Genomic Approaches to Improve Transfusion Therapy in SCD Patients

Summary

Principal Investigator: Marion Reid
Affiliation: New York Blood Center
Country: USA
Abstract: Although chronic transfusion is increasingly used to prevent life-threatening events in patients with sickle cell disease (SCD), alloimmunization to blood group antigens remains a major complication of chronic transfusions. We believe that a major contributing factor responsible for RBC alloimmunization is the variation in blood groups of these patients, especially in the Rh system, compared to the predominantly Caucasian donor pool. The main objective of this time-sensitive ancillary study to the Comprehensive Sickle Cell Center collaborative trials is to eliminate transfusion-induced alloimmunization in SCD patients by capitalizing on a nationally representative population of SCD patients as blood samples and relevant clinical data are collected. As a part of the study, we will use RBCs, collected prospectively for the trial and which otherwise would be discarded. Specifically, we aim to (1) determine whether the diversity and frequency of alleles encoding Rh blood group antigens are comparable in SCD patients and African-American blood donors. Using blood and DNA samples from these two populations, we will first determine the molecular bases for complex Rh phenotypes by sequencing the RHD and RHCE genes in those individuals whose serum contains unusual anti- Rh antibodies. The population frequency of these alleles will then be estimated by genotyping samples from SCD patients with simple or no Rh antibodies and from unrelated African American donors residing in the same geographic locations as the patients. (2) Using the knowledge gained from our RH gene sequencing studies together with our experience in designing blood group DNA chips, we will develop comprehensive microchips to detect clinically-relevant alleles in the Rh and other blood group systems. These high-throughput microchips will be designed to screen for donors with clinically significant variant Rh phenotypes and with different combinations of minor antigens, so that antigen-negative inventories may be increased and matching to patients with SCD optimized. (3) Two separate microchip platforms will be tested and compared using DNA samples from the SCD patient and blood donor samples in Aim 1, and an additional 2000 African-American donor samples from the New York Blood Center. Expertise in bioinformatics and specialized tools, including the Blood Operations Support Software developed at the New York Blood Center will permit seamless interfacing of data from multiple sources, as well as analysis and interpretation of the complex genotypic and phenotypic data collected for this project. Taken together, these investigations will enable us to effectively prevent alloimmunization by providing more precisely matched blood to patients with SCD and by allowing for more widespread use of transfusion, have an immediate impact on the care of this patient population. Although chronic transfusion is increasingly used to prevent life-threatening events in patients with sickle cell disease (SCD), alloimmunization to blood group antigens remains a major complication of chronic transfusions. The proposed study is to develop tools to revolutionize the way we type for blood groups antigens to increase inventories of antigen-negative blood and to match blood based on DNA analysis in order to eliminate transfusion-induced alloimmunization. We believe that data generated from this project will have an immediate impact in improving the transfusion of patients with SCD. (End of Abstract)
