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1.
Transfusion ; 64(6): 1109-1115, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38693059

RESUMO

BACKGROUND: Post-transfusion survival of donor red blood cells (RBCs) is important for effective chronic transfusion therapy in conditions including sickle cell disease (SCD). Biotin labeling RBCs allows direct in vivo measurement of multiple donor RBC units simultaneously post-transfusion. STUDY DESIGN AND METHODS: In an observational trial of patients with SCD receiving monthly chronic transfusion therapy, aliquots of RBCs from one transfusion episode were biotin-labeled and infused along with the unlabeled RBC units. Serial blood samples were obtained to measure RBC survival. Donor units were tested for RBC indices, hemoglobin fractionation, and glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. For microcytic donor RBCs (MCV < 70 fL), HBA1 and HBA2 genetic testing was performed on whole blood. RESULTS: We present one recipient, a pediatric patient with SCD and splenectomy who received two RBC units with aliquots from each unit labeled at distinct biotin densities (2 and 18 µg/mL biotin). One donor unit was identified to have microcytosis (MCV 68.5 fL after biotinylation); whole blood sample obtained at a subsequent donation showed 2-gene deletion alpha-thalassemia trait (ɑ-3.7kb/ɑ-3.7kb) and normal serum ferritin. G6PD activity was >60% of normal mean for both. The RBCs with alpha-thalassemia RBC had accelerated clearance and increased surface phosphatidylserine post-transfusion, as compared with the normocytic RBC (half life 65 vs. 86 days, respectively). DISCUSSION: Post-transfusion RBC survival may be lower for units from donors with alpha-thalassemia trait, although the impact of thalassemia trait donors on transfusion efficacy requires further study.


Assuntos
Anemia Falciforme , Doadores de Sangue , Transfusão de Eritrócitos , Eritrócitos , Talassemia alfa , Humanos , Anemia Falciforme/terapia , Anemia Falciforme/sangue , Talassemia alfa/terapia , Talassemia alfa/sangue , Eritrócitos/metabolismo , Masculino , Sobrevivência Celular , Biotinilação , Feminino , Criança
2.
Br J Haematol ; 189(6): 1204-1209, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32030737

RESUMO

Sickle cell disease (SCD) has a distinct pattern of transfusional iron overload (IO) when compared to transfusion-dependent ß-thalassaemia major (TDT). We conducted a single institution prospective study to evaluate plasma biomarkers of iron regulation and inflammation in patients with SCD with IO (SCD IO cases, n = 22) and without IO (SCD non-IO cases, n = 11), and non-SCD controls (n = 13). Hepcidin was found to be inappropriately low, as evidenced by a significantly higher median hepcidin/ferritin ratio in non-SCD controls compared to SCD IO cases (0·3 vs. 0·02, P < 0·0001) and SCD non-IO cases (0·3 vs. 0·02, P < 0·0001), suggesting that certain inhibitory mechanism (s) work to suppress hepcidin in SCD. As opposed to the SCD non-IO state, where hepcidin shows a strong significant positive correlation with ferritin (Spearman ρ = 0·7, P = 0·02), this correlation was lost when IO occurs (Spearman ρ = -0·2, P = 0·4). Although a direct non-linear correlation between erythroferrone (ERFE) and hepcidin did not reach statistical significance both in the IO (Spearman ρ = -0·4, P = 0·08) and non-IO state (Spearman ρ = -0·6, P = 0·07), patients with highest ERFE had low hepcidin levels, suggesting that ERFE contributes to hepcidin regulation in some patients. Our results suggest a multifactorial mechanism of hepcidin regulation in SCD.


Assuntos
Anemia Falciforme , Transfusão de Sangue , Hepcidinas/sangue , Homeostase , Sobrecarga de Ferro , Ferro/sangue , Hormônios Peptídicos/sangue , Adolescente , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/terapia , Feminino , Ferritinas/sangue , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
3.
Eur J Haematol ; 105(4): 419-425, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32497305

