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

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.

Alpha thalassemia, but not ßS-globin haplotypes, influence sickle cell anemia clinical outcome in a large, single-center Brazilian cohort.

Alpha thalassemia and beta-globin haplotype are considered classical genetic disease modifiers in sickle cell anemia (SCA) causing clinical heterogeneity. Nevertheless, their functional impact on SCA disease emergence and progression remains elusive. To better understand the role of alpha thalassemia and beta-globin haplotype in SCA, we performed a retrospective study evaluating the clinical manifestations of 614 patients. The univariate analysis showed that the presence of alpha-thalassemia -3.7-kb mutation (αα/-α and -α/-α) decreased the risk of stroke development (p = 0.046), priapism (p = 0.033), and cholelithiasis (p = 0.021). Furthermore, the cumulative incidence of stroke (p = 0.023) and cholelithiasis (p = 0.006) was also significantly lower for patients carrying the alpha thalassemia -3.7-kb mutation. No clinical effects were associated with the beta-globin haplotype analysis, which could be explained by the relatively homogeneous haplotype composition in our cohort. Our results reinforce that alpha thalassemia can provide protective functions against hemolysis-related symptoms in SCA. Although, several genetic modifiers can impact the inflammatory state of SCA patients, the alpha thalassemia mutation remains one of the most recurrent genetic aberration and should therefore always be considered first.

Association of the polymorphisms of the genes APOC3 (rs2854116), ESR2 (rs3020450), HFE (rs1799945), MMP1 (rs1799750) and PPARG (rs1801282) with lipodystrophy in people living with HIV on antiretroviral therapy: a systematic review.

The aim of this study was to perform a systematic review to identify data reported in the literature concerning the association of APOC3 (rs2854116), ESR2 (rs3020450), HFE (rs1799945), MMP1 (rs1799750) and PPARG (rs1801282) polymorphisms with lipodystrophy in people living with HIV (PLWHIV) on antirretroviral therapy. The research was conducted in six databases and the studies were selected in two steps. First, a search was undertaken in the following electronic databases: PubMed, Science Direct, Medline, World Wide Science, Directory of Open Access Journals, Scielo, Lilacs and Medcarib. The titles and abstracts of 24,859 articles were read to select those that match the elegibilty criteria. Five papers that addressed the association of HAART, lipodystrophy and polymorphisms were selected for the review. There was no association between the polymorphisms of the genes APOC3 and PPARG and lipodystrophy. Another study described an association between the variant allele (G) of HFE and protection concerning the development of lipoatrophy (0.02) when compared with the reference allele (C). On the other hand, the variant allele (T) of the ESR2 gene was associated with the development of lipoatrophy (p = 0.007) when compared with the reference allele (C). In addition, the genotype and the variant allele of the gene MMP1 (2G) were associated with lipodystrophy in PLWHIV on HAART (p = 0.0002 and p = 0.0008, respectively). Therefore, further studies with other populations, involving PLWHIV on HAART are necessary to better understand the role of genetic markers, which may be involved in a predisposition to lipodystrophy.

MicroRNA dysregulation in schistosomiasis-induced hepatic fibrosis: a systematic review.

BACKGROUND: MicroRNAs are involved in gene regulation in several common liver diseases and may play an essential role in activating hepatic stellate cells. The role of these post-transcriptional regulators in schistosomiasis needs to be further studied in populations from endemic areas for a better understanding of the disease, the development of new therapeutic approaches, and the use of biomarkers for the prognosis of schistosomiasis. AREAS COVERED: We performed a systematic review to describe the main human microRNAs identified in non-experimental studies associated with aggravation of the disease in people infected with Schistosoma mansoni (S. mansoni) and Schistosoma japonicum (S. japonicum). Structured searches were carried out in PubMed, Medline, Science Direct, Directory of Open Access Journals, Scielo, Medcarib, and Global Index Medicus databases without time and language restrictions. This is a systematic review following the guidelines of the PRISMA platform. EXPERT OPINION: The miR-146a-5p, miR-150-5p, let-7a-5p, let-7d-5p, miR-92a- 3p, and miR-532-5p are associated with liver fibrosis in schistosomiasis caused by S. japonicum, revealing that these miRNAs that have been shown to be associated with liver fibrosis are good targets for new studies that evaluate their potential as a biomarker or even treating liver fibrosis in schistosomiasis.

The 1G/1G+1G/2G Genotypes of MMP1 rs1799750 Are Associated with Higher Levels of MMP-1 and Are Both Associated with Lipodystrophy in People Living with HIV on Antiretroviral Therapy.

