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Fosfatasa Alcalina , Anemia de Células Falciformes , Biomarcadores , Humanos , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/sangre , Biomarcadores/sangre , Fosfatasa Alcalina/sangre , Masculino , Femenino , Adulto , Dolor/etiología , Adolescente , Persona de Mediana EdadRESUMEN
Transcriptional changes in compensatory erythropoiesis in sickle cell anemia (SCA) and their disease modulation are unclear. We detected 1226 differentially expressed genes in hemoglobin SS reticulocytes compared to non-anemic hemoglobin AA controls. Assessing developmental expression changes in hemoglobin AA erythroblasts for these genes suggests heightened terminal differentiation in early erythroblasts in SCA that diminishes toward the polychromatic to orthochromatic stage transition. Comparison of reticulocyte gene expression changes in SCA with that in Chuvash erythrocytosis, a non-anemic disorder of increased erythropoiesis due to constitutive activation of hypoxia inducible factors, identified 453 SCA-specific changes attributable to compensatory erythropoiesis. Peripheral blood mononuclear cells (PBMCs) in SCA contain elevated proportions of erythroid progenitors due to heightened erythropoiesis. Deconvolution analysis in PBMCs from 131 SCA patients detected 54 genes whose erythroid expression correlated with erythropoiesis efficiency, which were enriched with SCA-specific changes (OR = 2.9, P = 0.00063) and annotation keyword "ubiquitin-dependent protein catabolic process", "protein ubiquitination", and "protein polyubiquitination" (OR = 4.2, P = 7.5 × 10-5). An erythroid expression quantitative trait locus of one of these genes, LNX2 encoding an E3 ubiquitin ligase, associated with severe pain episodes in 774 SCA patients (OR = 1.7, P = 3.9 × 10-5). Thus, erythroid gene transcription responds to unique conditions within SCA erythroblasts and these changes potentially correspond to vaso-occlusive manifestations.
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Anemia de Células Falciformes , Reticulocitos , Humanos , Reticulocitos/metabolismo , Leucocitos Mononucleares/metabolismo , Eritroblastos/metabolismo , Eritropoyesis/genética , Expresión GénicaRESUMEN
Von Hippel-Lindau protein (VHL) is essential to hypoxic regulation of cellular processes. VHL promotes proteolytic clearance of hypoxia-inducible transcription factors (HIFs) that have been modified by oxygen-dependent HIF-prolyl hydroxylases. A homozygous loss-of-function VHLR200W mutation causes Chuvash erythrocytosis, a congenital disorder caused by augmented hypoxia-sensing. Homozygous VHLR200W results in accumulation of HIFs that increase transcription of the erythropoietin gene and raise hematocrit. Phlebotomies reduce hematocrit and hyperviscosity symptoms. However, the major cause of morbidity and mortality in Chuvash erythrocytosis is thrombosis. Phlebotomies cause iron deficiency, which may further elevate HIF activity and transferrin, the HIF-regulated plasma iron transporter recently implicated in thrombogenesis. We hypothesized that transferrin is elevated in Chuvash erythrocytosis, and that iron deficiency contributes to its elevation and to thrombosis. We studied 155 patients and 154 matched controls at steady state and followed them for development of thrombosis. Baseline transferrin was elevated, and ferritin reduced in patients. VHLR200W homozygosity and lower ferritin correlated with higher erythropoietin and transferrin. During 11 years of follow-up, risk of thrombosis increased 8.9-fold in patients versus controls. Erythropoietin elevation, but not hematocrit or ferritin, correlated with thrombosis risk. Unexpectedly, transferrin elevation associated with reduced rather than increased thrombosis risk. The A allele of the promoter EPO single nucleotide polymorphisms (SNP), rs1617640, associated with elevated erythropoietin and increased thrombosis risk, whereas the A allele of the intronic TF SNP, rs3811647, associated with higher transferrin and protection from thrombosis in patients. Our findings suggest an unexpected causal relationship between increased transferrin and protection from thrombosis in Chuvash erythrocytosis.
