Identification of an Association of <i>TNFAIP3</i> Polymorphisms With Matrix Metalloproteinase Expression in Fibroblasts in an Integrative Study of Systemic Sclerosis–Associated Genetic and Environmental Factors

Wei, Peng; Yang, Yang; Hei, Nainan; Lai, Syeling; Assassi, Shervin; Liu, Mengyuan; Tan, Filemon K.; Zhou, Xiaodong

doi:10.1002/art.39476

Cited by 27 publications

(19 citation statements)

References 51 publications

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“…Qualitative and quantitative changes in the extracellular matrix (ECM) related to a disturbed balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs) have been demonstrated to play a significant role in the pathophysiology of PH and SSc . In particular, the generation of fragments and the exposure of functionally important cryptic sites in collagens, laminins, elastin, or fibronectin are known to stimulate the production of matrix glycoproteins and release of growth factors that are encrypted in the ECM or from their cell membrane–bound precursors, and to facilitate pulmonary artery smooth muscle cell proliferation and contribute to their switch from a contractile to a migratory phenotype .…”

Section: Discussionmentioning

confidence: 99%

Role of Stromelysin 2 (Matrix Metalloproteinase 10) as a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated With Systemic Sclerosis

Avouac

Guignabert

Hoffmann-Vold

et al. 2017

Arthritis & Rheumatology

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Section: Discussionmentioning

confidence: 99%

Role of Stromelysin 2 (Matrix Metalloproteinase 10) as a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated With Systemic Sclerosis

Avouac

Guignabert

Hoffmann-Vold

et al. 2017

Arthritis & Rheumatology

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“…One recent study investigated the interactions between genetic and environmental factors (silica particles) in SSc using a fibroblast model [61]. The authors reported that the SNP rs58905141 in TNFAIP3 was strongly and persistently associated with silica particles-stimulated MMP1 and MMP3 expression in fibroblasts, suggesting a potential interaction of the SSc susceptibility locus in TNFAIP3 and silica particles, which might be associated with the development of SSc through inflammatory mechanisms.…”

Section: Genetic Involvementmentioning

confidence: 99%

Unfolding the pathogenesis of scleroderma through genomics and epigenomics

Tsou

Sawalha

2017

Journal of Autoimmunity

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With unknown etiology, scleroderma (SSc) is a multifaceted disease that comprises of immune activation, vascular complications, and excessive fibrosis in internal organs. Genetic studies, including candidate gene association studies, genome-wide association studies, and whole-exome sequencing have supported the notion that while modest, SSc patients are genetically predisposed to this disease. The strongest genetic association for SSc lies within the MHC region, with loci in HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DOA1 being the most replicated. The non-HLA genes associated with SSc are involved in various functions, with the most robust associations including genes for B and T cell activation and innate immunity. Other pathways include genes involved in extracellular matrix deposition, cytokines, and autophagy. Among these genes, IRF5, STAT4, and CD247 were replicated most frequently while SNPs rs35677470 in DNASE1L3, rs5029939 in TNFAIP3, and rs7574685 in STAT4 have the strongest associations with SSc. In addition to genetic predisposition, it became clear that environmental factors and epigenetic influences also contribute to the development of SSc. Epigenetics, which refers to studies that focus on heritable phenotypes resulting from changes in chromatin structure without affecting the DNA sequence, is one of the most rapidly expanding fields in biomedical research. Indeed extensive epigenetic changes have been described in SSc. Alteration in enzymes and mediators involved in DNA methylation and histone modification, as well as dysregulated miRNA levels all contribute to fibrosis, immune dysregulation, and impaired angiogenesis in this disease. Genes that were affected by epigenetic dysregulation include ones involved in autoimmunity, T cell function and regulation, TGFβ pathway, Wnt pathway, extracellular matrix, and transcription factors governing fibrosis and angiogenesis. In this review, we provide a comprehensive overview of the current findings of SSc genetic susceptibility, followed by an extensive description and a systematic review of epigenetic research that has been carried out to date in SSc. We also summarize the therapeutic potential of drugs that affect epigenetic mechanisms, and outline the future prospective of genomincs and epigenomics research in SSc.

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“…Out of the 19 genes that were previously identified as harboring SSc susceptibility SNPs in Whites, only TNFAIP3 was nominally significant in the gene-level analysis in African Americans. Previously, we showed that SNPs of TNFAIP3 had a strong association with expression of matrix metalloproteinase 1 and 3 in fibroblasts of ethnically diverse patients in response to silica particle stimulation [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Gene-level association analysis of systemic sclerosis: A comparison of African-Americans and White populations

Gorlova

Gorlov

et al. 2018

PLoS ONE

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Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.

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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

Cited by 27 publications

References 51 publications

Role of Stromelysin 2 (Matrix Metalloproteinase 10) as a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated With Systemic Sclerosis

Role of Stromelysin 2 (Matrix Metalloproteinase 10) as a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated With Systemic Sclerosis

Unfolding the pathogenesis of scleroderma through genomics and epigenomics

Gene-level association analysis of systemic sclerosis: A comparison of African-Americans and White populations

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