Can Polymorphisms in NLRP3 Inflammasome Complex Be Associated with Postmenopausal Osteoporosis Severity?

The immune system plays a critical role in bone homeostasis and, consequently, in the pathophysiology of postmenopausal osteoporosis (OP) since estrogen deficiency induces the inflammasome and increases production of pro-inflammatory cytokines, such as IL-1β and IL-18. NLRP3 inflammasome complex genes have been related with bone homeostasis in cellular and animal models. Here, we performed an association study evaluating SNVs (single-nucleotide variants) in inflammasome NLRP3 pathway genes (NLRP3, CARD8, CASP1, IL-18, and IL-1β) to assess whether variants in these genes could be related to susceptibility to primary OP in postmenopausal women. We genotyped 196 postmenopausal OP patients and 103 healthy controls using SNV-specific Taqman probes. Data and statistical analyses were performed using the SNPstats and GraphPad Prism 8 software. We showed an association between NLRP3 rs35829419 CA genotype and lower bone mineral density (BMD) mean at the lumbar spine ( = 0.001); we also observed an association between IL-1β rs16944 AA genotype and higher BMD mean at the total hip ( = 0.009). The IL-1β rs16944 GG was associated with lower alkaline phosphatase levels (ALP) ( = 0.009), and the IL-18 rs1946519 AA was associated with lower vitamin D levels ( = 0.018). Additionally, OP patients presented deficient vitamin D and parathyroid hormone (PTH). The NLRP3 inflammasome complex SNVs were associated with OP severity, possibly indicating these genes' participation in bone metabolism and its dysregulation.This research was funded by the following Brazilian research agencies: CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico)

Promiscuous Gene Expression in the Thymus: The Root of Central Tolerance

The thymus is a complex organ with an epithelium formed by two main cell types, the cortical thymic epithelial (cTECs) and medullary thymic epithelial cells (mTECs), referred to as stroma. Immature thymocytes arising from the bone marrow, macrophages and dendritic cells also populate the thymus. Thymocytes evolve to mature T cells featuring cell differentiation antigens (CDs), which characterize the phenotypically distinct stages, defined as double-negative (DN), double positive (DP) and single positive (SP), based on expression of the coreceptors CD4 and CD8. The thymus is therefore implicated in T cell differentiation and during development into T cells thymocytes are in close association with the stroma. Recent evidence showed that mTECs express a diverse set of genes coding for parenchymal organ specific proteins. This phenomenon has been termed promiscuous gene expression (PGE) and has led to the reconsideration of the role of the thymus in central T cell tolerance to self-antigens, which prevents autoimmunity. The evidence of PGE is causing a reanalysis in the scope of central tolerance understanding. We summarize the evidence of PGE in the thymus, focusing particularly the use of cDNA microarray technology for the broad characterization of gene expression and demarcation of PGE emergence during thymus ontogeny

CTLA-4 gene polymorphisms are associated with obesity in Turner syndrome

Turner syndrome (TS) is characterized by a set of clinical conditions, including autoimmune/inflammatory diseases and infectious conditions, that can compromise a patient's quality of life. Here we assessed polymorphisms in CTLA-4 +49A/G (rs231775), PTPN22 +1858G/A (rs2476601), and MBL2 -550 (H/L) (rs11003125), -221(X/Y) (rs7096206) and exon 1 (A/O) in women from northeastern Brazil to determine whether polymorphisms within these key immune response genes confer differential susceptibility to clinical conditions in TS. A case-control genetic association study was performed, including 86 female TS patients and 179 healthy women. An association was observed for the A/G genotype of CTLA-4 +49A/G in TS patients (p=0.043, odds ratio [OR]=0.54). In addition, an association between the CTLA-4 G/G genotype and obesity was detected in TS patients (p=0.02, OR=6.04). Regarding, the -550(H/L) polymorphism in the MBL2 promoter, the frequency of the H/L genotype was significantly higher in the TS group than healthy controls (p=0.01, OR=1.96). The H/H genotype indicated a protective effect in TS patients (p=0.01, OR=0.23). No differences were observed in the distribution of -221(X/Y), MBL2 exon 1 variants, and PTPN22 +1858G/A in any assessed groups. CTLA-4 variants are potentially involved in obesity in this cohort of TS patients from northeastern Brazil

Alterations in gene expression profiles correlated with cisplatin cytotoxicity in the glioma U343 cell line

