Hydroxyurea Induces Genome-Wide Epigenetic Changes In Sickle Cell Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2670-2670
Author(s):  
Allison E Ashley-Koch ◽  
Melanie Garrett ◽  
Karen Soldano ◽  
Latorya A. Barber ◽  
Marilyn J. Telen
Keyword(s):  
Dna Methylation ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Clinical Effects ◽  
Cell Disease ◽  
Cpg Sites ◽  
False Discovery ◽  
Genome Wide ◽  
Number Of Patients ◽  
Tgfβ Pathway

Abstract Abstract 2670 Introduction: Hydroxyurea (HU) is currently the only pharmacologic agent widely used to ameliorate the symptoms of sickle cell disease (SCD). The clinical effects of HU are diverse, including the well-known increase in levels of fetal hemoglobin (HbF), effects on leukocyte and platelet counts, and down-regulation of red cell adhesion despite increased expression of some adhesion receptors. However, the precise mechanisms by which HU exerts its ameliorative and pleiotropic actions are not well understood. HU is primarily thought to inhibit DNA replication and cause cell cycle arrest due to inhibition of ribonucleotide reductase (Yarbro, 1992). This mechanism is likely how HU exhibits its ameliorative effects in myeloproliferative conditions. But it is not as clear how this action results in an increase in the percentage of red blood cells that express a large percentage of HbF (Platt, 2008). Previous evidence suggests that HU may induce epigenetic (specifically, hypermethylation) changes to DNA (Nyce, 1989). Thus, we hypothesized that HU may increase HbF levels and cause other systemic changes through epigenetic mechanisms. Methods: To test the hypothesis that HU usage is associated with alterations in DNA methylation, we examined DNA samples from 24 adult patients with SCD, 12 of whom were taking HU at the time of DNA collection and 12 of whom were not. DNA from each individual was pre-treated with bisulfite (Zymo Research) and assessed for methylation levels at 27,578 CpG sites in 14,495 genes using the Illumina HumanMethylation27 BeadChip. One sample (off HU) failed to undergo a successful bisulfite DNA conversion and was subsequently removed from analysis. The relative levels of methylation (β) were calculated as the ratio of methylated probe signal to total locus signal intensity. Linear regression (PROC GLM, SAS version 9.1.3, Cary, NC) was used to test for differences in methylation (β) as a function of HU usage, controlling for sex and age. Results: On average, patients using HU had higher mean levels of methylation genome-wide compared with patients not taking HU, although the difference was not statistically significant, likely due to the small number of patients examined. Using the Benjamini-Hochberg false discovery correction for multiple testing and setting a stringent corrected p-value threshold of 0.05, we identified 247 out of the approximately 27,000 CpG sites that were differentially methylated as a function of HU usage. Eight CpG sites met a very stringent Bonferroni correction and represented a functionally diverse set of genes, including ones that encode a phosphatase, influence neural outgrowth, and play a role in vertebral development. CpG sites meeting the false discovery correction (n=247) were subsequently subjected to gene network and ontology analysis using DAVID pathway software (http://david.abcc.ncifcrf.gov/) to determine if specific biological pathways were statistically enriched for differences in DNA methylation. Several of these sites were associated with pathways involved in cell growth, senescence and differentiation, as might be expected given the known effects of HU on hematopoiesis. However, the TGFβ pathway was also significantly represented in this subset of CpG sites (pathway analysis p<0.05). Discussion: Consistent with findings by Nyce (1989), we observed a trend in which HU usage was associated with hypermethylation, so that patients taking HU had on average more methylation genome-wide than patients not taking HU. Genetic variation in the TGFβ pathway has been implicated in the occurrence of several SCD complications, including pulmonary hypertension (Ashley-Koch et al., 2008), risk for stroke (Sebastiani et al., 2005), leg ulcers (Nolan et al., 2006), bacteremia (Adewoye et al., 2006), and priapism (Elliott et al., 2007). Therefore, identification of this pathway as affected by HU is especially interesting. In summary, we have evidence that DNA epigenetic differences occur in sickle cell patients as a result of HU usage and are associated a wide variety of gene pathways, consistent with the diverse array of clinical and laboratory changes observed in patients on HU. Future studies will include confirmation of the epigenetic differences in the specific genes implicated among a larger cohort of SCD patients on and off HU, as well as functional studies of these genes. Disclosures: No relevant conflicts of interest to declare.

