系统性红斑狼疮易感区域FAM167A-BLK遗传变异的调控机制研究

doi:10.16288/j.yczz.25-064

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Hereditas(Beijing) ›› 2025, Vol. 47 ›› Issue (11): 1244-1255.doi: 10.16288/j.yczz.25-064

• Research Article • Previous Articles Next Articles

Exploration of the regulatory function of genetic variants at FAM167A-BLK locus in systemic lupus erythematosus

Ke Li(), Xiaorong Zhou, Dongli Zhu, Xiaofeng Chen, Yan Guo()

Biomedical Informatics & Genomics Center, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China

Received:2025-02-26 Revised:2025-05-09 Online:2025-11-20 Published:2025-05-12
Contact: Yan Guo E-mail:like77@stu.xjtu.edu.cn;guoyan253@xjtu.edu.cn
Supported by:
National Natural Science Foundation of China(82170896);High-Performance Computing Platform and Instrument Analysis Center of Xi’an Jiaotong University

Abstract

Abstract:

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

Ke Li, Xiaorong Zhou, Dongli Zhu, Xiaofeng Chen, Yan Guo. Exploration of the regulatory function of genetic variants at FAM167A-BLK locus in systemic lupus erythematosus[J]. Hereditas(Beijing), 2025, 47(11): 1244-1255.

Figures/Tables 10

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引物名称	引物序列(5′→3′)
BLK promoter扩增引物	上游：CCGCTCGAGCACCTCTCTTCCGCCTTTCT(Xho I)
BLK promoter扩增引物	下游：CCCAAGCTTGTTTTCATGGCTTGTGGCTT(Hind III)
FAM167A promoter扩增引物	上游：CCGCTCGAGGAAGATCTGGATCAAGGCTGTGAC(Xho I)
FAM167A promoter扩增引物	下游：CCCAAGCTTGCTGCTCCTTTCGGAAAGGACTTT(Hind III)
rs2736337片段扩增引物	上游：CGGGGTACCTGGAGCAATGCCTGTCATCA(Kpn I)
rs2736337片段扩增引物	下游：CCGCTCGAGTGCACATCTCGAAATTCTGTGG(Xho I)
rs2736337(C)突变引物	上游：TTGTCTTACCGTTCTGGAGGCTGGAAGTCCAA
rs2736337(C)突变引物	下游：CCAGAACGGTAAGACAATAAACTTCTATTGTTTAAGCCAC
rs2736340片段扩增引物	上游：CGGGGTACCCCACCCCTGTTCACCCATAA(Kpn I)
rs2736340片段扩增引物	下游：CCGCTCGAGTTACCCTTGCCTTGTGCCTT(Xho I)
rs2736340(C)突变引物	上游：TGTACCCACCAATCAGACCCATCACTAATGGTG
rs2736340(C)突变引物	下游：TCTGATTGGTGGGTACATATACAATGCGATGG
rs9693589片段扩增引物	上游：CGACGCGTCCCCCATCCCAGACCAAATC(Mlu I)
rs9693589片段扩增引物	下游：CCGCTCGAGTCAAGGCGGGACTGAGACTA(Xho I)
rs9693589(G)突变引物	上游：TCAAGTGATCTGCCCCGCCCTCAGCCTCCCAAAGTG
rs9693589(G)突变引物	下游：CGGGGCAGATCACTTGAGGTCAGGAGTTCGAG
rs2618476片段扩增引物	上游：CGGGGTACCATGAATGGATCGCTGCCTCA(Kpn I)
rs2618476片段扩增引物	下游：CCGCTCGAGTTACTGCAAACGCACAATTCCT(Xho I)
rs2618476(T)突变引物	上游：GGCAAATGACTGTTGCTTTCGTTTTATTTGTTTGTTTCTGAATG
rs2618476(T)突变引物	下游：AGCAACAGTCATTTGCCTTGAGCCAGATGCTC