RESUMO

OBJECTIVES: In this study, we investigated the evolution of chronic pain in sickle cell patients (SCD) as an age-dependent phenomenon and studied the frequency of vaso-occlusive episode frequency, opioid use, quantitative sensory testing (QST), and biomarkers of chronic pain (CP). METHODS: We undertook a cross-sectional study of the evolution of CP in SCD. A total of 72 subjects (age 15-66) were enrolled. VOE frequency, presence of CP hydroxyurea (HU) therapy, opioid use, and laboratory parameters were collected. QST was performed, and plasma tryptase, substance P, and NGF (Nerve Growth Factor) levels were assayed. RESULTS: There was an age-dependent increase in frequency of CP, VOEs, opioid use, and Von Frey monofilament values. CP patients had significantly higher opioid use (daily morphine equivalents) (52.8 mg vs 6.94 mg, P = .009), suggesting a correlation between opioid use and hyperalgesia. NGF levels were also significantly higher (P = .051). Our results confirm previous observations of an age-dependent increase in the proportion of patients with CP and support the contributing role of mast cell activation and neurogenic inflammation. CONCLUSIONS: This is the first study of NGF as a possible biomarker of CP in SCD. If confirmed, this could provide a diagnostic marker and therapeutic target for CP in SCD.


Assuntos
Síndrome Torácica Aguda/diagnóstico , Síndrome Torácica Aguda/etiologia , Anemia Falciforme/complicações , Anemia Falciforme/diagnóstico , Biomarcadores , Síndrome Torácica Aguda/terapia , Adolescente , Adulto , Fatores Etários , Idoso , Anemia Falciforme/terapia , Dor Crônica/diagnóstico , Dor Crônica/etiologia , Dor Crônica/terapia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Manejo da Dor , Medição da Dor , Avaliação de Sintomas , Resultado do Tratamento , Adulto Jovem
4.
Lancet ; 387(10019): 661-670, 2016 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-26670617

RESUMO

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Transfusão de Sangue/métodos , Hidroxiureia/uso terapêutico , Adolescente , Anemia Falciforme/fisiopatologia , Velocidade do Fluxo Sanguíneo , Circulação Cerebrovascular/fisiologia , Criança , Pré-Escolar , Terapia Combinada , Substituição de Medicamentos , Feminino , Humanos , Masculino , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento , Ultrassonografia Doppler Transcraniana
5.
Haematologica ; 102(12): 1995-2004, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28971909

RESUMO

Hydroxyurea (HU), the first of two drugs approved by the US Food and Drug Administration for treating patients with sickle cell disease (SCD), produces anti-sickling effect by re-activating fetal γ-globin gene to enhance production of fetal hemoglobin. However, approximately 30% of the patients do not respond to HU therapy. The molecular basis of non-responsiveness to HU is not clearly understood. To address this question, we examined HU-induced changes in the RNA and protein levels of transcription factors NF-Y, GATA-1, -2, BCL11A, TR4, MYB and NF-E4 that assemble the γ-globin promoter complex and regulate transcription of γ-globin gene. In erythroblasts cultured from peripheral blood CD34+ cells of patients with SCD, we found that HU-induced changes in the protein but not the RNA levels of activator GATA-2 and repressors GATA-1, BCL11A and TR4 correlated with HU-induced changes in fetal hemoglobin (HbF) levels in the peripheral blood of HU high and low responders. However, HU did not significantly induce changes in the protein or RNA levels of activators NF-Y and NF-E4. Based on HU-induced changes in the protein levels of GATA-2, -1 and BCL11A, we calculated an Index of Hydroxyurea Responsiveness (IndexHU-3). Compared to the HU-induced fold changes in the individual transcription factor protein levels, the numerical values of IndexHU-3 statistically correlated best with the HU-induced peripheral blood HbF levels of the patients. Thus, IndexHU-3 can serve as an appropriate indicator for inherent HU responsiveness of patients with SCD.


Assuntos
Anemia Falciforme/tratamento farmacológico , Eritroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroxiureia/farmacologia , gama-Globinas/genética , Anemia Falciforme/sangue , Células Cultivadas , Hemoglobina Fetal/análise , Hemoglobina Fetal/efeitos dos fármacos , Humanos , Hidroxiureia/uso terapêutico , RNA Mensageiro/sangue , RNA Mensageiro/efeitos dos fármacos , Fatores de Transcrição/sangue , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/genética
6.
Hemoglobin ; 39(1): 52-4, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25565447

RESUMO

The total number of hemoglobin (Hb) variants currently included in the globin gene server database is 1626 (November 12 2014), of which 131 are fetal Hb variants. These variants are observed as two different subunits of fetal Hb, (G)γ- and (A)γ-globin chains. Of the 131 documented fetal Hb variants, 73 are (G)γ- and 58 are (A)γ-globin chain variants. Although they are easily detected at birth, as the quantity of γ chains progressively decreases over the first few months of life, they are essentially undetectable after 6 months of age. In this report we discuss the molecular characteristics and diagnostic criteria of a new (A)γ chain variant that was detected during newborn screening and named Hb F-Sykesville MD [(A)γ113(G15)Val → Ile; HBG1: c.340G>A].