Experience of an Interdisciplinary Pediatric Pain Service

PEDIATRICS ◽  
1991 ◽  
Vol 88 (6) ◽  
pp. 1226-1232
Author(s):  
Barbara S. Shapiro ◽  
David E. Cohen ◽  
Kenneth W. Covelman ◽  
Carol J. Howe ◽  
Sam M. Scott
Keyword(s):  
Sickle Cell Disease ◽  
Patient Care ◽  
Sickle Cell ◽  
Health Care Professionals ◽  
Tertiary Care ◽  
Direct Patient Care ◽  
Team Approach ◽  
Cell Disease ◽  
Number Of Patients ◽  
Physician Time

This article is a report of our experience with an interdisciplinary pain service in a large tertiary care pediatric hospital. During the first 2 years of operation, we received 869 consultations and referrals from more than 19 hospital divisions. Postoperative pain was the most frequent reason for consultation (56% of patients). Patients with pain related to cancer and sickle cell disease comprised 25% of the consultations. The remaining patients had a wide variety of primary diagnoses and causes of pain. We calculated the time spent by pain service physicians in direct patient care. The majority (63%) of physician time was spent with a small number of patients (17%). Most of these patients had pain that was unrelated to surgery, cancer, or sickle cell disease, and many posed dilemmas in diagnosis and treatment. Physician time was correlated directly to the use of psychologic and physical therapies for the pain, involving multiple team members. This experience supports the demand for an interdisciplinary pain service in a tertiary care children's hospital. A significant amount of physician time is necessary to provide patient care and to maintain a team approach, however, and pediatricians and other health care professionals who aim to implement such services should be cognizant of the time required.

Adjuvant interventions with opioids for vaso-occlusive crisis in sickle cell disease: A mixed treatment network meta-analysis of randomized controlled clinical trials

2020 ◽  
Vol 16 (4) ◽  
pp. 267-275
Author(s):  
Kannan Sridharan, MD, DM ◽  
Gowri Sivaramakrishnan, MDS
Keyword(s):  
Nitric Oxide ◽  
Sickle Cell Disease ◽  
Adverse Events ◽  
Magnesium Sulfate ◽  
Sickle Cell ◽  
Meta Analysis ◽  
Favorable Effect ◽  
Secondary Outcome ◽  
Cell Disease ◽  
Number Of Patients

Objective: Vaso-occlusive crisis is the most common clinical feature requiring opioid analgesics in patients with sickle cell disease. We conducted a network meta-analysis to compare the drugs that can be used as add-on with opioids for vaso-occlusive crisis.Design: Network meta-analysis of randomized clinical trials.Patients: Sickle cell disease patients with vaso-occlusive crisis receiving adjuvants to opioids for pain management.Main outcome measures: A number of patients with complete pain relief and pain scores assessed either by visual analog or by a numerical rating scale were the primary outcomes. Adverse events and dose of opioids (in morphine equivalents) for pain alleviation between the treatment arms were the secondary outcome measures.Results: Eleven studies evaluating the addition of ketorolac, magnesium sulfate, ketoprofen, ibuprofen, methadone, inhalational nitric oxide, methylprednisolone, and arginine with morphine were obtained. The pooled analysis showed a favorable effect in the pain reduction for the additions of arginine {–2 [–3.39, –0.61]} and ibuprofen {–1.7 [–3.26, –0.14]} with morphine. Arginine has high probability of being the “best” in the pool followed by ibuprofen. No significant differences were observed in the risk of adverse events {ketoprofen—0.84 [0.42, 1.65]; magnesium sulfate—1.81 [0.64, 5.81]; and arginine—2.08 [0.18, 24.31]}. A significant lower dose of opioid was required when given adjunctive to arginine, inhalational nitric oxide, and methylprednisolone.Conclusion: We observed that arginine and ibuprofen could produce additional analgesic effects when combined with morphine in vaso-occlusive crisis.

Does Treatment with Hydroxyurea and Opioids Affect Age of Death in Sickle Cell Disease Patients?

