN, Goddard ME, Visscher PM. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat Genet, 2012, 44(4): 369-375. |
| [11] | Chen XF, Guo MR, Duan YY, Jiang F, Wu H, Dong SS, Zhou XR, Thynn HN, Liu CC, Zhang L, Guo Y, Yang TL. Multiomics dissection of molecular regulatory mechanisms underlying autoimmune-associated noncoding SNPs. JCI Insight, 2020, 5(17): e136477. |
| [12] | Bentham J, Morris DL, Cunninghame Graham DS, Pinder CL, Tombleson P, Behrens TW, Martín J, Fairfax BP, Knight JC, Chen LY, Replogle J, Syvänen AC, Rönnblom L, Graham RR, Wither JE, Rioux JD, Alarcón-Riquelme ME, Vyse TJ. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet, 2015, 47(12): 1457-1464. |
| [13] | Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience, 2015, 4(1): 7. |
| [14] | Paddison PJ, Cleary M, Silva JM, Chang K, Sheth N, Sachidanandam R, Hannon GJ. Cloning of short hairpin RNAs for gene knockdown in mammalian cells. Nat Methods, 2004, 1(2): 163-167. |
| [15] | Thakore PI, D’Ippolito AM, Song LY, Safi A, Shivakumar NK, Kabadi AM, Reddy TE, Crawford GE, Gersbach CA. Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements. Nat Methods, 2015, 12(12): 1143-1149. |
| [16] | Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, Boehnke M, Abecasis GR, Willer CJ. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics, 2010, 26(18): 2336-2337. |
| [17] | Ghodke-Puranik Y, Niewold TB. Immunogenetics of systemic lupus erythematosus: a comprehensive review. J Autoimmun, 2015, 64: 125-136. |
| [18] | Zhang YX, Pan YZ, Wang X. Progress in targeted lymphocyte therapy for systemic lupus erythematosus. Chin J Med, 2024, 59(11): 1168-1171. |
| 张月霞, 潘耀柱, 王璇. 靶向淋巴细胞治疗系统性红斑狼疮的研究进展. 中国医刊, 2024, 59(11): 1168-1171. | |
| [19] | Song GG, Lee YH. Association between BLK polymerphisms and susceptibility to SLE: a meta-analysis. Z Rheumatol, 2017, 76(2): 176-182. |
| [20] | Saint Just Ribeiro M, Tripathi P, Namjou B, Harley JB, Chepelev I. Haplotype-specific chromatin looping reveals genetic interactions of regulatory regions modulating gene expression in 8p23.1. Front Genet, 2022, 13: 1008582. |
| [21] | Jain S, Park G, Sproule TJ, Christianson GJ, Leeth CM, Wang HS, Roopenian DC, Morse HC. Interleukin 6 accelerates mortality by promoting the progression of the systemic lupus erythematosus-like disease of BXSB.Yaa mice. PLoS One, 2016, 11(4): e0153059. |
| [22] | Wang DC, John SA, Clements JL, Percy DH, Barton KP, Garrett-Sinha LA. Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease. Int Immunol, 2005, 17(9): 1179-1191. |
| [23] | John S, Russell L, Chin SS, Luo W, Oshima R, Garrett- Sinha LA. Transcription factor Ets1, but not the closely related factor Ets2, inhibits antibody-secreting cell differentiation. Mol Cell Biol, 2014, 34(3): 522-532. |
| [24] | Yang T, Sim KY, Ko GH, Ahn JS, Kim HJ, Park SG. FAM167A is a key molecule to induce BCR-ABL- independent TKI resistance in CML via noncanonical NF-κB signaling activation. J Exp Clin Cancer Res, 2022, 41(1): 82. |
| [25] | Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, Niewold TB. Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-α in lupus patients in vivo. J Immunol, 2009, 182(1): 34-38. |
| [26] | Hou XD, Zhang YH, Yang W, Zou GL, Liu Y. Expression and significance of NF-κB and HSP90 in renal puncture tissues and peripheral blood mononuclear cells of patients with lupus nephritis. Clin Exp Rheumatol, 2024. |
| [27] | Yang L, Zhang TT, Wang PL, Chen WT, Liu WM, He XY, Zhang YX, Jin SS, Luo ZJ, Zhang ZJ, Wang XZ, Liu J. Imatinib and M351-0056 enhance the function of VISTA and ameliorate the development of SLE via IFN-I and noncanonical NF-κB pathway. Cell Biol Toxicol, 2023, 39(6): 3287-3304. |
| [28] | Scharer CD, Blalock EL, Mi T, Barwick BG, Jenks SA, Deguchi T, Cashman KS, Neary BE, Patterson DG, Hicks SL, Khosroshahi A, Eun-Hyung Lee F, Wei C, Sanz I, Boss JM. Epigenetic programming underpins B cell dysfunction in human SLE. Nat Immunol, 2019, 20(8): 1071-1082. |
| [29] | Ma Q, Zhou SL, Dang J, Huo ZH, Ma ZB. Genes that escape from X-chromosome inactivation and sexual dimorphism of systemic lupus erythematosus. Hereditas(Beijing), 2024, 46(1): 18-33. |
| 马茜, 周少岚, 党洁, 霍正浩, 马占兵. 失活X染色体基因逃逸与系统性红斑狼疮的性别二态性. 遗传, 2024, 46(1): 18-33. | |
| [30] | Panousis NI, Bertsias GK, Ongen H, Gergianaki I, Tektonidou MG, Trachana M, Romano-Palumbo L, Bielser D, Howald C, Pamfil C, Fanouriakis A, Kosmara D, Repa A, Sidiropoulos P, Dermitzakis ET, Boumpas DT. Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity. Ann Rheum Dis, 2019, 78(8): 1079-1089. |
| [31] | Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, Burgess S, Jiang T, Paige E, Surendran P, Oliver-Williams C, Kamat MA, Prins BP, Wilcox SK, Zimmerman ES, Chi A, Bansal N, Spain SL, Wood AM, Morrell NW, Bradley JR, Janjic N, Roberts DJ, Ouwehand WH, Todd JA, Soranzo N, Suhre K, Paul DS, Fox CS, Plenge RM, Danesh J, Runz H, Butterworth AS. Genomic atlas of the human plasma proteome. Nature, 2018, 558(7708): 73-79. |
| [32] | Cui Y, Cheng M, Guo F. Advances in metabolomics research of systemic lupus erythematosus. J Huaihai Med, 2023, 41(6): 649-652. |
| 崔玙, 程淼, 郭峰. 系统性红斑狼疮的代谢组学研究进展. 淮海医药, 2023, 41(6): 649-652. |
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