Wu Cuiyan, Tan Sijian, Liu Li, Cheng Shiqiang, Li Peilin, Li Wenyu, Liu Huan, Zhang Feng'e, Wang Sen, Ning Yujie, Wen Yan, Zhang Feng
School of Public Health, Xi'an Jiaotong University Health Science Center; Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, No.76, Yan Ta West Road, Xi'an, 710061, People's Republic of China.
Arthritis Res Ther. 2021 Jan 22;23(1):38. doi: 10.1186/s13075-021-02419-9.
To identify rheumatoid arthritis (RA)-associated susceptibility genes and pathways through integrating genome-wide association study (GWAS) and gene expression profile data.
A transcriptome-wide association study (TWAS) was conducted by the FUSION software for RA considering EBV-transformed lymphocytes (EL), transformed fibroblasts (TF), peripheral blood (NBL), and whole blood (YBL). GWAS summary data was driven from a large-scale GWAS, involving 5539 autoantibody-positive RA patients and 20,169 controls. The TWAS-identified genes were further validated using the mRNA expression profiles and made a functional exploration.
TWAS identified 692 genes with P values < 0.05 for RA. CRIPAK (P = 0.01293, P = 0.00038, P = 0.02839, P = 0.0978), MUT (P = 0.00377, P = 0.00076, P = 0.00778, P = 0.00096), FOXRED1 (P = 0.03834, P = 0.01120, P = 0.01280, P = 0.00583), and EBPL (P = 0.00806, P = 0.03761, P = 0.03540, P = 0.04254) were collectively expressed in all the four tissues/cells. Eighteen genes, including ANXA5, AP4B1, ATIC (P = 0.0113, downregulated expression), C12orf65, CMAH, PDHB, RUNX3 (P = 0.0346, downregulated expression), SBF1, SH2B3, STK38, TMEM43, XPNPEP1, KIAA1530, NUFIP2, PPP2R3C, RAB24, STX6, and TLR5 (P = 0.04665, upregulated expression), were validated with integrative analysis of TWAS and mRNA expression profiles. TWAS-identified genes functionally involved in endoplasmic reticulum organization, regulation of cytokine production, TNF signaling pathway, immune response-regulating signaling pathway, regulation of autophagy, etc. CONCLUSION: We identified multiple candidate genes and pathways, providing novel clues for the genetic mechanism of RA.
通过整合全基因组关联研究（GWAS）和基因表达谱数据来鉴定类风湿关节炎（RA）相关的易感基因和通路。
使用FUSION软件针对RA进行全转录组关联研究（TWAS），研究对象包括EB病毒转化的淋巴细胞（EL）、转化的成纤维细胞（TF）、外周血（NBL）和全血（YBL）。GWAS汇总数据来自一项大规模GWAS，涉及5539例自身抗体阳性的RA患者和20169例对照。对TWAS鉴定出的基因进一步利用mRNA表达谱进行验证并进行功能探索。
TWAS鉴定出692个RA的P值<0.05的基因。CRIPAK（P = 0.01293，P = 0.00038，P = 0.02839，P = 0.0978）、MUT（P = 0.00377，P = 0.00076，P = 0.00778，P = 0.00096）、FOXRED1（P = 0.03834，P = 0.01120，P = 0.01280，P = 0.00583）和EBPL（P = 0.00806，P = 0.03761，P = 0.03540，P = 0.04254）在所有这四种组织/细胞中均有共同表达。包括ANXA5、AP4B1、ATIC（P = 0.0113，表达下调）、C12orf65、CMAH、PDHB、RUNX3（P = 0.0346，表达下调）、SBF1、SH2B3、STK38、TMEM43、XPNPEP1、KIAA1530、NUFIP2、PPP2R3C、RAB24、STX6和TLR5（P = 0.04665，表达上调）在内的18个基因通过TWAS和mRNA表达谱的综合分析得到验证。TWAS鉴定出的基因在功能上涉及内质网组织、细胞因子产生的调节、TNF信号通路、免疫反应调节信号通路、自噬调节等。结论：我们鉴定出多个候选基因和通路，为RA的遗传机制提供了新线索。
