基于基因的全基因组关联分析在欧洲和亚洲人群中鉴定出类风湿关节炎的新基因。
Gene-Based Genome-Wide Association Analysis in European and Asian Populations Identified Novel Genes for Rheumatoid Arthritis.
作者信息
Zhu Hong, Xia Wei, Mo Xing-Bo, Lin Xiang, Qiu Ying-Hua, Yi Neng-Jun, Zhang Yong-Hong, Deng Fei-Yan, Lei Shu-Feng
机构信息
Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, Jiangsu, China.
Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China.
出版信息
PLoS One. 2016 Nov 29;11(11):e0167212. doi: 10.1371/journal.pone.0167212. eCollection 2016.
OBJECTIVE
Rheumatoid arthritis (RA) is a complex autoimmune disease. Using a gene-based association research strategy, the present study aims to detect unknown susceptibility to RA and to address the ethnic differences in genetic susceptibility to RA between European and Asian populations.
METHODS
Gene-based association analyses were performed with KGG 2.5 by using publicly available large RA datasets (14,361 RA cases and 43,923 controls of European subjects, 4,873 RA cases and 17,642 controls of Asian Subjects). For the newly identified RA-associated genes, gene set enrichment analyses and protein-protein interactions analyses were carried out with DAVID and STRING version 10.0, respectively. Differential expression verification was conducted using 4 GEO datasets. The expression levels of three selected 'highly verified' genes were measured by ELISA among our in-house RA cases and controls.
RESULTS
A total of 221 RA-associated genes were newly identified by gene-based association study, including 71'overlapped', 76 'European-specific' and 74 'Asian-specific' genes. Among them, 105 genes had significant differential expressions between RA patients and health controls at least in one dataset, especially for 20 genes including 11 'overlapped' (ABCF1, FLOT1, HLA-F, IER3, TUBB, ZKSCAN4, BTN3A3, HSP90AB1, CUTA, BRD2, HLA-DMA), 5 'European-specific' (PHTF1, RPS18, BAK1, TNFRSF14, SUOX) and 4 'Asian-specific' (RNASET2, HFE, BTN2A2, MAPK13) genes whose differential expressions were significant at least in three datasets. The protein expressions of two selected genes FLOT1 (P value = 1.70E-02) and HLA-DMA (P value = 4.70E-02) in plasma were significantly different in our in-house samples.
CONCLUSION
Our study identified 221 novel RA-associated genes and especially highlighted the importance of 20 candidate genes on RA. The results addressed ethnic genetic background differences for RA susceptibility between European and Asian populations and detected a long list of overlapped or ethnic specific RA genes. The study not only greatly increases our understanding of genetic susceptibility to RA, but also provides important insights into the ethno-genetic homogeneity and heterogeneity of RA in both ethnicities.
目的
类风湿性关节炎（RA）是一种复杂的自身免疫性疾病。本研究采用基于基因的关联研究策略，旨在检测RA未知的易感性，并探讨欧洲和亚洲人群在RA遗传易感性方面的种族差异。
方法
使用公开可用的大型RA数据集（14361例欧洲RA患者和43923例对照，4873例亚洲RA患者和17642例对照），通过KGG 2.5进行基于基因的关联分析。对于新鉴定出的与RA相关的基因，分别使用DAVID和STRING 10.0版本进行基因集富集分析和蛋白质-蛋白质相互作用分析。使用4个GEO数据集进行差异表达验证。通过ELISA在我们内部的RA病例和对照中测量3个选定的“高度验证”基因的表达水平。
结果
通过基于基因的关联研究新鉴定出总共221个与RA相关的基因，包括71个“重叠”基因、76个“欧洲特异性”基因和74个“亚洲特异性”基因。其中，105个基因在至少一个数据集中RA患者和健康对照之间具有显著差异表达，特别是20个基因，包括11个“重叠”基因（ABCF1、FLOT1、HLA-F、IER3、TUBB、ZKSCAN4、BTN3A3、HSP90AB1、CUTA、BRD2、HLA-DMA）、5个“欧洲特异性”基因（PHTF1、RPS18、BAK1、TNFRSF14、SUOX）和4个“亚洲特异性”基因（RNASET2、HFE、BTN2A2、MAPK13），其差异表达在至少三个数据集中显著。在我们的内部样本中，血浆中两个选定基因FLOT1（P值 = 1.70E - 02）和HLA - DMA（P值 = 4.70E - 02）的蛋白质表达存在显著差异。
结论
我们的研究鉴定出221个新的与RA相关的基因，尤其突出了20个候选基因对RA的重要性。研究结果揭示了欧洲和亚洲人群在RA易感性方面的种族遗传背景差异，并检测到一长串重叠或种族特异性的RA基因。该研究不仅极大地增加了我们对RA遗传易感性的理解，还为两个种族中RA的民族遗传同质性和异质性提供了重要见解。
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