A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Bell et al. report 46 new loci associated with biomarkers of iron homeostasis, including ferritin levels, iron binding capacity, and iron saturation, in the Icelandic, Danish and UK populations. The associated loci point to new iron-regulating proteins and important genetic differences between men and women

A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Abstract: Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation

Biosynthesis of leukotriene B4 in hematological malignancies

Leukotrienes (LT) are biologically active metabolites of the fatty acid arachidonic acid (AA). After liberation of AA by phospholipase A 2 (PLA 2), this fatty acid can be converted to leukotrienes, lipoxins, prostaglandins or thromboxane. The conversion of AA to LTA 4 is catalyzed by five-lipoxygenase (5-LO). LTA 4 can then be further metabolized to LTB 4 or LTC 4 by the catalytic action of LTA 4 hydrolase or LTC 4 synthase, respectively. Cellular leukotriene synthesis is dependent on 5-LO activating protein (FLAP), a membrane protein that binds AA and facilitates the 5-LO reaction. LTB 4 is produced in myeloid cells and B-lymphocytes. Besides a role in various immunological and inflammatory reactions, several reports indicate that LTB 4 may have a role in the proliferation of myeloid and lymphoid cells. Cells from patients with precursor B-acute lymphoblastic leukemia (B-ALL) were studied. All eight investigated clones expressed the genes for FLAP, LTA 4 hydrolase and cyclooxygenase-1 (COX-1). Seven out of eight clones expressed COX-2. Four of the more mature cell clones expressed 5-LO but not cPLA 2 and the cells also produced LTB 4. The remaining four clones expressed cPLA 2 but not 5-LO and hence produced no leukotrienes. On the basis of the expression of cPLA 2 and 5-LO, two biologically different subsets of B-ALL were identified. This finding may be of clinical relevance in future treatment of B-ALL. Splice variants of the cytosolic calcium independent PLA 2 (iPLA 2) have been observed in myeloid and lymphoid cells and are suggested to regulate enzyme activity. The expression of iPLA 2 and its role in leukotriene synthesis was studied in immature myeloid cells and granulocytes. One additional splice variant, believed to function as a negative regulator of enzyme activity, was expressed in acute myeloid leukemia (AML) and HL-60 cells but not in granulocytes. Results obtained with inhibitors, suggest that iPLA 2 is involved in leukotriene synthesis in granulocytes. The majority of studied AML clones were found to express 5-LO, FLAP and LTA 4 hydrolase proteins. Only three of 16 clones produced similar amounts of leukotrienes as granulocytes upon calcium ionophore A23187 stimulation. Addition of exogenous AA and/or diamide, a redox active substance , resulted in activation of leukotriene synthesis. The AA release in AML cells was two to ten times less than that observed in granulocytes after calcium ionophore activation. The expression of cPLA 2 was high in all investigated clones. However, cPLA 2 may be activated by other mechanisms than calcium influx in AML cells, and contribute to proliferation in AML, and thus be a putative target in this disease. B-cell chronic lymphocytic leukemia (B-CLL) cells produced low amounts of LTB 4 after stimulation with A23187 and AA but similar amounts in homogenates as granulocytes. B-CLL cells expressed the high affinity LTB 4 receptor BLT1. Cultivation of B-CLL cells with CD40-ligand-transfected fibroblasts stimulated DNA synthesis and the expression of the activation markers CD23, CD150 and the adhesion molecule ICAM-1 (CD54). The specific leukotriene biosynthesis inhibitors MK886 and BWA4C counteracted this stimulation. Addition of exogenous LTB 4 (150 nM) almost completely reversed the effect of the inhibitors. In summary, these studies indicate that there are several enzymes and receptors in the arachidonic acid cascade that might be putative drug targets. Such drugs may have a therapeutic role in certain malignant hematological diseases

A comparison of platelet quality between platelets from healthy donors and hereditary hemochromatosis donors over seven-day storage.