In HIV-infected patients, antiretroviral therapy (ART) is associated to adipose tissue redistribution known as lipodystrophy (LD). This study aimed at verifying the association between the polymorphism of the MMP1 gene (rs1799750) (1G/2G) and the serum levels of matrix metalloproteinase 1 (MMP-1) with LD and its subtypes in people living with HIV on ART. This is a cross-secional study. LD was self-reported. The determination of the MMP1 rs1799750 gene polymorphism was performed by real-time PCR, and the serum concentrations of MMP-1 were quantified by the enzyme-linked immunosorbent assay (ELISA) method. Of 404 participants, 204 (51%) were diagnosed with LD, of whom 89 (43%) had mixed lipodystrophy (ML), 72 (35%) had lipohypertrophy (LH), and 43 (22%) had lipoatrophy (LA). There was an association between the genotypes 1G/1G+1G/2G and higher serum levels of MMP-1 (p = .025). There was no association of MMP1 (1G/2G) with LD. Other factors associated with LD were current CD4 ≤ 350 [odds ratio (OR) = 4.85, confidence interval (CI) = 1.78-47.99, p = .0033] and serum MMP-1 levels >6.81 (OR = 2.67, CI = 1.21-6.08, p = .0165). Factors associated with ML: current CD4 ≤ 350 (OR = 5.59, CI = 1.69-20.39, p = .006); with LH: number of antiretroviral regimens used: 2 (OR = 2.06, CI = 1.01-4.20, p = .0460) and 3+ (OR = 2.09, CI = 1.00-4.35, p = .0477), and current CD4 ≤ 350 (OR = 2.08, CI = 1.00-4.24, p = .0461); and with LA: current viral load >40 (OR = 2.52, CI = 1.03-5.91, p = .0372) and current use of zidovudine (OR = 2.97, CI = 1.32-6.54, p = .0074). Higher levels of MMP-1 were associated with genotypes 1G/2G+1G/1G and with LD. Other individual risk factors were independently associated with LD, and its subtypes, suggesting that the pathogenesis itself is differently manifested for each type of LD.

Expression of microRNAs (133b and 138) and Correlation with Echocardiographic Parameters in Patients with Alcoholic Cardiomyopathy.

INTRODUCTION: Alcoholic Cardiomyopathy (ACM) is a disease with a difficult diagnosis. The real mechanisms related to its pathophysiology are not fully understood. OBJECTIVE: The aims of this study were to investigate whether miR-133b and miR-138 could be associated with ACM. METHODS: Forty-four patients were included comprising 24 with ACM and 20 with cardiomyopathies of different etiologies (control group). Real-time PCR was performed to verify the relative expression among the studied groups. In the statistical analysis, the quantitative variables t-student Mann- Whitney and correlation of Pearson tests were carried out, while the qualitative variable comprised the chi-square test, with p<0.05 being considered statistically significant. RESULTS: There was no association between clinical and sociodemographic characteristics of the groups. The patients with ACM presented downregulation of miR-133b in comparison with control patients (p=0.004). On the other hand, for the miR-138, there was no association when the ACM group was compared with the control group. The presence of miR-133b among cases and controls was not correlated with any of the echocardiographic parameters. However, the increase in the expression of miR-138 was correlated with an increase in the ejection fraction (r=0.28, p=0.01) and the diameter of the left atrium (r=0.23, p=0.04) in patients with ACM. CONCLUSION: The downregulation of miR-133b might be a marker for ACM and, in addition, miR- 138 could be used to correlate the increase in ejection fraction with and normalization of the diameter of the left atrium diameter in patients with this disease.

Association of the SOD2 Polymorphism (Val16Ala) and SOD Activity with Vaso-occlusive Crisis and Acute Splenic Sequestration in Children with Sickle Cell Anemia.

The SOD2 polymorphism Val16Ala T→C influences the antioxidative response. This study investigated the association of the SOD2 polymorphism and superoxide dismutase (SOD) activity with the vaso-occlusive crisis (VOC) and acute splenic sequestration (ASS) in children with sickle cell anemia (SCA). One hundred ninety-five children with SCA aged 1-9 years old were analyzed. The TC and CC genotypes were associated with lower SOD activity compared with the TT genotype (p=0.0321; p=0.0253, respectively). Furthermore, TC and CC were more frequent in patients with VOC or ASS (p=0.0285; p=0.0090, respectively). These results suggest that the SOD2 polymorphism associated with low SOD activity could be a susceptibility factor for the occurrence of VOC and ASS.