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Eritropoyetina , Deficiencias de Hierro , Policitemia , Trombosis , Humanos , Policitemia/genética , Transferrina , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Trombosis/genética , Hipoxia , Eritropoyetina/genética , FerritinasRESUMEN
BACKGROUND: Hemolysis contributes to the anemia of sickle cell disease (SCD). Hemolysis and anemia are distinct but inter-related pathophysiological processes that underlie end-organ dysfunction in this condition. We hypothesized that real-world medical tests would reveal distinct contributions of hemolysis and anemia to certain cardiopulmonary changes in adults with SCD. METHODS: We assessed laboratory and clinical tests of cardiopulmonary function obtained during routine delivery of care in 442 adult SCD patients. We characterized hemolysis by the first principal component (PC1) of reticulocyte percent, lactate dehydrogenase (LDH), aspartate amino transferase (AST) and total bilirubin- the hemolytic component. The relationships of hemoglobin concentration and hemolysis to organ dysfunction were analyzed by multiple regression and path analysis to identify independent associations. RESULTS: Degree of hemolysis and degree of anemia both associated independently with elevated values for left atrial diameter (LAD) and left ventricular end-diastolic diameter (LVED), and with lower percent predicted forced expiratory volume in first second (FEV1). Degree of hemolysis, but not anemia, associated independently with low values for oxygen saturation, forced vital capacity (FVC), and total lung capacity (TLC)]. Path analysis reinforced the trend by multiple regression for association of both degree of hemolysis and anemia with elevated TRV but not with lower diastolic blood pressure. DISCUSSION: Analysis of real-world clinical tests suggest that, although they are inter-related, the degrees of hemolysis and of anemia make independent contributions to cardiopulmonary dysfunction and that treatments that specifically target both aspects of sickle cell disease may be of maximal benefit.
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Anemia de Células Falciformes , Hemólisis , Adulto , Humanos , Insuficiencia Multiorgánica , Presión SanguíneaRESUMEN
Haptoglobin (HP) is an acute-phase protein and the main scavenger of cell-free hemoglobin. When HP is depleted, as observed in hemolytic conditions such as sickle cell disease (SCD), cell-free hemoglobin can lead to acute organ damage. The impact of the HP 1-1, 2-1, and 2-2 isoforms on HP and cell-free hemoglobin concentrations and SCD-related complications is unclear. In a longitudinal cohort of patients with SCD, the HP 1 allele was associated with higher HP and lower cell-free hemoglobin concentrations at a routine clinic visit as well as during hospitalization for a vaso-occlusive episode or acute chest syndrome. With a median follow-up of 6.8 years, acute chest syndrome occurred in 42% (n = 163) and multiorgan failure in 14% (n = 53) of 391 patients with SCD with a minimum follow-up of 6 months. The HP 1 allele was independently associated with lower risk of developing multiorgan failure during acute chest syndrome (additive model hazard ratio, 0.5; P < .001). Future studies assessing the regulation of HP concentrations and ability to bind cell-free hemoglobin according to the HP genotype may help to identify patients with SCD at high risk for multiorgan failure and to guide interventions, such as rapid initiation of exchange transfusion or HP replacement therapy.
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Síndrome Torácico Agudo , Anemia de Células Falciformes , Humanos , Síndrome Torácico Agudo/complicaciones , Haptoglobinas/genética , Alelos , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/genética , Hemoglobinas , Insuficiencia Multiorgánica/etiologíaAsunto(s)
Anemia de Células Falciformes , Insuficiencia Multiorgánica , Trombomodulina/sangre , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/mortalidad , Línea Celular , Femenino , Humanos , Masculino , Insuficiencia Multiorgánica/sangre , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/mortalidadRESUMEN
FOXM1 transcription factor is an oncogene and a master regulator of chemoresistance in multiple cancers. Pharmacological inhibition of FOXM1 is a promising approach but has proven to be challenging. We performed a network-centric transcriptomic analysis to identify a novel compound STL427944 that selectively suppresses FOXM1 by inducing the relocalization of nuclear FOXM1 protein to the cytoplasm and promoting its subsequent degradation by autophagosomes. Human cancer cells treated with STL427944 exhibit increased sensitivity to cytotoxic effects of conventional chemotherapeutic treatments (platinum-based agents, 5-fluorouracil, and taxanes). RNA-seq analysis of STL427944-induced gene expression changes revealed prominent suppression of gene signatures characteristic for FOXM1 and its downstream targets but no significant changes in other important regulatory pathways, thereby suggesting high selectivity of STL427944 toward the FOXM1 pathway. Collectively, the novel autophagy-dependent mode of FOXM1 suppression by STL427944 validates a unique pathway to overcome tumor chemoresistance and improve the efficacy of treatment with conventional cancer drugs.