Assuntos
Hemoglobina Fetal/genética , Hemoglobinas Anormais/genética , gama-Globinas/genética , Sequência de Bases , Humanos , Recém-Nascido , Mutação
7.
Hemoglobin ; 38(5): 376-80, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25271994

RESUMO

The total number of hemoglobin (Hb) variants so far reported to the HbVar database is 1598 (April 9 2014) and 130 of them are fetal Hb variants. Fetal Hb are categorized as two different subunits, (G)γ- and (A)γ-globin chains, and γ chain variants can be observed in both subunits. There are 72 (G)γ- and 58 (A)γ-globin chain variants. Most of them are clinically silent and detected during newborn screening programs in the USA and outside the USA. In this report, we discuss the molecular characteristics and diagnostic difficulties of two new γ-globin chain variants found in an African American baby with no clinical symptoms. One is a new (G)γ-globin chain variant, Hb F-Augusta GA [(G)γ59(E3)Lys → Arg; HBG2: c.179A > G] and the other one is Hb F-Port Royal-II [(A)γ125(H3)Glu → Ala; HBG1: c.377A > C].


Assuntos
Hemoglobina Fetal/genética , Hemoglobinopatias/genética , Mutação , gama-Globinas/genética , Negro ou Afro-Americano , Substituição de Aminoácidos , Pai , Feminino , Hemoglobina Fetal/química , Georgia , Hemoglobinopatias/sangue , Hemoglobinopatias/diagnóstico , Hemoglobinopatias/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Recém-Nascido , Mães , Triagem Neonatal , Mutação Puntual , Índice de Gravidade de Doença , gama-Globinas/química
8.
Hemoglobin ; 38(3): 207-10, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24471829

RESUMO

Of the 1570 reported hemoglobin (Hb) variants detected to date, 390 are α2-globin chain (some variants have yet to be identified by DNA analyses and are therefore presumed) and 827 are the result of mutations of the ß-globin chain. Due to their location on the Hb structure, only a minority of these variants result in a clinical phenotype; most are silent and are detected during routine surveillance, are found incidentally during other disease-related investigations or following newborn screening programs. In this report we discuss phenotype/genotype and molecular characteristics of two new Hb variants, both of which were clinically silent. One is an α2-globin chain variant located at codon 3 [α3(A1)Ser→Tyr; HBA2: c.11C > A] named Hb Tallahassee and the other is a ß-globin chain variant located at codon 119 [ß119(GH2)Gly→Ser; HBB: c.358G > A] called Hb Madison-NC.


Assuntos
Códon/genética , Hemoglobinas Anormais/genética , Mutação , Fenótipo , alfa-Globinas/genética , Criança , Humanos , Lactente , Masculino
9.
Hemoglobin ; 37(5): 481-5, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24006930

RESUMO

We report a novel hemoglobin (Hb) variant that we named Hb Fulton-Georgia, caused by a point mutation in exon 1/codon 20 of the α-globin gene [α20(B1)His→Pro; HBA1: c.62A>C]. This α chain variant was identified in an adult African-American female with Hb SC disease who was also heterozygous for the α-thalassemia-2 (α-thal-2) (3.7 kb deletion or αα/-α(3.7)). The Hb Fulton-Georgia mutation was located on the intact α1-globin gene not involved by α-thal-2. Molecular models indicated that the α20 residue of Hb Fulton-Georgia was the first amino acid of the B helix, and was not involved in α1/ß1 or α1/ß2 contacts in Hb S [ß6(A3)Glu→Val; HBB: c.20A>T] or Hb C [ß6(A3)Glu→Lys; HBB: c.19G>A] tetramers. Furthermore, the histidine→proline substitution at α20 did not disrupt the helical structure. High performance liquid chromatography (HPLC) detected Hb Fulton-Georgia in 16.0% of total Hb, consistent with inheritance on the α1 gene. Coinheritance of Hb Fulton-Georgia, heterozygous α-thal-2 and Hb SC disease was associated with a mild phenotype, consisting of microcytosis and anisocytosis, but no anemia or other hematological abnormality.