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4808-4808
Author(s):  
Charlene M. Flahiff ◽  
Jude C Jonassaint ◽  
Charles R. Jonassaint ◽  
Soheir S. Adam ◽  
Marilyn J. Telen ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Treatment Modality ◽  
Group Analysis ◽  
Treatment Modalities ◽  
Age At Death ◽  
Cell Disease ◽  
Number Of Patients ◽  
Living Group ◽  
Age Of Death

Abstract Hydroxyurea (HU) is used to treat sickle cell disease and has been shown to decrease painful episodes (Charache, 1995) and possibly vaso-occlusive episodes associated morbidity and mortality (Steinberg, 2003). Opioids are often prescribed in adult patients for daily management of their chronic pain. The aim of the current study was to determine the age at death and the effect of treatment with HU and/or opioids prior to death in patients who died from sickle cell disease (SCD) related complications and to compare these parameters to those in our current patients population. Methods: Age, daily treatment with opioids, and HU treatment were determined for 185 patients currently followed at the Duke Comprehensive Sickle Cell Center (DCSCC) and for 50 patients who died between 2002 and 2008 due to SCD complications and who were regularly followed at the DCSCC for their care. The two cohorts, living and deceased patients were divided based on their treatment modality into the following 4 groups: opioid only, HU only, both drugs, and neither drug. Non-parametric chi-square test was performed to determine whether the treatment modality distribution was different in the deceased group compared to the living group. Analysis of variance was done to determine the relationship between treatment group and age at death. Results and Discussion: The distribution of treatment modalities in the deceased group was significantly different than that of the living group. The opioids only group had the largest number of patients in the deceased cohort (44%), and this percentage was almost twice that of the living group (25%). (Fig. 1) Moreover, 72 % of the deceased patients were treated with opioids vs. only 53 % of the living patients, perhaps because the sicker patients are often treated with daily opioids. However, the age of death in the opioids only group was 44 ± 15.5 years. (Fig. 2) In the living group, treatment with both drugs or with no drugs were equivalent (28%), while in the deceased group, more patients were treated with both drugs (28%) compared to no drug treatment (18%). The HU only group had the lowest number of deaths (10%), and the percentage of patients in this group was nearly half that the one of the living group (19%). This group also was the oldest at death (58 ±16 years). Age at death was also significantly higher in this group than in each of the other 3 groups (p&lt;0.05). The low use of HU in the deceased cohort, along with the higher age of death, support the reported effectiveness of this drug in reducing morbidity associated with SCD. The age of the living patients receiving treatment with both drugs was the same as that of the deceased. Similarly the age of the non treated living patients was comparable with that of the deceased group. Interestingly, the interaction of the 2 therapeutic interventions (HU and opiates) had a significant effect on the age at death (p=0.003). We conclude that opioid treatment, either alone or in conjunction with HU, appears to have a significant effect on the age at death and warrants further investigation.

Oral Administration of Low-Dose Decitabine and Tetrahydrouridine In Combination Increases Fetal Hemoglobin to Therapeutic Levels In the Absence of Cytotoxicity and Reduces Inter-Individual Drug Bioavailability In Baboons

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2147-2147
Author(s):  
Donald Lavelle ◽  
Kestutis Vaitkus ◽  
Maria Armila Ruiz ◽  
Cassandra List ◽  
Tatiana Kouznetsova ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Sickle Cell Disease ◽  
Oral Administration ◽  
Sickle Cell ◽  
Low Dose ◽  
Fetal Hemoglobin ◽  
High Dose ◽  
Cell Disease ◽  
Drug Bioavailability ◽  
Increased Risk