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Genomic analyses of RH alleles to improve transfusion therapy in patients with sickle cell disease
    Marion E Reid
    Laboratory of Immunochemistry, New York Blood Center, 310 East 67th Street, New York, NY 10065, USA Electronic address
    Blood Cells Mol Dis 52:195-202. 2014
  2. ncbi Prevalence of RHD*DOL and RHCE*ce(818T) in two populations
    C Halter Hipsky
    Laboratory of Immunochemistry, New York Blood Center, New York, NY 10065, USA
    Immunohematology 27:66-7. 2011
  3. pmc The low-prevalence Rh antigen STEM (RH49) is encoded by two different RHCE*ce818T alleles that are often in cis to RHD*DOL
    Marion E Reid
    Laboratory of Immunochemistry, New York Blood Center, New York, New York 10065, USA
    Transfusion 53:539-44. 2013
  4. pmc RHCE*ceTI encodes partial c and partial e and is often in cis to RHD*DIVa
    Connie M Westhoff
    Laboratory of Immunohematology and Genomics, New York Blood Center, Long Island City, New York 10065, USA
    Transfusion 53:741-6. 2013
  5. ncbi RHD deletion in a patient with chronic myeloid leukemia
    A Murdock
    Good Samaritan Hospital Medical Center, West Islip, NY, USA
    Immunohematology 24:160-4. 2008
  6. pmc Molecular basis of two novel and related high-prevalence antigens in the Kell blood group system, KUCI and KANT, and their serologic and spatial association with K11 and KETI
    Randall W Velliquette
    Laboratory of Immunohematology and Genomics, New York Blood Center, Long Island City, New York Laboratory of Immunochemistry, New York Blood Center, New York, New York Laboratory of Molecular Modeling and Drug Design, New York Blood Center, New York, New York Laboratory of Membrane Biochemistry, New York Blood Center, New York, New York Memorial Blood Centers, St Paul, Minnesota Medcenter One, Bismarck, North Dakota National Reference Center for Blood Groups, National Institute of Blood Transfusion, Paris, France Department of Transfusion Medicine, University Hospital Ulm, Institute of Clinical Transfusion Medicine and Immunogenetics, Ulm and German Red Cross Blood Donor Service, Baden W├╝rttemberg Hessen, Institute Ulm, Ulm, Germany Laboratory Services Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland American Red Cross, Southern California Region, Pomona, California
    Transfusion 53:2872-81. 2013
  7. pmc RHCE*ceMO is frequently in cis to RHD*DAU0 and encodes a hr(S) -, hr(B) -, RH:-61 phenotype in black persons: clinical significance
    Connie M Westhoff
    Laboratory of Immunohematology and Genomics, New York Blood Center Laboratory of Immunochemistry, New York Blood Center, New York, New York National Molecular Testing Laboratory, American Red Cross, Philadelphia, Pennsylvania
    Transfusion 53:2983-9. 2013
  8. pmc DIII Type 7 is likely the original serologically defined DIIIb
    Christine Lomas-Francis
    Laboratory of Immunohematology, New York Blood Center, New York, New York 10065, USA
    Transfusion 52:39-42. 2012
  9. ncbi Molecular basis of the rare gene complex, DIVa(C)-, which encodes four low-prevalence antigens in the Rh blood group system
    C H Hipsky
    Laboratory of Immunochemistry, New York Blood Center, New York, NY, USA
    Vox Sang 102:167-70. 2012
  10. doi Nucleotide deletion in RHCE*cE (907delC) is responsible for a D- - haplotype in Hispanics
    Connie M Westhoff
    National Molecular Blood Group and Platelet Testing Laboratory and NRLBGS, National Reference Laboratory for Blood Group Serology, American Red Cross, Philadelphia, Pennsylvania, USA
    Transfusion 51:2142-7. 2011

