Relevance of Plasma Homocysteine and Methylenetetrahydrofolate Reductase 677TT Genotype in Sickle Cell Disease: A Systematic Review and Meta-Analysis.

We evaluated the relevance of plasma homocysteine (HC) and the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) in sickle cell disease (SCD) and associated vaso-occlusive crisis (VOC) and ischemic stroke (IS). We identified in Embase and Medline 22 studies on plasma HC and 22 on MTHFR genotypes. Due to age-related HC differences, adult and paediatric SCD were separated: 879 adult SCD and 834 controls (CTR) yielded a neutral effect size; 427 paediatric SCD and 625 CTR favoured SCD (p = 0.001) with wide heterogeneity (I2 = 95.5%) and were sub-grouped by country: six studies (Dutch Antilles n = 1, USA n = 5) yielded a neutral effect size, four (India n = 1, Arab countries n = 3) favoured SCD (p < 0.0001). Moreover, 249 SCD in VOC and 419 out of VOC yielded a neutral effect size. The pooled prevalence of the MTHFR TT genotype in 267 SCD equalled that of 1199 CTR (4.26% vs. 2.86%, p = 0.45), and in 84 SCD with IS equalled that of 86 without IS (5.9% vs. 3.7%, p = 0.47); removal of one paediatric study yielded a significant effect size (p = 0.006). Plasma HC in paediatric SCD from Middle East and India was higher, possibly due to vitamin deficiencies. Despite its low prevalence in SCD, the MTHFR TT genotype relates to adult IS.

Homozygous methylentetrahydrofolate reductase C667T genotype anticipates age at venous thromboembolism by one decade.

The aim of the study was to compare age at first venous thromboembolism (VTE), plasma homocysteine and activated partial thromboplastin time ratio (aPTTr) amongst unprovoked VTE patients with the methylentetrahydrofolate reductase (MTHFR) C667T genotypes, and to identify predictors of age at first VTE, of plasma homocysteine and of the aPTTr; to evaluate whether heterozygous or homozygous prothrombin (PT) G20210A mutation lowered the age at first VTE when associated with MTHFR TT. Retrospective cohort study on 259 MTHFR TT, 76 MTHFR TC and 64 MTHFR CC participants with unprovoked VTE; each participant contributed age, sex, age at VTE, history of dyslipidaemia, hypertension, smoking, homocysteine (measured by enzyme immunoassay) and aPTTr (measured by standard coagulation assay). Age at first VTE was lower in MTHFR TT than MTHFR TC and CC (41 ±â€Š14 vs. 50 ±â€Š16 vs. 51 ±â€Š12 years, respectively, P < 0.0001); plasma homocysteine was higher in MTHFR TT than in the other groups (22 ±â€Š21 vs. 12 ±â€Š11.6 vs. 10 ±â€Š3.3 µmol/l, respectively, P = 0.0005) whilst aPTTr was not different. MTHFR TT independently predicted age at first VTE (P = 0.001), plasma homocysteine (P < 0.0001) alongside sex (P = 0.0007), age and smoking (P = 0.03 for both). Compound MTHFR TT with PT GA or AA had no lowering effect on age at first VTE compared with MTHFR TT alone (41 ±â€Š13 vs. 41 ±â€Š14 years). Plasma homocysteine inversely related to aPTTr in the MTHFR TT group (P = 0.003). MTHFR TT anticipates age at first VTE by an average of 10 years compared with MTHFR TC and CC genotypes.

Antiphospholipid Antibodies in Sickle Cell Disease: A Systematic Review and Exploratory Meta-Analysis.

The relationship between antiphospholipid antibodies (aPL) and sickle cell disease (SCD) has never been systematically addressed. Our aim was to evaluate potential links between SCD and aPL in all age groups. EMBASE/PubMed was screened from inception to May 2020 and Peto odds ratios for rare events were calculated. The pooled prevalence (PP) of IgG anticardiolipin antibodies (aCL) was higher in individuals with SCD than in controls (27.9% vs 8.7%, P < 0.0001), that of IgM aCL was similar in the two groups (2.9% vs 2.7%); only individuals with SCD were positive for lupus anticoagulant (LA) (7.7% vs 0%, P < 0.0001). The PP of leg ulcers was similar between aPL positive and negative individuals (44% vs 53%) and between patients in acute crisis and stable patients (5.6% vs 7.3%). Reporting of aPL as a binary outcome and not as a titer precluded further interpretation. The results indicate that a prospective case-control study with serial measurements of a panel of aPL in SCD patients might be warranted, in order to understand further the possible pathogenic role of aPL in SCD.

Glucose regulates insulin mitogenic effect by modulating SHP-2 activation and localization in JAr cells.

The glucose effect on cell growth has been investigated in the JAr human choriocarcinoma cells. When JAr cells were cultured in the presence of 6 mm glucose (LG), proliferation and thymidine incorporation were induced by serum, epidermal growth factor, and insulin-like growth factor 1 but not by insulin. In contrast, at 25 mm glucose (HG), proliferation and thymidine incorporation were stimulated by insulin, serum, epidermal growth factor, and insulin-like growth factor 1 to a comparable extent, whereas basal levels were 25% lower than those in LG. HG culturing also enhanced insulin-stimulated insulin receptor and insulin receptor substrate 1 (IRS1) tyrosine phosphorylations while decreasing basal phosphorylations. These actions of glucose were accompanied by an increase in cellular tyrosine phosphatase activity. The activity of SHP-2 in HG-treated JAr cells was 400% of that measured in LG-treated cells. SHP-2 co-precipitation with IRS1 was also increased in HG-treated cells. SHP-2 was mainly cytosolic in LG-treated cells. However, HG culturing largely redistributed SHP-2 to the internal membrane compartment, where tyrosine-phosphorylated IRS1 predominantly localizes. Further exposure to insulin rescued SHP-2 cytosolic localization, thereby preventing its interaction with IRS1. Antisense inhibition of SHP-2 reverted the effect of HG on basal and insulin-stimulated insulin receptor and IRS1 phosphorylation as well as that on thymidine incorporation. Thus, in JAr cells, glucose modulates insulin mitogenic action by modulating SHP-2 activity and intracellular localization.