Abstract Abstract 2147 Increased fetal hemoglobin (HbF) levels alleviate the symptoms and improve survival of patients with sickle cell disease and β-thalassemia. Because therapeutic options remain limited for a large group of patients refractory to hydroxyurea (HU) therapy, alternative therapeutic agents to increase HbF are urgently needed. Decitabine (DAC) increases HbF to therapeutic levels in sickle cell disease patients refractory to HU. Oral administration of DAC would ease administration, increase compliance, and lower costs. Previous studies showed that oral administration of high doses of DAC increased HbF levels in baboons (Lavelle et al Am J Hematol 82:981, 2007). The oral bioavailability of DAC is limited by the degradative action of cytidine deaminase (CDA), and patients with CDA polymorphisms associated with reduced CDA activity may exhibit increased risk of cytotocity. We hypothesized that oral administration of low-dose DAC in combination with the CDA inhibitor THU would improve the DAC concentration-time profile while avoiding high peak drug levels likely to cause DNA damage and cytotoxicity and reduce risks of cytotoxicity in patients with CDA polymorphisms. Pharmacokinetics (PK) analysis in six baboons following oral administration of high-dose DAC alone showed that a dose (10mg/kg) previously shown sufficient to induce maximal (62.3–72%) HbF levels in 3 of 5 baboons when administered daily for ten days was associated with a mean AUC value of 355min*ng/ml. PK analysis following administration of varying doses of DAC in combination with THU showed that this AUC of 355min*ng/ml was attained with a 0.5 mg/kg DAC dose administered orally in combination with THU. The effect of oral low-dose DAC in combination with THU on HbF was then evaluated in four baboons. Initially, a single baboon (7482) was treated at 0.5mg/kg/d 3X/week for 3 weeks followed by 2X/week for an additional 5 weeks. Three additional baboons (7484, 7472, and 7470) were treated with either 0.25 or 0.5mg/kg/d 2X/week for eight weeks. Results (Table 1) showed significant increases in HbF associated with modest decreases in ANC and increases in platelets in all animals.AnimalDecitabine dose (mg/kg/d)SchedulePre-treatment HbF (%)Maximal HbF (%)ΔHbFANC nadirPlt max(x103)74820.53Xwk/3wks 2Xwk/5wks3.523.820.32580100474840.52Xwk/8wks4.223.118.91680102974720.252Xwk/8wks12.830.117.3146060074700.252Xwk/8wks9.929.319.42130895 Decreased DNA methylation in the 5' γ-globin gene region was observed in post-treatment BM samples by quantitative MassARRAY DNA methylation analysis. PK analysis showed that DAC bioavailability following oral administration of high-dose DAC alone differed 33 fold between 7470 and 7484 but only 1.3 fold following oral administration of low-dose DAC in combination with THU. Thus co-administration of low-dose DAC with THU reduced inter-individual variability of drug bioavailability and this was consistent with the similar HbF responses observed in these animals. Importantly, the ability of oral low dose DAC-THU to increase HbF to similar levels in the absence of cytotoxicity in two baboons differing in DAC bioavailability following oral administration of high-dose DAC alone predicts that oral low-dose DAC-THU in combination will reduce risks of cytotoxicity in patients with differences in DAC bioavailability due to CDA polymorphisms. These experiments have determined a dose and schedule of oral low-dose DAC in combination with THU that effectively increases HbF to therapeutic levels in the absence of cytotoxic effects in baboons and thus provide critical information important for the design of a future clinical trial of this drug combination in patients with sickle cell disease refractory to hydroxyurea therapy. Disclosures: No relevant conflicts of interest to declare.

Selective Inhibitors of Arginine Methyl Transferase 5 (PRMT5) As a Novel Treatment for β-Thalassemia and Sickle Cell Disease.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2129-2129 ◽  
Author(s):  
Ian Street ◽  
Brendon Monahan ◽  
Hendrik Falk ◽  
Elizabeth Allan ◽  
Ylva Bergman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Cell Disease ◽  
Globin Mrna ◽  
Cpg Dinucleotides ◽  
Radiometric Assay ◽  
Adult Bone