Scientific Experts

  • Connie M Westhoff
  • Marion Reid
  • Christine Lomas-Francis
  • C Lomas-Francis
  • Randall W Velliquette
  • Christine Halter Hipsky
  • K Hue-Roye
  • C Halter Hipsky
  • Kim Hue-Roye
  • C H Hipsky
  • Akiko Fuchisawa
  • J Ong
  • S Vege
  • A Murdock
  • Jennifer Schierts
  • Soohee Lee
  • Barbara Gillen
  • Karen Rodberg
  • Asim K Debnath
  • Kristie Gentzkow
  • Willy A Flegel
  • Thierry Peyrard
  • Inge von Zabern
  • C H Huang
  • Pam Nickle
  • L Castilho
  • R Omoto
  • Marilyn Moulds
  • Carolyn Hoppe
  • Sunitha Vege
  • A Zanette
  • D C da Costa
  • Joann Christensen
  • A Fuchisawa
  • Lillian Castilho
  • Denden Alcantara
  • J R Storry
  • P S Walker
  • Joan Uehlinger
  • Marilia Valvasori
  • E Schmulbach
  • Z Hu
  • D Assip

Detail Information

Publications21

  1. pmc Genomic analyses of RH alleles to improve transfusion therapy in patients with sickle cell disease
    Marion E Reid
    Laboratory of Immunochemistry, New York Blood Center, 310 East 67th Street, New York, NY 10065, USA Electronic address
    Blood Cells Mol Dis 52:195-202. 2014
    ..The purpose of this study was to determine the diversity and frequency of RH alleles in African Americans and to assess the performance of a DNA microarray for RH allele determination...
  2. ncbi Prevalence of RHD*DOL and RHCE*ce(818T) in two populations
    C Halter Hipsky
    Laboratory of Immunochemistry, New York Blood Center, New York, NY 10065, USA
    Immunohematology 27:66-7. 2011
    ..Although the numbers are small, our study shows that in the United States, the frequency of RHCE*818T is 0.007 (2 in 290 samples) and in Brazil it is 0.004 (2 in 515 samples). The four RHCE*818T alleles were RHCE*ceBI...
  3. pmc The low-prevalence Rh antigen STEM (RH49) is encoded by two different RHCE*ce818T alleles that are often in cis to RHD*DOL
    Marion E Reid
    Laboratory of Immunochemistry, New York Blood Center, New York, New York 10065, USA
    Transfusion 53:539-44. 2013
    ..We report that two alleles with a RHCE*ce818C>T change encode a partial e, and a hr(S) -, hr(B) +, STEM+ phenotype and that both alleles are frequently in cis to RHD*DOL1 or RHD*DOL2...
  4. pmc RHCE*ceTI encodes partial c and partial e and is often in cis to RHD*DIVa
    Connie M Westhoff
    Laboratory of Immunohematology and Genomics, New York Blood Center, Long Island City, New York 10065, USA
    Transfusion 53:741-6. 2013
    ..In the Rh blood group system, variant RhD and RhCE express several partial antigens. We investigated RH in samples with partial DIVa that demonstrated weak and variable reactivity with anti-C...
  5. ncbi RHD deletion in a patient with chronic myeloid leukemia
    A Murdock
    Good Samaritan Hospital Medical Center, West Islip, NY, USA
    Immunohematology 24:160-4. 2008
    ..Based on finding a hybrid Rhesus box and absence of D-specific exons, we conclude that DNA from the patient's WBCs carries a deleted RHD. This explains the molecular mechanism underlying the change from D+ to D-...
  6. pmc Molecular basis of two novel and related high-prevalence antigens in the Kell blood group system, KUCI and KANT, and their serologic and spatial association with K11 and KETI
    Randall W Velliquette
    Laboratory of Immunohematology and Genomics, New York Blood Center, Long Island City, New York Laboratory of Immunochemistry, New York Blood Center, New York, New York Laboratory of Molecular Modeling and Drug Design, New York Blood Center, New York, New York Laboratory of Membrane Biochemistry, New York Blood Center, New York, New York Memorial Blood Centers, St Paul, Minnesota Medcenter One, Bismarck, North Dakota National Reference Center for Blood Groups, National Institute of Blood Transfusion, Paris, France Department of Transfusion Medicine, University Hospital Ulm, Institute of Clinical Transfusion Medicine and Immunogenetics, Ulm and German Red Cross Blood Donor Service, Baden W├╝rttemberg Hessen, Institute Ulm, Ulm, Germany Laboratory Services Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland American Red Cross, Southern California Region, Pomona, California
    Transfusion 53:2872-81. 2013
    ..Antibodies to antigens in this system can be clinically important. We describe six probands whose plasma contained antibodies to high-prevalence Kell antigens and discuss their relationship...
  7. pmc RHCE*ceMO is frequently in cis to RHD*DAU0 and encodes a hr(S) -, hr(B) -, RH:-61 phenotype in black persons: clinical significance
    Connie M Westhoff
    Laboratory of Immunohematology and Genomics, New York Blood Center Laboratory of Immunochemistry, New York Blood Center, New York, New York National Molecular Testing Laboratory, American Red Cross, Philadelphia, Pennsylvania
    Transfusion 53:2983-9. 2013