Gliomas are the most common tumors in the central nervous system, the average survival time of patients with glioblastoma multiforme being about 1 year from diagnosis, in spite of harsh therapy. Aiming to study the transcriptional profiles displayed by glioma cells undergoing cisplatin treatment, gene expression analysis was performed by the cDNA microarray method. Cell survival and apoptosis induction following treatment were also evaluated. Drug concentrations of 12.5 to 300 μM caused a pronounced reduction in cell survival rates five days after treatment, whereas concentrations higher than 25 μM were effective in reducing the survival rates to ~1%. However, the maximum apoptosis frequency was 20.4% for 25 μM cisplatin in cells analyzed at 72 h, indicating that apoptosis is not the only kind of cell death induced by cisplatin. An analysis of gene expression revealed 67 significantly (FDR < 0.05) modulated genes: 29 of which down- and 38 up-regulated. These genes belong to several classes (metabolism, protein localization, cell proliferation, apoptosis, adhesion, stress response, cell cycle and DNA repair) that may represent several affected cell processes under the influence of cisplatin treatment. The expression pattern of three genes (RHOA, LIMK2 and TIMP2) was confirmed by the real time PCR method

Farnesyl Diphosphate Synthase Gene Associated with Loss of Bone Mass Density and Alendronate Treatment Failure in Patients with Primary Osteoporosis

Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the FDPS gene, is associated with reduced gene transcription. This study evaluates the FDPS variant rs2297480 (A > C) association with OP patients’ response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) (n = 20) and non-responders (OP-NR) (n = 40). We observed an association of CC genotype with treatment failure (p = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = −2.21% ± 2.56; p = 0.026) and TH (CC = −2.06% ± 1.84; p = 0.015) after two years of alendronate sodium treatment. Relative expression of the FDPS gene was also evaluated in OP-R and OP-NR patients. Higher expression of the FDPS gene was also observed in OP-NR group (FC = 1.84 ± 0.77; p = 0.006) when compared to OP-R. In conclusion, the influence observed of FDPS expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis

PTPN22 1858C > T polymorphism and susceptibility to systemic lupus erythematosus: a meta-analysis update

Studies performed in the past years showed PTNP22 1858 C>T (rs2476601) polymorphism as associated with systemic lupus erythematosus susceptibility, although conflicting findings are still found. In this context, a powerful statistical study, such as meta-analysis, is necessary to establish a consensus. The aim of this study was to evaluate association studies between the PTPN22 1858 C>T polymorphism and SLE by a meta-analysis update, including three recently published studies in the last three - years. A total of 3868 SLE patients and 7458 healthy individuals were considered herein, enclosing 19 studies from Asian, American, European and Latin ethnic groups. Odds ratio (OR) was performed for allelic, dominant and recessive genetic models. Statistically significant association was found between the PTPN22 1858 C>T polymorphism and susceptibility to SLE in all inheritance models. Allelic genetic model data (OR\ubc1.54, 95% confidence interval (CI)\ubc1.38\u20131.72, p value\ubc.000) shows that T allele confers increased SLE susceptibility. As well as recessive genetic model (OR\ubc2.04, 95% CI\ubc1.09\u20133.82, p value\ubc.030) for T/T genotype. Instead, dominant genetic model shows that C/C genotype confers lower susceptibility for SLE development (OR\ubc0.62, 95% CI\ubc0.54\u20130.72, p value\ubc.000). In addition, we provided an ethnicity-derived meta-analysis. The results showed association in Caucasian (OR\ubc1.47, p value\ubc.000) and Latin (OR\ubc2.41, p value\ubc.000) ethnic groups. However, rs2476601 polymorphism is not associated nor in Asian (OR\ubc1.31; p value\ubc.54) and African (OR\ubc2.04; p value \ubc.22) populations. In conclusion, present meta-analysis update confirms that T allele and T/T genotype in PTPN22 1858 C>T polymorphism confers SLE susceptibility, particular in Caucasian and Latin groups, suggesting PTPN22 1858 C>T as a potential genetic marker in SLE susceptibility

Follow up of lupus nephritis patients cohort in northeastern Brazil

Escola Paulista Med UNIFESP, Nephrol, Sao Paulo, BrazilUniv Fed Pernambuco, Nephrol, Recife, PE, BrazilInst Med Integral Prof Fernando Figueira, Nephrol, Recife, PE, BrazilKeiso Azami Immunopathol Lab LIKA UFPE, Genet, Recife, PE, BrazilEscola Paulista Med UNIFESP, Nephrol, Sao Paulo, BrazilWeb of Scienc