系统性硬化症患者存在与DNA修复基因多态性差异相关的DNA损伤增加。

Patients with systemic sclerosis present increased DNA damage differentially associated with DNA repair gene polymorphisms.

作者信息

Palomino Gustavo Martelli, Bassi Carmen L, Wastowski Isabela J, Xavier Danilo J, Lucisano-Valim Yara M, Crispim Janaina C O, Rassi Diane M, Marques-Neto Joao F, Sakamoto-Hojo Elza T, Moreau Philippe, Sampaio-Barros Percival D, Donadi Eduardo A

机构信息

From the Program of Basic and Applied Immunology, Faculdade de Medicina de Ribeirão Preto, University of São Paulo (FMRP-USP); Department of Basic Sciences in Health, Faculty of Medical Sciences, Federal University of Mato Grosso (UFMT); Department of Genetics, FMRP-USP; Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto (FCFRP-USP); Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University Federal Rio Grande do Norte State (UFRN); Department of Medicine, FMRP-USP; Unit of Rheumatology, Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, (UNICAMP), Brazil; Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Therapies Innovantes, Service de Recherches en Hemato-Immunologies, Hôpital Saint-Louis, Paris, France; Division of Rheumatology, Faculdade de Medicina, Universidade de São Paulo (FM-USP), São Paulo, Brazil.

出版信息

J Rheumatol. 2014 Mar;41(3):458-65. doi: 10.3899/jrheum.130376. Epub 2014 Feb 1.

DOI:10.3899/jrheum.130376

PMID:24488411

Abstract

OBJECTIVE

Patients with systemic sclerosis (SSc) exhibit increased toxicity when exposed to genotoxic agents. In our study, we evaluated DNA damage and polymorphic sites in 2 DNA repair genes (XRCC1 Arg399Gln and XRCC4 Ile401Thr) in patients with SSc.

METHODS

A total of 177 patients were studied for DNA repair gene polymorphisms. Fifty-six of them were also evaluated for DNA damage in peripheral blood cells using the comet assay.

RESULTS

Compared to controls, the patients as a whole or stratified into major clinical variants (limited or diffuse skin involvement), irrespective of the underlying treatment schedule, exhibited increased DNA damage. XRCC1 (rs: 25487) and XRCC4 (rs: 28360135) allele and genotype frequencies observed in patients with SSc were not significantly different from those observed in controls; however, the XRCC1 Arg399Gln allele was associated with increased DNA damage only in healthy controls and the XRCC4 Ile401Thr allele was associated with increased DNA damage in both patients and controls. Further, the XRCC1 Arg399Gln allele was associated with the presence of antinuclear antibody and anticentromere antibody. No association was observed between these DNA repair gene polymorphic sites and clinical features of patients with SSc.

CONCLUSION

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.

摘要

目的

系统性硬化症（SSc）患者在接触基因毒性剂时表现出更高的毒性。在我们的研究中，我们评估了SSc患者2个DNA修复基因（XRCC1 Arg399Gln和XRCC4 Ile401Thr）中的DNA损伤和多态性位点。

方法

共对177例患者进行了DNA修复基因多态性研究。其中56例还使用彗星试验评估了外周血细胞中的DNA损伤。

结果

与对照组相比，无论基础治疗方案如何，整体患者或分为主要临床亚型（局限性或弥漫性皮肤受累）的患者均表现出DNA损伤增加。在SSc患者中观察到的XRCC1（rs：25487）和XRCC4（rs：28360135）等位基因和基因型频率与对照组中观察到的频率无显著差异；然而，XRCC1 Arg399Gln等位基因仅在健康对照组中与DNA损伤增加相关，而XRCC4 Ile401Thr等位基因在患者和对照组中均与DNA损伤增加相关。此外，XRCC1 Arg399Gln等位基因与抗核抗体和抗着丝粒抗体的存在相关。未观察到这些DNA修复基因多态性位点与SSc患者临床特征之间的关联。