title: 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.
abstract: OBJECTIVE
  Systemic sclerosis (SSc) is a fibrotic disease attributed to both genetic susceptibility and environmental factors. This study was undertaken to investigate the associations between SSc-associated genetic variants and the expression of extracellular matrix (ECM) genes in human fibroblasts stimulated with silica particles in time-course and dose-response experiments.
  
  
  METHODS
  A total of 200 fibroblast strains were examined for ECM gene expression after stimulation with silica particles. The fibroblasts were genetically profiled using Immunochip assays and then subjected to whole-genome genotype imputation. Associations of genotypes and gene expression were first analyzed in a Caucasian cohort and then validated in a meta-analysis combining the results from Caucasian, African American, and Hispanic subjects. A linear mixed model for longitudinal data analysis was used to identify genetic variants associated with the expression of ECM genes, and the associations were validated by using a haplotype-based longitudinal association test on regions that included the loci identified.
  
  
  RESULTS
  The single-nucleotide polymorphism rs58905141 in TNFAIP3 was consistently associated with time-course and/or dose-response expression of MMP3 and MMP1 in the fibroblasts stimulated with silica particles in both the analysis of Caucasian subjects only and the meta-analysis. Results of the haplotype-based analysis validated the association signals.
  
  
  CONCLUSIONS
  Our findings indicate that a genetic variant of TNFAIP3 is strongly associated with the silica-induced profibrotic response of fibroblasts. In silico functional analysis based on the ENCODE database revealed that rs58905141 might affect the binding activities of the transcription factors for TNFAIP3. This is the first genome-wide study of interactions between genetic and environmental factors in a complex SSc fibroblast model.
authors.affiliation: University of Texas Health Science Center at Houston.
authors.forename: Peng
authors.initials: P
authors.lastname: Wei
authors.affiliation: University of Texas Health Science Center at Houston.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: University of Texas Health Science Center at Houston.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Guo
authors.affiliation: University of Texas Health Science Center at Houston.
authors.forename: Nainan
authors.initials: N
authors.lastname: Hei
authors.affiliation: Baylor College of Medicine, Houston, Texas.
authors.forename: Syeling
authors.initials: S
authors.lastname: Lai
authors.affiliation: University of Texas Health Science Center at Houston.
authors.forename: Shervin
authors.initials: S
authors.lastname: Assassi
authors.affiliation: University of Texas Health Science Center at Houston.
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Liu
authors.affiliation: University of Texas Health Science Center at Houston.
authors.forename: Filemon
authors.initials: F
authors.lastname: Tan
authors.affiliation: University of Texas Health Science Center at Houston.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004306:Dose-Response Relationship, Immunologic; D005109:Extracellular Matrix / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012595:Scleroderma, Systemic / Q000235:genetics*; D012822:Silicon Dioxide / Q000494:pharmacology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D044465:White People / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D012822:Silicon Dioxide; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1