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Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Proteína Forkhead Box M1/antagonistas & inhibidores , Perfilación de la Expresión Génica , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Estabilidad Proteica , Transporte de Proteínas , Proteolisis , RNA-Seq , TranscriptomaRESUMEN
Haemolysis and vaso-occlusion underlie multi-organ system complications in sickle cell disease (SCD). We assessed real-world biomarkers in University of Illinois adult SCD patients, categorised as severe (HbSS/Sß0 -thalassaemia; n = 342) or mild (HbSC/Sß+ -thalassaemia; n = 100) genotypes and stratified according to treatment. African-American controls from the National Health and Nutrition Examination Survey (NHANES) were matched with each genotype category. Most measures of haemolysis, anaemia, inflammation and function of kidneys, liver and lungs differed markedly in untreated severe genotype patients compared to NHANES controls. These same biomarkers were significantly closer to the NHANES control range in untreated mild versus severe genotype patients, but they were not improved in severe genotype patients receiving treatment with hydroxycarbamide or blood transfusions, except that haemoglobin and HbF were higher with hydroxycarbamide. Systolic blood pressures did not differ among the SCD and NHANES groups, but diastolic pressures were higher in mild genotype patients. Ferritin in severe genotype patients on chronic transfusions was 50-fold higher than NHANES controls. The cross-sectional real-world biomarkers of patients on hydroxycarbamide or transfusions were not markedly improved compared to untreated patients. This may be due partly to poor compliance or more severe disease. Our findings highlight the need for more effective treatments.
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Anemia de Células Falciformes/diagnóstico , Adulto , Negro o Afroamericano/genética , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/terapia , Antidrepanocíticos/uso terapéutico , Transfusión Sanguínea , Estudios Transversales , Femenino , Genotipo , Humanos , Hidroxiurea/uso terapéutico , Masculino , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Sickle cell disease (SCD) and apolipoprotein L1 (APOL1) G1/G2 variants increase chronic kidney disease (CKD) risk in African Americans by poorly understood mechanisms. We applied bioinformatics to identify new candidate genes associated with SCD-related CKD. An interaction network demonstrated APOA1 connecting haemoglobin subunit ß (HBB) and APOL1 with 36 other candidate genes. Gene expression revealed upregulation of engulfment and cell motility 1 (ELMO1) and downregulation of APOA1 in the kidney cortex of SCD versus non-SCD mice. Analysis of candidate genes identified ELMO1 rs10951509 to be associated with albuminuria and APOA1 rs11216132 with haemoglobinuria in patients with SCD. A bioinformatic approach highlights ELMO1 and APOA1 as potentially associated with SCD nephropathy.
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Proteínas Adaptadoras Transductoras de Señales , Anemia de Células Falciformes , Apolipoproteína A-I , Movimiento Celular/genética , Regulación hacia Abajo , Redes Reguladoras de Genes , Insuficiencia Renal Crónica , Regulación hacia Arriba , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Albuminuria/genética , Albuminuria/metabolismo , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/metabolismo , Animales , Apolipoproteína A-I/biosíntesis , Apolipoproteína A-I/genética , Femenino , Humanos , Masculino , Ratones , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismoRESUMEN
BACKGROUND: Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as 'test-and-treat' policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM. METHODS AND FINDINGS: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify. CONCLUSIONS: Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.