Assuntos
Hemoglobinas Glicadas/genética , Hemoglobinas Anormais/genética , Mutação Puntual , Adulto , Análise Mutacional de DNA , Feminino , Doença da Hemoglobina SC/complicações , Doença da Hemoglobina SC/genética , Humanos , Deleção de Sequência , Talassemia alfa/complicações , Talassemia alfa/genética
10.
J Pediatr Hematol Oncol ; 33(8): 589-91, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22042275

RESUMO

The occurrence of multiple abnormalities of α, ß, δ, and γ globin genes may lead to unusual and complex phenotypes when they arise simultaneously in the same individual. Here, we report the findings of an African American boy who coinherited 3 heterozygous globin gene abnormalities: the unstable ß-globin chain variant; hemoglobin (Hb) Showa-Yakushiji [ß110(G12) Leu→Pro], the δ-globin chain variant; HbB2 [δ16(A13) Gly→Arg] and α-thalassemia (α-thal); (α-/αα). Hb Showa-Yakushiji had been previously described in Japanese, Indian, and European populations. We report its first occurrence in a child of African ancestry who presented with anemia not responsive to iron and an incomplete ß-thalassemia minor phenotype. Although the clinical and laboratory features of Hb Showa-Yakushiji mimic those of a ß-thalassemia, the coinheritance of the δ-globin chain variant Hb B2 suppressed the relative increase in Hb A2 usually observed in heterozygotes for the Hb Showa-Yakushiji mutation. Protein-based methods detected only a trace amount of HbB2 and failed to reveal presence of Hb Showa-Yakushiji and α-thal. The latter were only identified through DNA analyses. The diagnostic difficulties, molecular characteristics, and genotype/phenotype correlations of this novel complex hemoglobinopathy syndrome are reviewed.


Assuntos
Anemia/genética , Hemoglobinas Anormais/genética , Talassemia alfa/genética , Talassemia beta/genética , Talassemia delta/genética , Negro ou Afro-Americano/genética , Anemia/etiologia , Pré-Escolar , Heterozigoto , Humanos , Masculino , Fenótipo , Talassemia alfa/sangue , Talassemia alfa/complicações , Talassemia beta/sangue , Talassemia beta/complicações , Talassemia delta/complicações
11.
PLoS One ; 16(2): e0247324, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33617594

RESUMO

Vaso-occlusive episodes (VOEs) are a hallmark of sickle cell disease (SCD), and account for >90% of health care encounters for this patient population. The Cooperative Study of Sickle Cell Disease, a large study enrolling >3000 patients, showed that the majority of SCD patients (80%) experienced 0-3 major pain crises/year. Only a small minority (~5%) experienced ≥6 VOEs/year. Our study sought to further understand this difference in VOE frequency between SCD patients. We analyzed 25 patients (13M/12F, mean age of 28.8) with ≥6 ED visits or hospitalizations/year (high utilizers), and compared these with 9 patients (6M/3F, mean age of 37.6) who had ≤2 ED visits or hospitalizations/year (low utilizers). All subjects were given a demographic survey along with questionnaires for depression, anxiety, and Health Locus of Control. Each subject then underwent quantitative sensory testing (QST) with three different modalities: pressure pain sensitivity, heat and cold sensitivity, and Von Frey monofilament testing. Laboratory and clinical data were collected through subjects' medical records. CBC and chemistry analysis showed high utilizers had higher WBC (p<0.01), ANC (p<0.01), total bilirubin (p = 0.02), and lower MCV (p = 0.03). Opioid use (morphine equivalents) over the past 6 months was significantly higher in the high utilizer group (12125.7 mg vs 2423.1 mg, p = 0.005). QST results showed lower pressure pain threshold at the ulna (224.4 KPa vs 338.9 KPa, p = 0.04) in the high utilizer group. High utilizers also had higher anxiety (9.0 vs 4.6, p = 0.04) and depression scores (10.0 vs 6.0, p = 0.051). While the low utilizer group had higher education levels with more associate and bachelor degrees (p = 0.009), there was no difference in income or employment. These data show that many biological and psychosocial factors contribute to high health care utilization in SCD. A multi-disciplinary and multi-faceted approach will be required to address this complex problem.