Abstract Abstract 2129 The developmental switch in human β-like globin gene subtype from fetal (γ) to adult (β) that begins at birth foreshadows the onset of the hemoglobinopathies, β-thalassemia and sickle cell disease (SCD). In the clinical setting it is established that β-thalassemia and SCD patients with hereditary persistence of fetal hemoglobin mutations enjoy a significant amelioration of disease severity due to the continued expression of γ-globin. This has prompted the search for therapeutic strategies to reverse γ-globin gene silencing. Central to the mechanism of γ-gene silencing is DNA methylation, which marks critical CpG dinucleotides flanking the γ-gene transcriptional initiation site in adult bone marrow erythroid cells. These marks are established by recruitment of DNMT3A, a DNA methyltransferase, to the γ-globin promoter by protein arginine methyltransferase 5 (PRMT5)[Zhao Q et al. Nat Struct Mol Biol. 2009;16(3):304–311]. PRMT5 catalyses the symmetric dimethylation of arginine 3 of Histone 4 (H4R3me2), which serves as a template for direct binding of DNMT3A and the subsequent DNA methylation of the γ-gene promoter. Loss of PRMT5 or its enzymatic activity is sufficient to induce demethylation of the CpG dinucleotides and reactivation of γ-globin gene expression [Rank, G., et al. Blood, 116(9), 1585–92]. Based on these observations we hypothesize that small molecule inhibitors of PRMT5 activity could provide a beneficial treatment for β-thalassemia and SCD. To identify small molecule inhibitors of PRMT5 a high throughput screen (HTS) was performed. Both radiometric and non-radiometric assay formats were developed to support the screening campaign. The radiometric assay format measures the ability of PRMT5 purified from K562 cells to catalyse the labelling of a short peptide based on the N-terminal sequence of Histone H4 by 3H-Methyl-S-Adenosyl-L-methionine (SAM). In contrast, the non-radiometric assay format employs recombinant PRMT5/MEP50 and measures the production of S-adenosyl-L-homocysteine (SAH), which is generated by PRMT5-catalysed methylation of H4 peptide. SAH is measured with Transcreener EPIGEN” and the assay is formatted in 1536-well microtitre plates in a total assay volume of 4 μL. Using these assays, a chemical library of 350,000 lead-like molecules and known pharmacologically active agents was screened to identify inhibitors of PRMT5 methyltransferase activity. A number of compounds with low micromolar or submicromolar inhibitory activity were identified by the HTS campaign, and six were selected for re-synthesis. The inhibitory activity of five of the six compounds was confirmed. To provide an initial appraisal of inhibitor selectivity the five active compounds were subsequently tested against a panel of enzymes consisting of 23 protein and DNA methyltransferases and 12 kinases. These compounds were found to be remarkably selective PRMT5 inhibitors, inhibition of MLL4 being the only significant off-target activity noted for one of the scaffolds. We have established a critical path for selection and progression of new chemical analogues which entails testing the compounds for: i) inhibition of PRMT5, other protein methyl transferases and kinases; ii) the ability to induce expression of γ-globin mRNA in the K562 erythroleukemic cell line; iii) the ability to induce expression of γ-globin mRNA in adult bone marrow erythroid cells; and iv) the induction of γ-globin in vivo in β-YAC mice, a transgenic model which carries the 250-kb human globin locus. In parallel, the physicochemical, metabolism, and pharmacokinetic properties of the most promising compounds are also determined. Medicinal chemistry efforts have now produced molecules with > 100-fold increased inhibitory potency against PRMT5 compared to the original hits, and preliminary results indicate that the more potent compounds have the ability to induce γ-globin mRNA in our cell based models. These early results illustrate the potential of PRMT5 inhibitors as a novel approach for the treatment of β-thalassemia and sickle cell disease. Disclosures: No relevant conflicts of interest to declare.

Implementation of a European Cohort to Follow Sickle Cell Children and Adults Treated with Hydroxycarbamide

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 564-564
Author(s):  
Mariane De Montalembert ◽  
Frédéric Galacteros ◽  
Jean Antoine Ribeil ◽  
Uwe Kordes ◽  
Jean Benoit Arlet ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Safety Profile ◽  
Conflicts Of Interest ◽  
Subcutaneous Tissue ◽  
Acute Chest Syndrome ◽  
Control Group ◽  
Cell Disease ◽  
Skin Reactions ◽  
Number Of Patients

