Genetic architecture of band neutrophil fraction in Iceland

Publisher Copyright: © 2022, The Author(s).The characteristic lobulated nuclear morphology of granulocytes is partially determined by composition of nuclear envelope proteins. Abnormal nuclear morphology is primarily observed as an increased number of hypolobulated immature neutrophils, called band cells, during infection or in rare envelopathies like Pelger-Huët anomaly. To search for sequence variants affecting nuclear morphology of granulocytes, we performed a genome-wide association study using band neutrophil fraction from 88,101 Icelanders. We describe 13 sequence variants affecting band neutrophil fraction at nine loci. Five of the variants are at the Lamin B receptor (LBR) locus, encoding an inner nuclear membrane protein. Mutations in LBR are linked to Pelger-Huët anomaly. In addition, we identify cosegregation of a rare stop-gain sequence variant in LBR and Pelger Huët anomaly in an Icelandic eight generation pedigree, initially reported in 1963. Two of the other loci include genes which, like LBR, play a role in the nuclear membrane function and integrity. These GWAS results highlight the role proteins of the inner nuclear membrane have as important for neutrophil nuclear morphology.Peer reviewe

Defining new reference intervals for serum free light chains in individuals with chronic kidney disease : Results of the iStopMM study

Publisher Copyright: © 2022. The Author(s). © 2022. The Author(s).Serum free light chain (FLC) concentration is greatly affected by kidney function. Using a large prospective population-based cohort, we aimed to establish a reference interval for FLCs in persons with chronic kidney disease (CKD). A total of 75422 participants of the iStopMM study were screened with serum FLC, serum protein electrophoresis and immunofixation. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. Central 99% reference intervals were determined, and 95% confidence intervals calculated. Included were 6461 (12%) participants with measured FLCs, eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, and without evidence of monoclonality. Using current reference intervals, 60% and 21% had kappa and lambda FLC values outside the normal range. The FLC ratio was outside standard reference interval (0.26-1.65) in 9% of participants and outside current kidney reference interval (0.37-3.10) in 0.7%. New reference intervals for FLC and FLC ratio were established. New reference intervals for the FLC ratio were 0.46-2.62, 0.48-3.38, and 0.54-3.30 for eGFR 45-59, 30-44, and < 30 mL/min/1.73 m2 groups, respectively. The crude prevalence of LC-MGUS in CKD patients was 0.5%. We conclude that current reference intervals for FLC and FLC ratio are inaccurate in CKD patients and propose new eGFR based reference intervals to be implemented.Peer reviewe

Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore present a target population for MGUS screening. This two-part study is the first study to evaluate the relationship of MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio (OR)= 1.10; 95% confidence interval (CI): 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer associated with the progression of MGUS, except for myeloid malignancies which were associated with lower risk of progression (hazard ratio (HR)=0.37; 95%CI: 0.16-0.89; p=0.028). Our findings indicate that a prior cancer are not a significant aetiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer

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

Mesenteric panniculitis presenting with autoimmune haemolytic anaemia

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldMesenteric panniculitis is a rare idiopathic inflammatory disorder that can lead to sclerosis. We describe a patient with mesenteric panniculitis presenting with abdominal symptoms and autoimmune haemolytic anaemia. The symptoms remitted after splenectomy and gradual steroid taper. This may suggest an autoimmune component in the aetiology of mesenteric panniculitis

A 'pilot' study on air-travel and venous thromboembolism

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldNo abstract availabl

Progressive multifocal leukoencephalopathy after fludarabine therapy for low-grade lymphoproliferative disease.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldFludarabine is becoming the initial therapy for low-grade lymphoproliferative malignancies, such as CLL and follicular lymphoma. Fludarabine is highly immunosuppressive in addition to being myelosuppressive and has been associated with neurotoxicity. Progressive multifocal leukoencephalopathy (PML) is an infection with JC virus of the white matter of the central nervous system seen mostly in immunosuppressed patients. We describe two patients treated with fludarabine who developed PML. Immunolabeling was positive for JCV in both patients, but PCR was repeatedly negative in one of them. We suggest that fludarabine may increase the risk of PML in patients with lymphoproliferative diseases

Red blood cell utilization and transfusion triggers in patients diagnosed with chronic lymphocytic leukaemia in Iceland 2003-2016.

To access publisher's full text version of this article click on the hyperlink belowBACKGROUND AND OBJECTIVES: Revised Icelandic guidelines proposed a restrictive haemoglobin (Hb) threshold of 70 g/l for red blood cell (RBC) transfusions in general, but 100 g/l for malignancies/bone marrow suppression. Chronic lymphocytic leukaemia (CLL) is frequently complicated by anaemia. The objective was to investigate RBC transfusion practices in CLL. MATERIALS AND METHODS: This retrospective nation-wide study utilized an Icelandic registry of CLL patients diagnosed between 2003 and 2016. Medical records were reviewed and haemoglobin transfusion triggers compared for two periods: Earlier (2003-2012) and latter (2013-2017). RESULTS: Two hundred and thirteen patients were diagnosed with CLL over the period whereof 77 (36·2%) received RBC transfusion(s). Median time from diagnosis to first transfusion was 2·2 years. Higher age, Rai stage 3/4 at diagnosis (P < 0·05) and chemotherapy (P < 0·001) were associated with increased odds of transfusions. Shorter time to first transfusion correlated with higher age (P < 0·001) and Rai stage (P = 0·02) at diagnosis. The mean Hb trigger was 90·4 and 81·2 in the earlier and latter period respectively (P = 0·01). This difference in Hb triggers was most pronounced in patients without documented bone marrow involvement, or 80·5 g/l compared to 93·5 g/l (P = 0·004). The median time from diagnosis to transfusion was longer in the latter period (2·9 years vs. 1·6 years, P = 0·01). After RBC transfusions the survival decreased significantly (P < 0·001). CONCLUSION: One-third of CLL patients received RBC transfusions but few were heavily transfused. Older age, Rai stage, and chemotherapy predicted RBC use. The Hb transfusion trigger decreased over time while time to first RBC transfusion increased. RBC transfusions predict poor survival.Harold-Gunson foundatio

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