Identification of an Association of TNFAIP3 Polymorphisms With Matrix Metalloproteinase Expression in Fibroblasts in an Integrative Study of Systemic Sclerosis-Associated Genetic and Environmental Factors.
Identification of an Association of TNFAIP3 Polymorphisms With Matrix Metalloproteinase Expression in Fibroblasts in an Integrative Study of Systemic Sclerosis-Associated Genetic and Environmental Factors.
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DOI：
10.1002/art.39476
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Zhou X
中科院分区：
文献类型：
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作者：
Wei P;Yang Y;Guo X;Hei N;Lai S;Assassi S;Liu M;Tan F;Zhou X
系统性硬化症(SSC)是一种遗传性和环境因素共同作用的纤维化疾病。我们的研究试图展示具有SSC相关基因变体的人成纤维细胞如何在二氧化硅颗粒刺激下对细胞外基质(ECM)基因的时程和剂量反应做出反应。用二氧化硅颗粒刺激200株成纤维细胞，检测细胞外基质基因的表达。用免疫芯片技术对成纤维细胞进行基因分析，然后进行全基因组基因定位。首先在高加索人群中分析了基因类型和基因表达的相关性，然后通过结合高加索人、黑人和西班牙裔结果的荟萃分析进行验证。我们应用线性混合模型进行纵向数据分析来识别与ECM基因表达相关的遗传变异；作为验证方法，我们对识别出的基因座区域进行了基于单倍型的纵向关联检验。仅在高加索和Meta分析中，TNFAIP3的SNP rs58905141与二氧化硅颗粒刺激的成纤维细胞MMP3和MMP1基因表达的时程和(或)剂量效应相关。基于单倍型的分析验证了关联信号。TNFAIP3的一个基因变异与二氧化硅诱导的成纤维细胞的促纤维化反应密切相关。在基于ENCODE的电子功能分析中，rs58905141可能影响转录因子与TNFAIP3的结合活性。这是第一次在复杂的SSC成纤维细胞模型中对遗传和环境因素之间的相互作用进行全基因组研究。
Systemic Sclerosis (SSc) is a fibrotic disease attributed to both genetic susceptibility and environmental factors. Our studies tried to demonstrate how human fibroblasts with SSc associated genetic variants respond to time-course and dose-response expression of the extracellular matrix (ECM) genes with silica particle stimulation. A total of 200 fibroblast strains were examined for ECM gene expression after stimulation by silica particles. The fibroblasts were genetically profiled with Immunochip assays, and followed by whole-genome genotype imputation. Associations of genotypes and gene expressions were first analyzed in a Caucasian cohort, and then validated by a meta-analysis which combines the results from Caucasian, Blacks and Hispanics. We applied the linear mixed model for longitudinal data analysis to identify genetic variants associated with ECM genes’ expressions; we implemented haplotype-based longitudinal association test on identified loci region as a validation approach. SNP rs58905141 of TNFAIP3 was consistently associated with time-course and/or dose-response expressions of MMP3 gene and MMP1 gene of the fibroblasts stimulated with silica particles in both Caucasian only and meta-analysis. The haplotype-based analysis validated the association signals. A genetic variant of TNFAIP3 is strongly associated with the silica-induced profibrotic response of the fibroblasts. In silico functional analysis based on ENCODE revealed that rs58905141 might affect binding activities of the transcription factors for TNFAIP3. This is the first genome-wide study of interaction between genetic and environmental factors in a complex SSc fibroblast model.