Abstract Hydroxycarbamide (HU) is a myelosuppressive drug marketed since 1968 for the treatment of hematological cancer, and authorized since 2007 in Europe as orphan medicinal product for the prevention of recurrent vaso-occlusive crises including acute chest syndrome in adults and children older than 2 years with sickle cell disease (SCD). ESCORT-HU (European Sickle Cell Disease Cohort – Hydroxyurea) is a multicenter prospective non interventional study implemented in Europe to collect more information about the safety profile of HU and morbi-mortality in SCD patients treated with HU. The study responds to EMA (European Medicines Agency) request and has been approved by the Ethical of Necker Enfants Malades Hospital (Paris, France).The ongoing study involves the largest number so far of patients with SCD treated with HU. Primary endpoints of ESCORT HU are to determine frequency of adverse events, and possible consequent changes of HU treatment. Secondary endpoints are to evaluate morbi-mortality of the disease although in the absence of control group. From June 2008 to June 2014, 483 patients (255 females; 228 males) were enrolled from 3 European countries, Greece (24%), Germany (19%), and France (56%). 67% patients were adults, median aged 37.35 yrs (17-83.5) and 33% were children, median aged 11.06 yrs (2.6-16.9). genotypes were HbS/HbS in 71.4% cases, and compound heterozygotous HbS/β-thalassemia in 22.8 % (Table 1). 137 (28.4%) patients experienced 421 events (Table 2). 132 (32.2%) of these events may be attributed to HU. The safety profile is roughly similar in children and adults. As expected the most frequent side effects were firstly blood disorders (n=86 events, 42.4%) such as neutropenia or thrombocytopenia. In all cases, these cytopenias were rapidly resolved with the transitory stop of HU. 71 events related to skin and subcutaneous tissue disorders were observed, mostly cutaneous dryness, skin reactions, alopecia and nails or skin pigmentation; 4 patients had a leg ulcer (34.8%). Most of these events are ongoing or stabilized despit the decrease of HU. No secondary cancer has been reported until now. Even if HU is an old drug with a relatively well-known safety profile, some uncertainties remain in terms of long-term safety as well as tolerance in the youngest people. The main interest of ESCORT HU is to offer the possibility of safety surveillance of hydroxycarbamide in European sickle cell patients. Table 1 Demographic data Adults Children < 17 years old Total Number of patients 322 (67%) 161 (33%) 483 Females/Males 183/139 72/89 255/228 Median age (yrs) (range) 37.35 (17-83.5) 11.06 (2.6-16.9) 28.58 Genotype SS 206 (64%) 139 (86.3%) 345 (71.4%) SC 1 (0.3%) 3 (1.86%) 4 (0.8%) Sβ0 51 (15.8%) 11 (6.8%) 62 (12.8%) Sβ+ 46 (14.2%) 2 (1.2%) 48 (9.9%) Other 18 (5.5%) 6 (3.7%) 24 (4.9%) Treatment with HU before enrollment in ESCORT HU No of pts 232 83 315 (65%) Median duration (range) of HU treatment before ESCORT HU 8.2 yrs (0.5 ans-24 yrs) 3. 1 yrs ( 71 days – 8.9 yrs) 6.85 (71 days-24 years)] HU ESCORT Daily mean dose (mg/kg/d) 16.11 ± 4.79 19.63 ± 4.69 17.32 ± 4.94 Abstract 564. Table 2 The most frequent events of hydroxycarbamide in the two populations of SCD patients ADULTS CHILDREN No ofGerman(%) No of adults No ofEpisodes(%) No of children Total(% /411) Events Related to HU treatment (Siklos®)(%**) Blood and lymphatic system disorders (%) 32 (17.7) 22 54 (31.03) 28 86 (20.9) 56 (65.1) Skin and subcutaneous tissue disorders (%) 42 (23.2) 28 29 (16.7) 19 71 (17.3) 46 (64.8) Nervous system disorders Headache (24), Dizziness/vertigo (14), 32 (17.7) 23 12(6.9) 10 44 (10.7) 11 (25) Gastrointestinal disorders Nausea (14), diarrhea (8), other (14) 20 (11) 17 23 (13.2) 16 43 (10.4) 7 (16.3) Metabolic and nutrition disorders: vit D deficiency (17), weight gain (5) 13 (7) 11 18 (18.3) 18 36 (8.75) 4 (11.1) Fever 11 (6) 10 12(6.9) 7 23 (5.6) 1 (4.3) Cardiac disorders (hypertension, bradycardia, chest pain, cardiomegaly) 4 4 2 2 6 1 (16.6) General disorders : fatigue 5 5 0 0 5 0 Hepatobiliary disorders 2 2 0 0 2 0 Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Harmatoma, benign vulvar sebaceous cyst 2 2 0 0 2 0 Renal & urinary disorders 2 2 0 0 2 0 Reproductive system and breast disorders 3 3 0 0 3 0 Other 13 13 21 14 34 6 (17.1%) 181 80 /181(24.8%) 174 57 / 174(35.4%) 411 132/411 (32.2%) ** compared to the total number of “system organ class” events Disclosures No relevant conflicts of interest to declare.

scholarly journals Gene-centric association study of acute chest syndrome and painful crisis in sickle cell disease patients

Blood ◽  
2013 ◽  
Vol 122 (3) ◽  
pp. 434-442 ◽  
Author(s):  
Geneviève Galarneau ◽  
Sean Coady ◽  
Melanie E. Garrett ◽  
Neal Jeffries ◽  
Mona Puggal ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Association Study ◽  
Sickle Cell ◽  
Genome Wide Association Study ◽  
Inflammatory Responses ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Genome Wide ◽  
Key Points ◽  
Painful Crisis

Key Points Using genome-wide association study, we found the first replicated genetic association with acute chest syndrome in sickle cell disease patients. The locus identified includes COMMD7, a gene highly expressed in the lung that interacts with NFκB to control inflammatory responses.

