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Genome-wide association study to identify variants associated with acute severe vaso-occlusive pain in sickle cell anemia.
Chaturvedi S, Bhatnagar P, Bean CJ, Steinberg MH, Milton JN, Casella JF, Barron-Casella E, Arking DE, DeBaun MR
(2017) Blood 130: 686-688
MeSH Terms: Acute Pain, Adolescent, African Continental Ancestry Group, Anemia, Sickle Cell, Arterial Occlusive Diseases, Child, Child, Preschool, Chromosomes, Human, Pair 4, Epistasis, Genetic, Female, Fetal Hemoglobin, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, Humans, Male, Multicenter Studies as Topic, Polymorphism, Single Nucleotide, Prospective Studies
Added June 7, 2017
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19 MeSH Terms
Acute chest syndrome is associated with single nucleotide polymorphism-defined beta globin cluster haplotype in children with sickle cell anaemia.
Bean CJ, Boulet SL, Yang G, Payne AB, Ghaji N, Pyle ME, Hooper WC, Bhatnagar P, Keefer J, Barron-Casella EA, Casella JF, Debaun MR
(2013) Br J Haematol 163: 268-76
MeSH Terms: Acute Chest Syndrome, Adolescent, Alleles, Anemia, Sickle Cell, Child, Child, Preschool, Female, Fetal Hemoglobin, Haplotypes, Humans, Linkage Disequilibrium, Male, Multigene Family, Patient Admission, Polymorphism, Single Nucleotide, beta-Globins
Show Abstract · Added October 14, 2013
Genetic diversity at the human β-globin locus has been implicated as a modifier of sickle cell anaemia (SCA) severity. However, haplotypes defined by restriction fragment length polymorphism sites across the β-globin locus have not been consistently associated with clinical phenotypes. To define the genetic structure at the β-globin locus more thoroughly, we performed high-density single nucleotide polymorphism (SNP) mapping in 820 children who were homozygous for the sickle cell mutation (HbSS). Genotyping results revealed very high linkage disequilibrium across a large region spanning the locus control region and the HBB (β-globin gene) cluster. We identified three predominant haplotypes accounting for 96% of the β(S) -carrying chromosomes in this population that could be distinguished using a minimal set of common SNPs. Consistent with previous studies, fetal haemoglobin level was significantly associated with β(S) -haplotypes. After controlling for covariates, an association was detected between haplotype and rate of hospitalization for acute chest syndrome (ACS) (incidence rate ratio 0·51, 95% confidence interval 0·29-0·89) but not incidence rate of vaso-occlusive pain or presence of silent cerebral infarct (SCI). Our results suggest that these SNP-defined β(S) -haplotypes may be associated with ACS, but not pain or SCI in a study population of children with SCA.
© 2013 John Wiley & Sons Ltd.
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16 MeSH Terms
Association between baseline fetal hemoglobin levels and incidence of severe vaso-occlusive pain episodes in children with sickle cell anemia.
Bhatnagar P, Keefer JR, Casella JF, Barron-Casella EA, Bean CJ, Hooper CW, Payne AB, Arking DE, Debaun MR
(2013) Pediatr Blood Cancer 60: E125-7
MeSH Terms: Adolescent, Anemia, Sickle Cell, Child, Child, Preschool, Constriction, Pathologic, Female, Fetal Hemoglobin, Follow-Up Studies, Humans, Male, Pain
Show Abstract · Added October 14, 2013
The ameliorating effect of high fetal hemoglobin (HbF) levels on the incidence of pain episodes in sickle cell anemia (SCA) is well-known; however, in children this relationship is less clearly established. We hypothesized that higher HbF levels in children with SCA are associated with fewer severe pain episodes. A meta-analysis of data from the Silent Infarct Transfusion Trial (n = 456) and the Cooperative Study of Sickle Cell Disease (n = 764), demonstrated that baseline HbF levels were associated with the incidence of severe pain, commonly defined across studies as an event requiring hospitalization (P-value = 0.02).
Copyright © 2013 Wiley Periodicals, Inc.
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11 MeSH Terms
Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the major modifiers of HbF in African Americans.
