ABSTRACT
OBJECTIVE: Mesolimbic dopamine sensitization has been hypothesized to be a mediating factor of childhood adversity (CA) on schizophrenia risk. Activity of catechol-O-methyltransferase (COMT) Val158Met increases mesolimbic dopamine signaling and may be further regulated by methylenetetrahydrofolate reductase (MTHFR) C677T. This study investigates the three-way interaction between CA, COMT, and MTHFR. METHODS: We conducted a nested case-control study on individuals born after 1981, linking population-based registers to study the three-way interaction. We included 1699 schizophrenia cases and 1681 controls, and used conditional logistic regression to report incidence rate ratios (IRRs). RESULTS: Childhood adversity was robustly associated with schizophrenia. No main genetic effects were observed. MTHFR C677T increased schizophrenia risk in a dose-dependent manner per MTHFR T allele (P = 0.005) consequent upon CA exposure. After inclusion of the significant (P = 0.03) COMT × MTHFR × CA interaction, the risk was further increased per high-activity COMT Val allele. Hence, exposed COMT Val/Val and MTHFR T/T carriers had an IRR of 2.76 (95% CI, 1.66-4.61). Additional adjustments for ancestry and parental history of mental illness attenuated the results with the interaction being only marginally significant. CONCLUSION: MTHFR C677T and COMT Val158Met interact with CA to increase risk of schizophrenia.
Subject(s)
Adult Survivors of Child Adverse Events , Catechol O-Methyltransferase/genetics , Child Abuse , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Registries , Schizophrenia , Adolescent , Adult , Adult Survivors of Child Adverse Events/statistics & numerical data , Case-Control Studies , Child , Child Abuse/statistics & numerical data , Denmark/epidemiology , Female , Humans , Male , Schizophrenia/epidemiology , Schizophrenia/etiology , Schizophrenia/genetics , Young AdultABSTRACT
To prevent human platelet alloimmunization, Blood Transfusion Centres have to develop a strategy close to the erythrocytes' one. The first step of this strategy is to perform the HPA typing of donors with an accurate method. We applied the PCR-SSP to type 800 platelet donors in the HPA-1 and HPA-5 systems and 350 in the HPA-2 and HPA-3 ones. This study reports the human platelet antigen frequencies of four platelet-specific alloantigen systems in the French population. The results are quite similar to those currently published for Caucasian population frequencies. Low prevalences are observed for the HPA-1b, (2%), HPA-2b (0.6%) and HPA-5b (2%) groups. Furthermore, this study confirms the need to type donors and recipients in the HPA-1 system at least, in case of post-transfusion pupura and platelet refractoriness to platelet transfusion therapy.
Subject(s)
Antigens, Human Platelet/genetics , Blood Donors/statistics & numerical data , DNA Primers , Ethnology , France , Gene Frequency , Genotype , Humans , Phenotype , Polymerase Chain ReactionABSTRACT
Peripheral blood stem cells (PBSC) from 15 patients with advanced non-Hodgkin's lymphoma (NHL), two patients with chronic lymphocytic leukemia, and two patients with myeloma were collected by continuous-flow leukapheresis after chemotherapy with MIV (mitoxantrone, ifosfamide, and etoposide, five patients) or high-dose cyclophosphamide (14 patients), followed by administration of GM-CSF. Sixteen patients (84%) had persistent marrow involvement at time of inclusion. Results were compared to those obtained in a control group of similar age and disease status in whom collection had been performed after MIV chemotherapy alone. The number of mononuclear cells, granulocyte-macrophage colony-forming units (CFU-GM), CD34+ cells were higher in GM-CSF treated patients with a lower mean number of leukapheresis (3.5 versus 6.4). Among the 19 patients harvested after chemotherapy plus GM-CSF, more progenitor cells were obtained in the cyclophosphamide group than in the MIV group. In all these patients except one, the number of mononuclear cells was sufficient to realize a transplantation. Seventeen patients received intensification with BEAM regimen (8 patients) or cyclophosphamide plus etoposide and total body irradiation (9 patients). Two patients failed to reconstitute correct hematopoiesis and three early toxic deaths occurred for a total of five procedure-related deaths. Nine of these 17 patients are in persistent complete remission with a median post-transplant follow-up of 18 months. Time to reach granulocyte and platelet recovery was not correlated with the number of mononuclear cells, CFU-GM, granulocyte-erythroid-macrophage-megakaryocyte colony-forming units (CFU-GEMM), CD34+ cells, and CD34+ CD33- cells but with the number of previous chemotherapy regimens. PBSC harvesting is achievable after chemotherapy plus GM-CSF in heavily pretreated patients with persistent marrow involvement. Moreover, these cells are able to reconstitute correct hematopoiesis after intensive treatment in these patients.
