Instituto Aggeu Magalhães Research Center - IAM-FIOCRUZ-PE, Av. Professor Moraes Rego, S/N, Recife, PE, 50.740-465, Brazil.
Institute of Biological Sciences and Faculty of Medical Sciences, University of Pernambuco, Recife, PE, Brazil.
Mol Biol Rep. 2023 Apr;50(4):3341-3353. doi: 10.1007/s11033-023-08262-2. Epub 2023 Feb 1.
Sickle cell anemia (SCA) is a genetic disease with great clinical heterogeneity and few viable strategies for treatment; hydroxyurea (HU) is the only widely used drug. Thus, the study of single nucleotide polymorphisms (SNPs) and the gene expression of MMPs 1, 2, 9, 7 and TIMPs 1 and 2, which are involved in the regulation of extracellular matrix, inflammation, and neuropathies, may provide further insights into the pathophysiology of the disease and elucidate biomarkers and molecules as potential therapeutic targets for patients with SCA.
We evaluated 251 young individuals with SCA from northeastern Brazil. The groups were divided according to vaso-occlusive crisis (VOC) and cerebrovascular disease (CVD), compared to control individuals. SNP detection and gene expression assays were performed by real-time PCR, TaqMan system®. Both the expression levels of MMP1 gene, and the SNP MMP1-1607 1G/2G were associated with the risk of cerebral ischemic stroke (IS), and the expression of MMP1 was also associated with a higher frequency of VOC/year. Expression levels of MMP7, TIMP1, and TIMP2 were increased in patients conditioned to IS. The SNP 372T>C (rs4898) TIMP1 T alleles were more frequent in patients with > 5 VOC events/year. The SNP rs17576 of MMP9 showed differences in gene expression levels; it was increased in the genotypes AG, and AG+GG.
The findings of this study, the SNPs, and expression provide initial support for understanding the role of MMPs-TIMPs in the pathophysiology of SCA in young patients.
镰状细胞贫血（SCA）是一种具有很大临床异质性的遗传性疾病，治疗方法很少；羟基脲（HU）是唯一广泛使用的药物。因此，研究涉及细胞外基质调节、炎症和神经病变的单核苷酸多态性（SNPs）和 MMPs 1、2、9、7 和 TIMPs 1 和 2 的基因表达，可能为该疾病的病理生理学提供进一步的见解，并阐明生物标志物和分子作为 SCA 患者的潜在治疗靶点。
我们评估了来自巴西东北部的 251 名年轻 SCA 患者。根据血管阻塞性危象（VOC）和脑血管疾病（CVD）将这些组与对照组进行比较。通过实时 PCR、TaqMan 系统®进行 SNP 检测和基因表达检测。MMP1 基因的表达水平和 SNP MMP1-1607 1G/2G 均与脑缺血性中风（IS）的风险相关，MMP1 的表达也与 VOC/年的更高频率相关。MMP7、TIMP1 和 TIMP2 的表达水平在患有 IS 的患者中增加。TIMP1 基因的 SNP 372T>C（rs4898）T 等位基因在每年有>5 次 VOC 事件的患者中更为常见。MMP9 的 SNP rs17576 显示出基因表达水平的差异；在 AG 和 AG+GG 基因型中增加。
本研究的发现、SNP 和表达为理解 MMPs-TIMPs 在年轻 SCA 患者病理生理学中的作用提供了初步支持。