Bae HT, Baldwin CT, Sebastiani P, Telen MJ, Ashley-Koch A, Garrett M, Hooper WC, Bean CJ, Debaun MR, Arking DE, Bhatnagar P, Casella JF, Keefer JR, Barron-Casella E, Gordeuk V, Kato GJ, Minniti C, Taylor J, Campbell A, Luchtman-Jones L, Hoppe C, Gladwin MT, Zhang Y, Steinberg MH
(2012) Blood 120: 1961-2
MeSH Terms: African Americans, Anemia, Sickle Cell, Carrier Proteins, DNA, Intergenic, Fetal Hemoglobin, Genetic Variation, Genome-Wide Association Study, Humans, Nuclear Proteins, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-myb, Repressor Proteins
Added November 27, 2013
1 Communities
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12 MeSH Terms
Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients.
Bhatnagar P, Purvis S, Barron-Casella E, DeBaun MR, Casella JF, Arking DE, Keefer JR
(2011) J Hum Genet 56: 316-23
MeSH Terms: African Continental Ancestry Group, Anemia, Sickle Cell, Bayes Theorem, Carrier Proteins, Chromosomes, Human, Pair 17, Cohort Studies, Erythrocyte Count, Erythrocytes, Fetal Hemoglobin, Genome-Wide Association Study, Genotype, Glucagon-Like Peptide-1 Receptor, Haplotypes, Humans, Male, Nuclear Proteins, Polymorphism, Single Nucleotide, Receptors, Glucagon, Repressor Proteins
Show Abstract · Added November 27, 2013
Fetal hemoglobin (HbF) level has emerged as an important prognostic factor in sickle-cell disease (SCD) and can be measured by the proportion of HbF-containing erythrocytes (F-cells). Recently, BCL11A (zinc-finger protein) was identified as a regulator of HbF, and the strongest association signals were observed either directly for rs766432 or for correlated single-nucleotide polymorphisms (SNPs). To identify additional independently associated genetic variants, we performed a genome-wide association study (GWAS) on the proportion of F-cells in individuals of African ancestry with SCD from the Silent Infarct Transfusion (SIT) Trial cohort. Our study not only confirms the association of rs766432 (P-value <3.32 × 10(-13)), but also identifies an independent novel intronic SNP, rs7606173, associated with F-cells (P-value <1.81 × 10(-15)). The F-cell variances explained independently by these two SNPs are ∼13% (rs7606173) and ∼11% (rs766432), whereas, together they explain ∼16%. Additionally, in men, we identify a novel locus on chromosome 17, glucagon-like peptide-2 receptor (GLP2R), associated with F-cell regulation (rs12103880; P-value <3.41 × 10(-8)). GLP2R encodes a G protein-coupled receptor and involved in proliferative and anti-apoptotic cellular responses. These findings highlight the importance of denser genetic screens and suggest further exploration of the BCL11A and GLP2R loci to gain additional insight into HbF/F-cell regulation.
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19 MeSH Terms
Hydroxyurea therapy requires HbF induction for clinical benefit in a sickle cell mouse model.
Lebensburger JD, Pestina TI, Ware RE, Boyd KL, Persons DA
(2010) Haematologica 95: 1599-603
MeSH Terms: Anemia, Sickle Cell, Animals, Blood Cell Count, Disease Models, Animal, Fetal Hemoglobin, Genetic Therapy, Hydroxyurea, Mice, Mice, Inbred C57BL, Treatment Outcome
Show Abstract · Added March 20, 2014
Hydroxyurea has proven clinical efficacy in patients with sickle cell disease. Potential mechanisms for the beneficial effects include fetal hemoglobin induction and the reduction of cell adhesive properties, inflammation and hypercoagulability. Using a murine model of sickle cell disease in which fetal hemoglobin induction does not occur, we evaluated whether hydroxyurea administration would still yield improvements in hematologic parameters and reduce end-organ damage. Animals given a maximally tolerated dose of hydroxyurea that resulted in significant reductions in the neutrophil and platelet counts showed no improvement in hemolytic anemia and end-organ damage compared to control mice. In contrast, animals having high levels of fetal hemoglobin due to gene transfer with a gamma-globin lentiviral vector showed correction of anemia and organ damage. These data suggest that induction of fetal hemoglobin by hydroxyurea is an essential mechanism for its clinical benefits.
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10 MeSH Terms
Urinary cysteinyl leukotriene E4 significantly increases during pain in children and adults with sickle cell disease.