Assuntos
Anemia Falciforme/patologia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Adulto , Analgésicos Opioides/uso terapêutico , Anemia Falciforme/psicologia , Ansiedade/psicologia , Estudos Transversais , Depressão/psicologia , Feminino , Humanos , Masculino , Dor/tratamento farmacológico , Dor/patologia , Dor/psicologia , Medição da Dor/métodos
13.
Lab Hematol ; 15(3): 20-4, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19758965

RESUMO

We report a case of compound heterozygous hemoglobins S [beta6(A3)Glu6Val] and Korle-Bu [beta73(E17)Asp73Asn] in a 2-year-old girl. This hemoglobin genotype is associated with a benign clinical course, much like the sickle cell trait; however, its laboratory characteristics are very similar to compound heterozygous hemoglobin S and hemoglobin D-Los Angeles [beta121(GH4)Glu121Gln], which produces severe sickling hemolytic anemia. We describe laboratory data used to resolve this important differential diagnosis and review the interactions between hemoglobin S and the variant hemoglobins that may account for the different clinical phenotypes in compound heterozygotes.


Assuntos
Triagem de Portadores Genéticos , Hemoglobina Falciforme/genética , Hemoglobinas Anormais/genética , Globinas beta/química , Negro ou Afro-Americano , Contagem de Células Sanguíneas , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Códon , Diagnóstico Diferencial , Eletroforese , Feminino , Hemoglobina Falciforme/isolamento & purificação , Hemoglobinopatias/diagnóstico , Hemoglobinas Anormais/isolamento & purificação , Humanos , Modelos Moleculares , Fenótipo , Reação em Cadeia da Polimerase , Análise de Sequência de Proteína
14.
Genet Test Mol Biomarkers ; 20(10): 609-615, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27551817

RESUMO

AIMS: Interindividual variability in drug response and adverse effects have been described for proton pump inhibitors, anticonvulsants, selective serotonin reuptake inhibitors, tricyclic antidepressants, and anti-infectives, but little is known about the safety and efficacy of these medications in patients with sickle cell disease (SCD). We genotyped the CYP2C19 gene which has been implicated in the metabolism of these drugs in an SCD patient cohort to determine the frequencies of reduced function, increased function, or complete loss-of-function variants. MATERIALS AND METHODS: DNAs from 165 unrelated SCD patients were genotyped for nine CYP2C19 (*2, *3, *4, *5, *6, *7,*8, *12, and *17) alleles using the iPLEX® ADME PGx multiplex panel. RESULTS: Three CYP2C19 alleles (*2, *12, and *17) were detected with the following frequencies: 0.209, 0.006, and 0.236, respectively. The predicted phenotype frequencies were distributed as extensive (31.5%), intermediate (24.8%), poor (5.5%), ultrarapid (30.3%), and unknown metabolizers (7.9%). DISCUSSION: Prognostic genotyping is potentially useful for identifying SCD patients with allelic variants linked to proven clinical pharmacokinetic consequences for several drugs metabolized by the CYP2C19 gene. However, the main challenge to implementing a genetics-guided prescribing practice is ensuring concordance between CYP2C19 genotypes and metabolic phenotypes in SCD patients.


Assuntos
Alelos , Anemia Falciforme/genética , Citocromo P-450 CYP2C19/genética , Frequência do Gene , Testes Farmacogenômicos , Variantes Farmacogenômicos , Adolescente , Adulto , Anemia Falciforme/tratamento farmacológico , Feminino , Técnicas de Genotipagem/métodos , Humanos , Masculino , Pessoa de Meia-Idade
15.
Clin Transl Sci ; 8(4): 272-80, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25640739

