Patients with Systemic Sclerosis Present Increased DNA Damage Differentially Associated with DNA Repair Gene Polymorphisms

Palomino, Gustavo Martelli; Bassi, C.; Wastowski, Isabela Jubé; Xavier, Deise Ferreira; Lucisano-Valim, Yara Maria; Crispim, Juliane de Almeida; Rassi, Diane Meyre; Marques-Neto, João Francisco; Sakamoto-Hojo, Elza T.; Moreau, Philippe; Sampaio-Barros, Percival D.; Donadi, Eduardo Antônio

doi:10.3899/jrheum.130376

Cited by 21 publications

(21 citation statements)

References 47 publications

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“…However, SSc patients with either XRCC1 allele presented increased DNA damage compared to healthy individuals. Regarding the XRCC4 gene, both healthy individuals and SSc patients with the Ile401Thr allele presented higher levels of DNA damage compared to healthy individuals or SSc patients with the XRCC4 wild type allele [23]. Together, these results indicate that SSc patients with polymorphisms at genes of DNA repair enzymes are characterized by increased DNA damage.…”

Section: Systemic Sclerosismentioning

confidence: 76%

“…Moreover, increased DNA damage levels have also been detected in the peripheral blood of patients with SSc, regardless of disease subtype (diffuse or limited SSc) or treatment [23]. To examine whether DNA damage is a result of dysfunction of DNA repair enzymes, DNA damage and polymorphic sites in two genes encoding DNA repair enzymes XRCC1 [arginine to glutamine polymorphism at position 399 (Arg399Gln)] and XRCC4 [Isoleucine to threonine polymorphism at position 401 (Ile401Thr)] were evaluated.…”

Section: Systemic Sclerosismentioning

confidence: 99%

“…Aberrant DDR/R has been reported in patients with systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) [3,4], systemic sclerosis (SSc) [23], and rheumatoid arthritis (RA) [24,25]. Polymorphisms of nucleases or molecules central in the DNA repair process have been detected with increased frequency among patients with autoimmune diseases, whereas gene/protein expression assays have shown downregulation of molecular components that are implicated in the DNA repair machinery and upregulation of apoptosis genes among patients with autoimmune disease [4].…”

Section: Introductionmentioning

confidence: 99%

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DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Souliotis

Vlachogiannis

Παππά

et al. 2019

IJMS

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The DNA damage response and repair (DDR/R) network, a sum of hierarchically structured signaling pathways that recognize and repair DNA damage, and the immune response to endogenous and/or exogenous threats, act synergistically to enhance cellular defense. On the other hand, a deregulated interplay between these systems underlines inflammatory diseases including malignancies and chronic systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Patients with these diseases are characterized by aberrant immune response to self-antigens with widespread production of autoantibodies and multiple-tissue injury, as well as by the presence of increased oxidative stress. Recent data demonstrate accumulation of endogenous DNA damage in peripheral blood mononuclear cells from these patients, which is related to (a) augmented DNA damage formation, at least partly due to the induction of oxidative stress, and (b) epigenetically regulated functional abnormalities of fundamental DNA repair mechanisms. Because endogenous DNA damage accumulation has serious consequences for cellular health, including genomic instability and enhancement of an aberrant immune response, these results can be exploited for understanding pathogenesis and progression of systemic autoimmune diseases, as well as for the development of new treatments.

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Section: Systemic Sclerosismentioning

confidence: 76%

Section: Systemic Sclerosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Souliotis

Vlachogiannis

Παππά

et al. 2019

IJMS

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“…XRCC1 and XRCC4 are two DNA repair genes that encode protein that forms a complex with other enzymes involved in repairing DNA double strand breaks [ 169 - 171 ]. Patients with SSc were reported to have an increased frequency of unstablized DNA breaks and spontaneous chromosomal damage [ 172 - 175 ]. Moreover, this increased DNA damages were found in even higher rate in patients with anti-centromere antibodies (ACA) [ 174 ].…”

Section: Functional Allelic Studies On Xrcc1 and Xrcc4mentioning

confidence: 99%

“…Moreover, this increased DNA damages were found in even higher rate in patients with anti-centromere antibodies (ACA) [ 174 ]. In a study that evaluated DNA damage and polymorphic sites in these two genes in patients with SSc, patients with the XRCC1 Arg399Gln allele showed increased frequency of ANA and ACA compared to patients with the XRCC1 Arg399Arg allele [ 172 ]. Patients with the XRCC4 Il3401Thr allele exhibited increased DNA damage compared with those with the Ile401Ile allele [ 172 ].…”

Section: Functional Allelic Studies On Xrcc1 and Xrcc4mentioning

confidence: 99%

Systemic Sclerosis is a Complex Disease Associated Mainly with Immune Regulatory and Inflammatory Genes

Jin¹,

Chou²,

Lima³

et al. 2014

TORJ

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Systemic sclerosis (SSc) is a fibrotic and autoimmune disease characterized clinically by skin and internal organ fibrosis and vascular damage, and serologically by the presence of circulating autoantibodies. Although etiopathogenesis is not yet well understood, the results of numerous genetic association studies support genetic contributions as an important factor to SSc. In this paper, the major genes of SSc are reviewed. The most recent genome-wide association studies (GWAS) are taken into account along with robust candidate gene studies. The literature search was performed on genetic association studies of SSc in PubMed between January 2000 and March 2014 while eligible studies generally had over 600 total participants with replication. A few genetic association studies with related functional changes in SSc patients were also included. A total of forty seven genes or specific genetic regions were reported to be associated with SSc, although some are controversial. These genes include HLA genes, STAT4, CD247, TBX21, PTPN22, TNFSF4, IL23R, IL2RA, IL-21, SCHIP1/IL12A, CD226, BANK1, C8orf13-BLK, PLD4, TLR-2, NLRP1, ATG5, IRF5, IRF8, TNFAIP3, IRAK1, NFKB1, TNIP1, FAS, MIF, HGF, OPN, IL-6, CXCL8, CCR6, CTGF, ITGAM, CAV1, MECP2, SOX5, JAZF1, DNASEIL3, XRCC1, XRCC4, PXK, CSK, GRB10, NOTCH4, RHOB, KIAA0319, PSD3 and PSOR1C1. These genes encode proteins mainly involved in immune regulation and inflammation, and some of them function in transcription, kinase activity, DNA cleavage and repair. The discovery of various SSc-associated genes is important in understanding the genetics of SSc and potential pathogenesis that contribute to the development of this disease.

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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

Wei

Yang

Hei

et al. 2016

Arthritis & Rheumatology

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Objectives 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. Methods 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. Results 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. Conclusions 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.

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Patients with Systemic Sclerosis Present Increased DNA Damage Differentially Associated with DNA Repair Gene Polymorphisms

Abstract: These results corroborate the presence of genomic instability in SSc peripheral blood cells, as evaluated by increased DNA damage, and show that polymorphic sites of the XRCC1 and XRCC4 DNA repair genes may differentially influence DNA damage and the development of autoantibodies.

Cited by 21 publications

References 47 publications

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Systemic Sclerosis is a Complex Disease Associated Mainly with Immune Regulatory and Inflammatory Genes

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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