    ..We compiled serologic and DNA testing data on samples with RHCE*ceMO to determine the red blood cell (RBC) antigen expression, antibody specificity, RHD association, and the prevalence in African-American persons...
  8. pmc DIII Type 7 is likely the original serologically defined DIIIb
    Christine Lomas-Francis
    Laboratory of Immunohematology, New York Blood Center, New York, New York 10065, USA
    Transfusion 52:39-42. 2012
    ..Our study describes hemagglutination tests on this sample and raises a question regarding the molecular basis of the originally defined DIIIb category...
  9. ncbi Molecular basis of the rare gene complex, DIVa(C)-, which encodes four low-prevalence antigens in the Rh blood group system
    C H Hipsky
    Laboratory of Immunochemistry, New York Blood Center, New York, NY, USA
    Vox Sang 102:167-70. 2012
    ..Her RBCs expressed a partial D, weak C and four low-prevalence Rh antigens: Go(a) (RH30), Rh33 (RH33), Riv (RH45) and FPTT (RH50). The purpose of this study was to determine the molecular basis associated with this rare DIVa(C)- complex...
  10. doi Nucleotide deletion in RHCE*cE (907delC) is responsible for a D- - haplotype in Hispanics
    Connie M Westhoff
    National Molecular Blood Group and Platelet Testing Laboratory and NRLBGS, National Reference Laboratory for Blood Group Serology, American Red Cross, Philadelphia, Pennsylvania, USA
    Transfusion 51:2142-7. 2011
    ..We investigated RH in eight samples, three presenting as D- -, whose c-E- red blood cell (RBC) typing was discordant with the RHCE genotype that predicted c+E+...
  11. pmc Red cells from the original JAL+ proband are also DAK+ and STEM+
    K Hue-Roye
    Laboratory of Immunochemistry, New York Blood Center, New York, NY, USA
    Vox Sang 101:61-4. 2011
    ..The purpose of this study was to investigate the other low-prevalence antigen(s) on J. Allen's RBCs...
  12. pmc DNA-based methods in the immunohematology reference laboratory
    Marion E Reid
    Laboratory of Immunochemistry, New York Blood Center, 310 East 67th Street, New York, NY 10065, United States
    Transfus Apher Sci 44:65-72. 2011
    ..DNA-based testing in immunohematology is a valuable tool used to resolve blood group incompatibilities and to support patients in their transfusion needs...
  13. pmc The JAL antigen (RH48) is the result of a change in RHCE that encodes Arg114Trp
    Connie M Westhoff
    Molecular Blood Group and Platelet Testing Laboratory, American Red Cross, Penn Jersey Region, Philadelphia, PA 19130, USA
    Transfusion 49:725-32. 2009
    ..This study was undertaken to investigate the RH gene(s) responsible for expression of JAL and to determine the structural relationship between JAL and other Rh antigens...
  14. pmc JAL (RH48) blood group antigen: serologic observations
    Christine Lomas-Francis
    Laboratory of Immunohematology, New York Blood Center, 310 East 67th Street, New York, NY 10065, USA
    Transfusion 49:719-24. 2009
    ....
  15. pmc DIIIa and DIII Type 5 are encoded by the same allele and are associated with altered RHCE*ce alleles: clinical implications
    Connie M Westhoff
    National Molecular Blood Group and Platelet Testing Laboratory, American Red Cross, Philadelphia, Pennsylvania, USA
    Transfusion 50:1303-11. 2010
    ..We also studied additional DIIIa samples to clarify the RHD background and establish the associated RHCE...
  16. pmc A novel RHCE*ce 48C, 733G allele with Nucleotide 941C in Exon 7 encodes an altered red blood cell e antigen
    Kim Hue-Roye
    Laboratory of Immunochemistry, New York Blood Center, New York, New York 10065, USA
    Transfusion 51:32-5. 2011
    ..We also screened blood samples from African Americans to determine the frequency of the novel allele...
  17. pmc RHCE*ceCF encodes partial c and partial e but not CELO, an antigen antithetical to Crawford
    Christine Halter Hipsky
    Laboratories of Immunohematology and Immunochemistry, New York Blood Center, New York, New York 10065, USA
    Transfusion 51:25-31. 2011
    ..RH43 (Crawford) is encoded by RHCE*ce with nucleotide changes 48G>C, 697C>G, and 733C>G (RHCE*ceCF). We investigated the Rh antigen expression and antibody specificities in four patients with this allele...
  18. ncbi RHCE*ceAR encodes a partial c (RH4) antigen
    C Halter Hipsky
    Laboratory of Immunochemistry, New York Blood Center, 310 East 67th Street, New York, NY 10065, USA
    Immunohematology 26:57-9. 2010
    ..This case shows that RhceAR carries a partial c antigen and illustrates the value of DNA testing as an adjunct to hemagglutination to aid in antibody identification in unusual cases...
  19. pmc Alloanti-c in a c-positive, JAL-positive patient
    J Ong
    Blood Centers of the Pacific, San Francisco, CA, USA
    Vox Sang 96:240-3. 2009
    ..The finding of an apparent alloanti-c in a transfused c+ patient initiated this investigation...