qRT-PCR靶向基因	引物序列(5′→3′)
BLK	上游：GGATGGGGCTGGTAAGTAGC
BLK	下游：CATCCAGGTGTTCATCGGGC
FAM167A	上游：AAGGAACTGACGGAGATGCG
FAM167A	下游：GCTCGTAGGTGGCATCGTT
PRDM1	上游：GCAACTGGATGCGCTATGTG
PRDM1	下游：GCAGGGATGGGCTTAATGGT
ETS1	上游：ATGAATGGAGCAGCCCTCTG
ETS1	下游：CGGGATTCTGGATAGGCTGG
LYN	上游：TGTGAGAGATCCAACGTCCA
LYN	下游：GGTGGATGCCATCATAGGGG
BANK1	上游：CAGCGCCCCCAGGAAATAC
BANK1	下游：CAGCAACTCCAAATGCCGAA
IRF5	上游：GGGCTTCAATGGGTCAACG
IRF5	下游：GCCTTCGGTGTATTTCCCTG
IL-6	上游：TTCGGTCCAGTTGCCTTCTC
IL-6	下游：CTGAGATGCCGTCGAGGATG
STAT4	上游：GAGACCAGCTCATTGCCTGT
STAT4	下游：CAATGTGGCAGGTGGAGGAT

引物名称	引物序列(5′→3′)
BLK_dCas9-1- sgRNA1	上游：ACCGACCAGTGAGGCTGAAAGAA
BLK_dCas9-1- sgRNA1	下游：TAACTTCTTTCAGCCTCACTGGT
BLK_dCas9-1- sgRNA2	上游：ACCGTTGCTAACTCTGCCGGACT
BLK_dCas9-1- sgRNA2	下游：TAACAGTCCGGCAGAGTTAGCAA
BLK_dCas9-2- sgRNA1	上游：ACCGCTGCCCTGGTGCACACAGA
BLK_dCas9-2- sgRNA1	下游：TAACTCTGTGTGCACCAGGGCAG
BLK_dCas9-2- sgRNA2	上游：ACCGGCTGTTAAACCAAAACCCC
BLK_dCas9-2- sgRNA2	下游：TAACGGGGTTTTGGTTTAACAGC
FAM167A_dCas9-1- sgRNA1	上游：ACCGCCGGAAGGTGGGTTCGCGC
FAM167A_dCas9-1- sgRNA1	下游：TAACGCGCGAACCCACCTTCCGG
FAM167A_dCas9-1- sgRNA2	上游：ACCGGGCGCTGCTCCTTTCGGAA
FAM167A_dCas9-1- sgRNA2	下游：TAACTTCCGAAAGGAGCAGCGCC
FAM167A_dCas9-2- sgRNA1	上游：ACCGGAGGAGGCGGCGGGGACAC
FAM167A_dCas9-2- sgRNA1	下游：TAACGTGTCCCCGCCGCCTCCTC
FAM167A_dCas9-2- sgRNA2	上游：ACCGAACCGCCCTGACGCAACGC
FAM167A_dCas9-2- sgRNA2	下游：TAACGCGTTGCGTCAGGGCGGTT

SNP	位置	基因	JASPAR_ CORE_2018	HOCO MOCOv11	Transfac	Swiss Regulon	Jolma 2013
rs2736337 (C/T)	基因间区	BLK、FAM167A	SMAD3(C)	SMAD4(C)、TBX2(C)	HNF1A(T)	HNF1A(T)	−
rs2736340 (T/C)	基因间区	BLK	NFYA(C)、NFYB(C)、RREB1(C)	NFYA(C)、NFYB(C)、NFYC(C)、RREB1(C)、EVX1(T)、HOXA1(T)、HOXA5(T)	NFYA(C)、NFYC(C)	RREB1(C)	−
rs9693589 (A/G)	基因间区	BLK、FAM167A	SP4(G)、E2F3(G)、E2F4(G)	E2F1(G)、 E2F3(G)、 E2F4(G)、SALL4(A)、 SPIC(A)	SP4(G)、E2F3(G)、E2F4(G)、MAZ(G)、KLF1(A)、KLF13(A)	MAZ(G)	SP4(G)
rs2618476 (C/T)	内含子区	BLK、FAM167A	IRF7(T)、IRF9(T)、IRF1(T)	IRF7(T)、IRF2(T)、 IRF1(T)	IRF7(T)、IRF9(T)、IRF5(T)、IRF2(T)、RFX1(C)、 ZNF350(C)	−	IRF7(T)、IRF9(T)、IRF5(T)

Exploration of the regulatory function of genetic variants at FAM167A-BLK locus in systemic lupus erythematosus

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