Field JJ, Strunk RC, Knight-Perry JE, Blinder MA, Townsend RR, DeBaun MR
(2009) Am J Hematol 84: 231-3
MeSH Terms: Acetates, Adolescent, Adult, Anemia, Sickle Cell, Anti-Asthmatic Agents, Asthma, Biomarkers, Child, Cohort Studies, Female, Fetal Hemoglobin, Hemoglobin C Disease, Heterozygote, Hospitalization, Humans, Ischemia, Leukotriene Antagonists, Leukotriene E4, Male, Pain, Quinolines, Retrospective Studies, Sickle Cell Trait, Young Adult, beta-Thalassemia
Show Abstract · Added November 27, 2013
Baseline level of the cysteinyl leukotriene (CysLT), leukotriene E4 (LTE4), is associated with an increased pain rate in children and adults with sickle cell disease (SCD). To provide additional evidence for a role of CysLTs in the pathogenesis of vaso-occlusion, we tested the hypothesis that LTE4 levels will increase within an individual during painful episodes compared to baseline. In a cohort of 19 children and adults with SCD, median LTE4 levels increased from 82.36 pg/mg creatinine at baseline to 162.81 pg/mg creatinine during a painful episode (P < 0.001). These data further support a contribution of CysLTs to the process of vaso-occlusion.
Copyright 2009 Wiley-Liss, Inc.
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25 MeSH Terms
Correction of murine sickle cell disease using gamma-globin lentiviral vectors to mediate high-level expression of fetal hemoglobin.
Pestina TI, Hargrove PW, Jay D, Gray JT, Boyd KM, Persons DA
(2009) Mol Ther 17: 245-52
MeSH Terms: Anemia, Sickle Cell, Animals, Blotting, Southern, Cells, Cultured, Electrophoresis, Fetal Hemoglobin, Flow Cytometry, Genetic Therapy, Genetic Vectors, Hematopoietic Stem Cell Transplantation, Lentivirus, Mice, Models, Genetic, Reverse Transcriptase Polymerase Chain Reaction, Spleen, gamma-Globins
Show Abstract · Added March 5, 2014
Increased levels of red cell fetal hemogloblin, whether due to hereditary persistence of expression or from induction with hydroxyurea therapy, effectively ameliorate sickle cell disease (SCD). Therefore, we developed erythroid-specific, gamma-globin lentiviral vectors for hematopoietic stem cell (HSC)-targeted gene therapy with the goal of permanently increasing fetal hemoglobin (HbF) production in sickle red cells. We evaluated two different gamma-globin lentiviral vectors for therapeutic efficacy in the BERK sickle cell mouse model. The first vector, V5, contained the gamma-globin gene driven by 3.1 kb of beta-globin regulatory sequences and a 130-bp beta-globin promoter. The second vector, V5m3, was identical except that the gamma-globin 3'-untranslated region (3'-UTR) was replaced with the beta-globin 3'-UTR. Adult erythroid cells have beta-globin mRNA 3'-UTR-binding proteins that enhance beta-globin mRNA stability and we postulated this design might enhance gamma-globin expression. Stem cell gene transfer was efficient and nearly all red cells in transplanted mice expressed human gamma-globin. Both vectors demonstrated efficacy in disease correction, with the V5m3 vector producing a higher level of gamma-globin mRNA which was associated with high-level correction of anemia and secondary organ pathology. These data support the rationale for a gene therapy approach to SCD by permanently enhancing HbF using a gamma-globin lentiviral vector.
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16 MeSH Terms
Preparation and properties of a hemoglobin containing heme only in gamma subunits.
Gondko R, Obrebska MJ, Waterman MR
(1974) Biochem Biophys Res Commun 56: 444-50
MeSH Terms: Apoproteins, Carbon Monoxide, Carboxyhemoglobin, Chromatography, Ion Exchange, Electrophoresis, Starch Gel, Female, Fetal Hemoglobin, Hemoglobins, Humans, Mercuribenzoates, Oxygen, Oxyhemoglobins, Peptides, Pregnancy, Protein Binding, Spectrophotometry, Spectrophotometry, Ultraviolet, Umbilical Cord
Added February 12, 2015
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18 MeSH Terms
Effect of ligands on alkaline denaturation of fetal hemoglobin and isolated gamma subunits.
Painter TD, Waterman MR
(1973) Biochem Biophys Res Commun 55: 812-7
MeSH Terms: Carboxyhemoglobin, Chromatography, Ion Exchange, Electrophoresis, Disc, Female, Fetal Hemoglobin, Humans, Hydrogen-Ion Concentration, Iron, Kinetics, Ligands, Mercuribenzoates, Methemoglobin, Peptides, Pregnancy, Protein Denaturation, Spectrophotometry, Time Factors, Umbilical Cord
Added February 12, 2015
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18 MeSH Terms