A truncating mutation in EPOR leads to hypo-responsiveness to erythropoietin with normal haemoglobin.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadThe cytokine erythropoietin (EPO), signalling through the EPO receptor (EPO-R), is essential for the formation of red blood cells. We performed a genome-wide association study (GWAS) testing 32.5 million sequence variants for association with serum EPO levels in a set of 4187 individuals. We detect an association between a rare and well imputed stop-gained variant rs370865377[A] (p.Gln82Ter) in EPOR, carried by 1 in 550 Icelanders, and increased serum EPO levels (MAF = 0.09%, Effect = 1.47 SD, P = 3.3 × 10-7). We validated these findings by measuring serum EPO levels in 34 additional pairs of carriers and matched controls and found carriers to have 3.23-fold higher EPO levels than controls (P = 1.7 × 10-6; Pcombined = 1.6 × 10-11). In contrast to previously reported EPOR mutations, p.Gln82Ter does not associate with haemoglobin levels (Effect = -0.045 SD, P = 0.32, N = 273,160), probably due to a compensatory EPO upregulation in response to EPO-R hypo-responsiveness

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 rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

Efst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinnIL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.Netherlands Asthma Foundation University Medical Center Groningen Ministry of Health and Environmental Hygiene of Netherlands Netherlands Asthma Stichting Astma Bestrijding BBMRI European Respiratory Society private and public research funds AstraZeneca ALK-Abello, Denmar

Sequence variants associating with urinary biomarkers

Urine dipstick tests are widely used in routine medical care to diagnose kidney and urinary tract and metabolic diseases. Several environmental factors are known to affect the test results, whereas the effects of genetic diversity are largely unknown. We tested 32.5 million sequence variants for association with urinary biomarkers in a set of 150 274 Icelanders with urine dipstick measurements. We detected 20 association signals, of which 14 are novel, associating with at least one of five clinical entities defined by the urine dipstick: glucosuria, ketonuria, proteinuria, hematuria and urine pH. These include three independent glucosuria variants at SLC5A2, the gene encoding the sodium-dependent glucose transporter (SGLT2), a protein targeted pharmacologically to increase urinary glucose excretion in the treatment of diabetes. Two variants associating with proteinuria are in LRP2 and CUBN, encoding the co-transporters megalin and cubilin, respectively, that mediate proximal tubule protein uptake. One of the hematuria-associated variants is a rare, previously unreported 2.5 kb exonic deletion in COL4A3. Of the four signals associated with urine pH, we note that the pH-increasing alleles of two variants (POU2AF1, WDR72) associate significantly with increased risk of kidney stones. Our results reveal that genetic factors affect variability in urinary biomarkers, in both a disease dependent and independent context

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

Factor-sparing use of the COX-2 inhibitor rofecoxib in haemophilic arthropathy

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldExamines the use of the cyclo-oxygenase 2 inhibitor anti-inflammatory drug rofecoxib in patients with hemophilic arthropathy. Case study of a patient of severe hemophilia; Features of the drug; Reduction of symptoms in the patient

Reactivation of rheumatoid arthritis and development of leukocytoclastic vasculitis in a patient receiving granulocyte colony-stimulating factor for Felty's syndrome

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldPatients with Felty’s syndrome, the combination of rheumatoid arthritis, splenomegaly, and neutropenia, have increased susceptibility to bacterial infections. The patients are usually b-elated with steroids or splenectomy. Granulocyte-macrophage colony-stimulating factor (GM-CSF)1-6 and granulocyte colony-stimulating factor (G-CSF)5g have been reported to correct the neutropenia of Felty’s syndrome. Both drugs have also been reported to exacerbate inflammatory diseases such as vasculitis,loJ1 but to our knowledge, only GM-CSF has been reported to cause arthritis flare-up in palzients with Felty’s syndrome. 1,12 This report describes reactivation of previously inactive arthritis and development of leukocytoclastic vasculitis in a patient with Felty’s syndrome treated with G-CSF

Warfarin anticoagulation intensity in specialist-based and in computer-assisted dosing practice

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldThe efficacy and safety of oral anticoagulation (OA) with vitamin K antagonists depends on maintaining anticoagulation intensity, measured as international normalized ratio (INR), within defined target ranges. We assessed the quality of our current software-assisted warfarin dosing in the year 2006 in 941 unselected consecutive patients on stable OA with atrial fibrillation (AF), venous thromboembolism (VTE) and prosthetic heart valves (PHV) by comparing it to our previous cardiologist-based dosing practice in 1992 when a study was carried out on 241 comparable patients. Over 14 years, the time within target range increased in all three anticoagulated groups, i.e. in AF patients from 46% to 81%, in VTE patients from 62% to 84% and in patients with PHV from 40% to 64%. Only 1% of the treatment time is now spent at INR 4.0 presently compared to 2.8% in the past (P < 0.0001). INR-targets are better achieved with the current software-assisted dosing practice and extreme low and high values are less common than previously. The results provide indirect evidence suggesting that both efficacy and safety has improved with the current practice

Risk of excessive bleeding associated with marginally low von Willebrand factor and mild platelet dysfunction

To access Publisher full text version of this article. Please click on the hyperlink in Additional LinkBackground: Bleeding symptoms are so commonly reported that it is not known whether they associate causally or coincidentally with mild but measureable primary hemostatic defects. Objectives/Patients/Methods: In order to evaluate if the mild primary hemostatic defects are truly causative of increased bleeding symptoms, we surveyed a population of healthy teenagers for bleeding symptoms. Using a case-control approach, we then estimated the risk of excessive bleeding associated with low von Willebrand factor (defined as VWF below the 5th percentile of a normal reference population) or mild platelet dysfunction (PD, defined as concurrent reduced platelet aggregation responses to two agonists (ADP and epinephrine). Results: Excessive bleeding was present in 63 out of 809 teenagers (7.8%). Among the 49 cases who were tested for VWF, low values by three measures was more commonly present than in 166 controls, specifically, ristocetin cofactor activity (20.4% vs 5.4%, odds ratio 4.5), collagen binding (14.3% vs 4.2%, OR 3.8), and antigen level (20.4% vs 6.0%, OR 4.0). The low ristocetin cofactor values ranged from 35-45 U/dL except for a single case with 26 U/dL. Of the 47 teenagers with excessive bleeding who underwent platelet aggregation studies, reduced responses were more common than in controls (12.8% vs 4.4%, OR 3.2). Twenty nine percent of cases with excessive bleeding had either low ristocetin cofactor or PD. Conclusions: Almost one in three teenagers who report excessive bleeding are likely to have a measurable hemostatic disturbance manifested either by marginally low VWF (by three measures) or mild PD

Interior view of the factory floor at British Tube Mills, Adelaide, South Australia, 1958 [2] [picture] /

Condition: Good.; Title devised by cataloguer based on inscription on reverse.; Part of Wolfgang Sievers photographic archive.; Sievers number: 2570 AH.; Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn3998207