To access publisher's full text version of this article click on the hyperlink belowBackground: Therapeutic phlebotomy is the standard treatment of hereditary hemochromatosis (HH), the most common genetic disease in people of Northern European descent. Red cell concentrates from HH donors have been reported safe for transfusion, but little data is available on the storage properties of platelet concentrates from HH donors. Study design and methods: Whole blood was collected from 10 healthy individuals and 10 newly diagnosed HH patients with elevated serum ferritin. Platelet-rich plasma (PRP) was prepared and split into four 20-mL units. Platelet quality tests were performed on days 0, 1, 3, 5, and 7 of storage, including platelet aggregation (ADP, arachidonic acid, collagen, and epinephrine agonists), blood gas analysis, flow cytometry (CD41, CD42b, and CD62P expression), and ELISA (sCD40L and sCD62p in supernatant). Results: Mean serum ferritin levels were higher in HH patients than in controls (847.5 vs 45.8 ng/mL, P .05), including blood gas analysis, platelet aggregation, and expression of surface (CD62p and CD42b) and secreted (sCD62P and sCD40L) activation markers. Expected alterations in metabolic (CO2 and glucose decrease, O2 and lactate increase, P < .001) and platelet activation markers (CD42b decrease, CD62P increase, P < .05) over time were observed in both groups. Conclusion: Although these findings indicate that platelets of individuals with HH are comparable to platelets from healthy donors, more extensive studies are needed before definite conclusions can be drawn.Landspitali National University Hospital Research Fun

To Wash or Not to Wash? Comparison of Patient Outcome after Infusion of Cryopreserved Autologous Hematopoietic Stem Cells before and after the Replacement of Manual Washing by Bedside Thawing.

To access publisher's full text version of this article click on the hyperlink belowPrior to infusion, cryopreserved autologous peripheral blood stem cell (auto-PBSC) grafts can either be thawed at the bedside or thawed and washed at the laboratory. At our center, manual washing of grafts prior to infusion was discontinued in April 2012 and bedside thawing was implemented. This study compares the outcomes of two patient groups who received auto-PBSC either after post-thaw washing (n = 84) or bedside thawing (n = 83). No life-threatening infusion-related side effects were reported in either group. There was no significant difference in the mean CD34+ cells/kg dose of infused auto-PBSC in the two groups (p = 0.41), nor in the number of days to neutrophils > 0.5 × 109/L (p = 0.14), days to platelets > 20 × 109/L (p = 0.64), or days to platelets > 50 × 109/L (p = 0.62) after transplant. There was also no difference in the number of days on total parenteral nutrition (p = 0.69), days on G-CSF therapy (p = 0.48), or days with fever (p = 0.73). Finally, there was no significant difference in the number of red cell units transfused (p = 0.32), or platelet units transfused (p = 0.94) after the transplant. One-hundred-day mortality was identical in the two groups (2.4%). Both thawing procedures are safe and result in acceptable engraftment and patient outcomes

Localization of a Gene for Peripheral Arterial Occlusive Disease to Chromosome 1p31

Peripheral arterial occlusive disease (PAOD) results from atherosclerosis of large and medium peripheral arteries, as well as the aorta, and has many risk factors, including smoking, diabetes, hypertension, and hyperlipidemia. PAOD often coexists with coronary artery disease and cerebrovascular disease. Cross-matching a population-based list of Icelandic patients with PAOD who had undergone angiography and/or revascularization procedures with a genealogy database of the entire Icelandic nation defined 116 extended families containing 272 patients. A genomewide scan with microsatellite markers revealed significant linkage to chromosome 1p31 with an allele-sharing LOD score of 3.93 (P=1.04×10(-5)). We designate this locus as “PAOD1.” Subtracting 35 patients with a history of stroke increased the LOD score to 4.93. This suggests that, although PAOD and other vascular diseases share risk factors, genetic factors specific to subtypes of vascular disease may exist