RESUMO

Interindividual variability in analgesic effects of nonsteroidal anti-inflammatory drugs prescribed for sickle cell disease (SCD) pain is attributed to polymorphisms in the CYP2C8 and CYP2C9 enzymes. We described CYP2C8 and CYP2C9 genotype/phenotype profiles and frequency of emergency department (ED) visits for pain management in an African American SCD patient cohort. DNA from 165 unrelated patients was genotyped for seven CYP2C8 and 15 CYP2C9 alleles using the iPLEX ADME PGx multiplexed panel. CYP2C8*1 (0.806),*2 (0.164), *3 (0.018), and *4 (0.012) alleles were identified. Genotype frequencies were distributed as homozygous wild type (66.7%), heterozygous (27.8%), and homozygous variant/compound heterozygous (5.4%), respectively. CYP2C9*1 (0.824), *2 (0.027), *3 (0.012), *5 (0.009), *6 (0.009), *8 (0.042), *9 (0.061), and *11(0.015) were observed with extensive (68.5%), intermediate (18.1%) and poor predicted metabolizers (0.6%), respectively. Fifty-two and 55 subjects, respectively had at least one variant CYP2C8 or CYP2C9 allele. Although the distribution of the CYP2C9 (p = 0.0515) phenotypes was marginally significantly in high and low ED users; some CYP2C8 and CYP2C9 allelic combinations observed in 15.2% (25) of the cohort are associated with higher risks for analgesic failure. CYP2C8 and CYP2C9 preemptive genotyping could potentially enable clinicians to identify patients with impaired metabolic phenotypes.


Assuntos
Anemia Falciforme/genética , Anti-Inflamatórios não Esteroides/metabolismo , Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP2C9/genética , Manejo da Dor , Adolescente , Adulto , Alelos , Anemia Falciforme/metabolismo , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
16.
Clin Transl Sci ; 7(5): 396-401, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24889181

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat pain in patients with sickle cell disease (SCD) are metabolized by the CYP2C9 enzyme. Racial differences in CYP2C9 allele frequencies impact NSAIDs efficacy and safety. We determined the frequencies of CYP2C9 alleles in an African American pediatric SCD cohort. Genomic DNA was isolated from blood samples of 30 patients aged between 7 and 17 years. Genotyping of nine CYP2C9 alleles (*1,*2, *3, *4, *5, *6, *8, *11, and *13) was performed using restriction fragment length polymorphism-PCR assays and the Tag-It™ Mutation Detection System. The wild type *1 allele frequency was 0.850. The most common variant allele detected was CYP2C9*8 (0.067). The combined frequency of the *2, *5, *6, *8, and *11 variants was 0.151. Seventy percent of the study cohort were predicted extensive metabolizers (*1/*1) and 30% were intermediate metabolizers due mainly to the *1/*8 genotype. Analysis of CYP2C9 using an expanded assay panel facilitated improved classification of predicted drug metabolic phenotypes in our cohort. However, the pharmacokinetic effects of the CYP2C9*5,*6,*8, and *11 alleles on NSAIDs metabolism has not been evaluated and underscores the need for studies on substrate-specific effects of variant alleles common in populations with genetic susceptibility to SCD.


Assuntos
Alelos , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/genética , Anti-Inflamatórios não Esteroides/uso terapêutico , Citocromo P-450 CYP2C9/genética , Frequência do Gene/genética , Adolescente , Criança , Estudos de Coortes , Demografia , Feminino , Genótipo , Humanos , Fenótipo
17.
Clin Biochem ; 46(3): 278-81, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23123915

RESUMO

OBJECTIVES: To investigate the concordance of blood count indices measured locally and at a central laboratory. DESIGN AND METHODS: In a multi-center clinical trial of hydroxyurea therapy in infants with sickle cell anemia (BABY HUG), the concordance between blood count indices measured locally and at a central laboratory was investigated. RESULTS: Local laboratory measurements of neutrophil and monocyte counts were significantly higher (44% and 37%, respectively) compared to the central measurements (p<0.0001), and mean corpuscular volume (MCV) was higher centrally. CONCLUSION: Overnight shipping with processing delay causes spurious reductions in absolute neutrophil count (ANC) and absolute monocyte count (AMC) that may result in incorrect monitoring decisions in multicenter clinical trials.


Assuntos
Anemia Falciforme/sangue , Contagem de Células Sanguíneas/métodos , Laboratórios/normas , Ensaio de Proficiência Laboratorial , Anemia Falciforme/diagnóstico , Anemia Falciforme/tratamento farmacológico , Hematologia/normas , Humanos , Hidroxiureia/uso terapêutico , Lactente , Linfócitos/química , Monócitos/química , Neutrófilos/química , Análise de Regressão , Reprodutibilidade dos Testes
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