Analysis of gene expression to predict dynamics of future hypertension incidence in type 2 diabetic patients

BACKGROUND: The main focus of the Genetic Analysis Workshop 19 (GAW19) is identification of genes related to the occurrence of hypertension in the cohort of patients with type 2 diabetes mellitus (T2DM). The aim of our study was to predict dynamics of the future hypertension incidence, based on gene expression profiles, systolic and diastolic blood pressure changes in time, sex, baseline age, and cigarette smoking status. We analyzed data made available to GAW19 participants, which included gene expression profiles of peripheral blood mononuclear cells (PBMCs) from the diabetic members of 20 Mexican American families. METHODS: On the basis of mid blood pressure measurements at several time points, the coefficient of regression (slope) was calculated for each individual. We corrected the slope value in patients treated with antihypertensive medications. Feature preprocessing methods were used to remove highly correlated probes and linear dependencies between them. Subsequently, multiple linear regression model was used to associate gene expression with the regression coefficient calculated for each T2DM patient. Tenfold cross-validation was used to validate the model. We used linear mixed effects model and kinship coefficients to account for the family structure. All calculations were performed in R. RESULTS: This analysis allowed us to identify 6 well-annotated genes: RTP4, FXYD6, GDF11, IFNAR1, NOX3, and HLA-DQ2, associated with dynamics of future hypertension incidence. Two of them, IFNAR1 and NOX3 were previously implicated in pathogenesis of hypertension. CONCLUSIONS: There is no obvious mechanism that links all detected genes with dynamics of hypertension incidence. Identification of possible connection with hypertension needs further investigation

Bradykinin and oxidative stress in patients with hereditary angioedema due to C1 inhibitor deficiency

Introduction Hereditary angioedema (HAE) is a rare autosomal dominant disease caused by genetic dysfunction of C1 inhibitor (C1‑INH) due to mutations in the SERPING1 gene. The disorder is mediated mainly by bradykinin. The clinical course of the disease is varied and not related to genetic changes. Objectives We aimed to evaluate redox homeostasis of peripheral blood mononuclear cells (PBMCs) in patients with HAE due to C1‑INH deficiency (C1‑INH‑HAE) by measuring the levels of reactive oxygen species (ROS) of PBMCs as well as plasma advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs). We also aimed to assess the effect of bradykinin on ROS levels. Patient s and methods We enrolled 30 adults with C1‑INH‑HAE and 15 healthy individuals. The levels of ROS were measured by flow cytometry, while the plasma levels of AGEs and AOPPs were determined spectrophotometrically by enzyme‑linked immunosorbent assays. Result s Basal and hydrogen peroxide (H2O2)–induced ROS levels were higher in patients with HAE when compared with controls (P = 0.002 and P = 0.001, respectively), indicating abnormalities in redox homeostasis. Plasma AOPP and AGE levels were similar in both groups. Bradykinin reduced basal and H2O2‑induced ROS generation in PBMCs only in patients with HAE (P = 0.03). Conclusions The higher basal and H2O2‑induced ROS levels in patients with C1‑INH‑HAE indicate redox imbalance. However, by reducing basal and H2O2‑induced ROS levels, bradykinin shows antioxidant action in this disorder

The Pediatric Choroidal and Ciliary Body Melanoma Study A Survey by the European Ophthalmic Oncology Group

Purpose: To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. Design: Retrospective, multicenter observational study. Participants: Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults. Methods: Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. Main Outcome Measures: Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. Results: Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. Conclusions: This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups. (C) 2016 by the American Academy of Ophthalmology.Peer reviewe