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Polymorphisms and gene expression of metalloproteinases and their inhibitors associated with cerebral ischemic stroke in young patients with sickle cell anemia

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Abstract

Background

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.

Methods and results

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.

Conclusion

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.

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Acknowledgements

The present work was carried out with the support of the Coordination for the Improvement of Higher Education Personnel-Brazil (CAPES)-Funding Code 001. We are grateful for the IAM/Fiocruz (Aggeu Magalhlhães Institute/Oswaldo Cruz Foundation) for awarding us a scholarship as a form of financial support.

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Authors and Affiliations

  1. Instituto Aggeu Magalhães Research Center - IAM-FIOCRUZ-PE, Av. Professor Moraes Rego, S/N, Recife, PE, 50.740-465, Brazil

    Ó. do Kleyton Palmeira, Débora Nascimento de Nóbrega, Roberta dos Santos Souza & Luydson Richardson Silva Vasconcelos

  2. Institute of Biological Sciences and Faculty of Medical Sciences, University of Pernambuco, Recife, PE, Brazil

    Ana Karla da Silva Freire, Isabela Cristina Cordeiro Farias, Taciana Furtado de Mendonça Belmont, Andreia Soares da Silva, Patricia Muniz Mendes Freire de Moura & Maria do Socorro Mendonça Cavalcanti

  3. Department of Biological Sciences, Federal University of Pernambuco, Recife, PE, Brazil

    Gabriela da Silva Arcanjo, Ana Cláudia Mendonça dos Anjos, Antônio Roberto Lucena de Araujo & Marcos André Cavalcanti Bezerra

  4. Hematology and Hemotherapy Foundation of Pernambuco – HEMOPE, Recife, Brazil

    Aderson da Silva Araujo

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Contributions

(KPÓ, DNdN, RdSS, AKdSF) performed experiments, analyzed and interpreted data, and drafted the manuscript. (ICCF, GdSA, ACMdA, KPdÓ) recruited patients, updated the clinical data, and reviewed the manuscript. (KPdÓ, ARLdA, MACB, LRSV, TFdMB) analyzed and interpreted data, performed statistical analyses and drafted the manuscript. (PMMFdM, MdSMC, MACB, AdSA, LRSV, TFdMB) conceived and designed the study and reviewed the manuscript.

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Correspondence to Luydson Richardson Silva Vasconcelos.

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do Kleyton Palmeira, Ó., da Silva Freire, A.K., de Nóbrega, D.N. et al. Polymorphisms and gene expression of metalloproteinases and their inhibitors associated with cerebral ischemic stroke in young patients with sickle cell anemia. Mol Biol Rep 50, 3341–3353 (2023). https://doi.org/10.1007/s11033-023-08262-2

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