Genome-wide association study of erythrocyte density in sickle cell disease patients

2017 ◽  
Vol 65 ◽  
pp. 60-65 ◽  
Author(s):  
Yann Ilboudo ◽  
Pablo Bartolucci ◽  
Alicia Rivera ◽  
Josepha-Clara Sedzro ◽  
Mélissa Beaudoin ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Association Study ◽  
Sickle Cell ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Cell Disease ◽  
Genome Wide ◽  
Erythrocyte Density

scholarly journals Genome-Wide Association Study of Glomerular Filtration Rate in a Cohort of Sickle Cell Disease Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1381-1381
Author(s):  
Melanie E. Garrett ◽  
Karen L. Soldano ◽  
Blair R. Anderson ◽  
Eugene P. Orringer ◽  
James R. Eckman ◽  
...  
Keyword(s):  
Renal Function ◽  
Glomerular Filtration Rate ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Filtration Rate ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Cell Disease ◽  
Data Set ◽  
Genome Wide

Abstract BACKGROUND: Nephropathy is a common and devastating complication of sickle cell disease (SCD) associated with mortality (Elmariah et al, 2014). However, early detection of SCD nephropathy (SCDN) has proven difficult. Discovery of genetic markers associated with SCDN could greatly improve our ability to identify patients at risk for renal decline. To that end, we have performed a genome-wide association study (GWAS) of glomerular filtration rate (GFR) in our adult SCD cohort. METHODS: Medical history, laboratory values and DNA for genotyping were collected as part of a multicenter study of outcome-modifying genes in SCD. Participating institutions included sickle cell centers at Duke University, University of North Carolina at Chapel Hill, Emory University, and East Carolina University. GFR was estimated using the ‘Modification of Diet in Renal Disease’ (MDRD) study definition (Levey et al, 1999) and dichotomized at the clinically relevant threshold of 90 ml/min/1.73m2. 463 patients with complete data were included in the analysis (54.6% female, mean age 34.2 ± 12 years, 17.5% GFR < 90 ml/min/1.73m2). Genotyping was performed using the Illumina Human610-Quad BeadChip (Illumina, San Diego, CA), and a global reference panel from the 1000 Genomes project was used to impute genotypes not covered on the GWAS chip. Samples were pre-phased with SHAPEIT (Delaneau et al, 2012) and genotypes inferred using IMPUTE2 (Howie et al, 2009). After data cleaning and removal of single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) < 5%, 3,021,990 SNPs were available for analysis. Principal component (PC) analysis was performed to obtain measures of population stratification in our data set using EIGENSOFT (Patterson et al, 2006). Logistic regression was utilized to test for association between each SNP and dichotomized GFR, controlling for genome-wide PCs using PLINK (Purcell et al, 2008). False discovery rate (FDR) p-values were generated using PROC MULTTEST in SAS (SAS Systems, Cary, NC). RESULTS: Because GWAS chips capture common variation, several of the most highly associated SNPs were intergenic. The SNP with the most evidence for association that also lies within a gene was rs72777730 in XYLT1 (p=6.8E-6). For each additional C allele, the odds of having GFR < 90 ml/min/1.73m2 increased by 2.7. Other top hits included rs1990628 in ZNF423 (p=2.7E-5) and rs6449202 in SLC2A9 (p=3.8E-5). None of the findings met FDR significance. To further investigate our findings, we assessed the role of rare variants on renal function in our data set. We observed SNPs in XYLT1 from the Illumina HumanExome BeadChips associated with proteinuria (p=0.008) using the gene-based SKAT test (Wu et al, 2011). Further, we performed whole-exome sequencing of 15 patients with disparate GFR levels using VCRome 2.1 capture and 100bp paired-end reads generated from an Illumina HiSeq. One novel non-synonymous SNP (chr16:17353261, C>T) was identified in XYLT1 in 6 of 7 patients with low GFR (≤ 70 ml/min/1.73m2) but was absent in patients with normal GFR (> 90 ml/min/1.73m2). Additionally, four known non-synonymous SNPs were observed in low GFR patients but were absent in those with normal GFR levels. DISCUSSION: Xylosyltransferase 1 (XYLT1, also known as XT-1) encodes the enzyme responsible for biosynthesis of heparin sulfate proteoglycans, which affect permeability of the glomerular basement membrane. The c.343G>T polymorphism in XYLT1 has been implicated in diabetic nephropathy (Schön et al, 2006), and XT-1 is up-regulated in rats with adriamycin nephropathy (Sichuan et al, 2007). Zinc finger protein 423 (ZNF423) is involved in DNA damage response signaling, and mutations in ZNF423 have been identified in patients with nephronophthisis and Joubert syndrome (Chaki et al, 2012). Finally, solute carrier family 2 member 9 (SLC2A9, also known as GLUT9) is a transporter involved in urate reabsorption in the renal tubules. Mutations in this gene have been identified in patients with renal hypouricemia-2 (Matsuo et al, 2008). Thus, while none of the SNPs reached genome-wide significance, likely due to the modest size of our data set, we have identified several promising candidate genes nominally associated with renal function in our cohort of SCD patients and demonstrate that both common and rare variation in these genes likely contributes to risk for renal decline. Disclosures No relevant conflicts of interest to declare.