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Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Antimaláricos/uso terapéutico , Benin/epidemiología , Agentes Comunitarios de Salud , Progresión de la Enfermedad , Gambia/epidemiología , Humanos , Malaria/tratamiento farmacológico , Malaria/epidemiología , Malasia/epidemiología , Mozambique/epidemiología , Plasmodium falciparum/patogenicidad , Tanzanía/epidemiología , Tiempo de Tratamiento/economía , Uganda/epidemiología , Yemen/epidemiología , Zambia/epidemiologíaRESUMEN
Genetic modifiers of anemia in Plasmodium falciparum infection and sickle cell disease (SCD) are not fully known. Both conditions are associated with oxidative stress, hemolysis and anemia. The CYB5R3 gene encodes cytochrome b5 reductase 3, which converts methemoglobin to hemoglobin through oxidation of NADH. CYB5R3c.350C > G encoding CYB5R3T117S , the most frequent recognized African-specific polymorphism, does not have known functional significance, but its high allele frequency (23% in African Americans) suggests a selection advantage. Glucose-6-phosphate dehydrogenase (G6PD) is essential for protection from oxidants; its African-polymorphic X-linked A+ and A- alleles, and other variants with reduced activity, coincide with endemic malaria distribution, suggesting protection from lethal infection. We examined the association of CYB5R3c.350C > G with severe anemia (hemoglobin <5 g/dL) in the context of G6PD A+ and A- status among 165 Zambian children with malaria. CYB5R3c.350C > G offered protection against severe malarial anemia in children without G6PD deficiency (G6PD wild type or A+/A- heterozygotes) (odds ratio 0.29, P = .022) but not in G6PD A+ or A- hemizygotes/homozygotes. We also examined the relationship of CYB5R3c.350C > G with hemoglobin concentration among 267 children and 321 adults and adolescents with SCD in the US and UK and found higher hemoglobin in SCD patients without G6PD deficiency (ß = 0.29, P = .022 children; ß = 0.33, P = .004 adults). Functional studies in SCD erythrocytes revealed mildly lower activity of native CYB5R3T117S compared to wildtype CYB5R3 and higher NADH/NAD+ ratios. In conclusion, CYB5R3c.350C > G appears to ameliorate anemia severity in malaria and SCD patients without G6PD deficiency, possibly accounting for CYB5R3c.350C > G selection and its high prevalence.
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Alelos , Anemia de Células Falciformes , Citocromo-B(5) Reductasa , Glucosafosfato Deshidrogenasa/genética , Malaria Falciparum , Plasmodium falciparum/metabolismo , Mutación Puntual , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/metabolismo , Anemia de Células Falciformes/parasitología , Preescolar , Citocromo-B(5) Reductasa/genética , Citocromo-B(5) Reductasa/metabolismo , Femenino , Glucosafosfato Deshidrogenasa/metabolismo , Humanos , Lactante , Malaria Falciparum/genética , Malaria Falciparum/metabolismo , Masculino , Índice de Severidad de la Enfermedad , ZambiaAsunto(s)
Células Precursoras Eritroides/metabolismo , Eritropoyesis/genética , Leucocitos Mononucleares/metabolismo , Policitemia/sangre , Policitemia/genética , Diferenciación Celular/fisiología , Células Precursoras Eritroides/patología , Expresión Génica , Humanos , Leucocitos Mononucleares/patología , Policitemia/patología , Fibrosis Pulmonar/sangre , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/patologíaRESUMEN
Sickle cell disease (SCD) patients are at a four- to 100-fold increased risk for thrombosis compared with the general population, although the mechanisms and risk factors are not clear. We investigated the incidence and predictors for thrombosis in a retrospective, longitudinal cohort of 1193 pediatric and adult SCD patients treated at our institution between January 2008 and December 2017. SCD diagnosis and thrombotic complications were identified using International Classification of Diseases coding and verified through medical chart review. Clinical and laboratory data were extracted from the medical records. With a median follow-up of 6.4 years, 208 (17.4%) SCD patients experienced 352 thrombotic events (64 strokes, 288 venous thromboembolisms [VTE]). Risk factors for stroke included older age and HbSS/Sß0-genotype and a lower hemoglobin (Hb) F% in the subset of HbSS/Sß0-genotype patients (P < .05). VTE risk was independently associated with lower estimated glomerular filtration rate, hydroxyurea (HU) use, HbSS/Sß0 genotype, and higher white blood cell (WBC) counts and Hb (P ≤ .03). Two thrombomodulin gene variants previously associated with thrombosis in the general African American population, THBD rs2567617 (minor allele frequency [MAF] 0.25; odds ratio [OR], 1.5; P = .049) and THBD rs1998081 (MAF, 0.24; OR, 1.5; P = .059), were associated with thrombosis in this cohort. In summary, thrombotic complications are common, and several traditional and SCD-specific risk factors are associated with thrombotic risk. Future studies integrating clinical, laboratory, and genetic risk factors may improve our understanding of thrombosis and guide intervention practices in SCD.