scholarly journals Improved Utilization Amongst Adult Sickle Cell Disease Patients: A Multi-Disciplinary Medical Home Approach

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Daniel Sop ◽  
Shirley Johnson ◽  
Benjamin Jaworowski ◽  
Wally R Smith
Keyword(s):  
Sickle Cell Disease ◽  
Length Of Stay ◽  
Sickle Cell ◽  
Medical Home ◽  
Research Funding ◽  
Readmission Rate ◽  
Cost Savings ◽  
Multidisciplinary Teams ◽  
Cell Disease ◽  
Number Of Patients

Background Worldwide, Sickle Cell Disease (SCD) is the most common monogenetic disorder. SCD is costly to the American health care system: $460,151 per patient for the 100,000 affected US patients. Biological and behavioral health comorbidities with limited hospital resources contributed to a cost increase in SCD readmissions at the Virginia Commonwealth University Health System (VCUHS) from 2012-2016, after a long history of decline. With increasing census, in FY16 the 30-day SCD readmission rate was 33.7%, up from 22.5% in FY14. The average SCD length of stay was 6.7 days, compared with an expected length of 4.2 days. The number of ED visits for SCD patients in FY17 was projected to be double that of FY14. The percent of ED returns in 3 days was projected to be triple that of FY14. Method The VCU Adult SCD Medical Home (ASCMH) was funded and launched to address this issue, based on the success of a pilot that showed cost savings of $333,000 for 5 patients in 12 months. The SCD ASCMH officially began January 1,2018 with a two-year pilot funding period. The ASCMH was structured and designed using quality improvement (QI) principles and consisted of multidisciplinary teams to coordinate inpatient care, emergency care, and ambulatory care respectively. Evaluation compared utilization during CY 2017 (pre-intervention) versus CY 2019 (2 years post intervention). For all patients we compared the average 30-day readmission rate, the average length of stay (ALOS), the average 3-Day ED return rate, the number of ED discharges, the numbers of inpatient days, inpatient discharges, and outpatient visits, the number of patients who used the ED, and total VCU charges. Results Among 541 (2017) and 592 (2019) SCD adults, including 40.6% males and 59.4% females, comparing pre-intervention to intervention, average utilization and VCU charges were either numerically or statistically significantly reduced. Mean 30-day readmission rates were reduced (31.60% vs 20.40%) ALOS was reduced (5.6 days vs 4.3 days), inpatient days were reduced (5313 days vs 3340 days), and total charges were significantly reduced ($15,664,895 vs $13,939,842). Conclusion At VCU, a multi-disciplinary ASCMH that featured intensive case management (CM) reduced annual utilization and cost savings for adult SCD patients. CM program elements that were most effective should be studied in the future and next steps should include a randomized controlled trial that can demonstrate evidence of their efficacy in strengthening and improving utilization Table Disclosures Smith: Emmaeus Pharmaceuticals, Inc.: Consultancy; GlycoMimetics, Inc.: Consultancy; Novartis, Inc.: Consultancy, Other: Investigator, Research Funding; Shire, Inc.: Other: Investigator, Research Funding; Imara: Research Funding; Novo Nordisk: Consultancy; Ironwood: Consultancy; Pfizer: Consultancy; Incyte: Other: Investigator; Health Resources and Services Administration: Other: Investigator, Research Funding; NHLBI: Research Funding; Patient-Centered Outcomes Research Institute: Other: Investigator, Research Funding; Global Blood Therapeutics, Inc.: Consultancy, Research Funding; Shire: Research Funding.

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