Document Detail


Genetic determinants of haemolysis in sickle cell anaemia.
MedLine Citation:
PMID:  23406172     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Haemolytic anaemia is variable among patients with sickle cell anaemia and can be estimated by reticulocyte count, lactate dehydrogenase, aspartate aminotransferase and bilirubin levels. Using principal component analysis of these measurements we computed a haemolytic score that we used as a subphenotype in a genome-wide association study. We identified in one cohort and replicated in two additional cohorts the association of a single nucleotide polymorphism in NPRL3 (rs7203560; chr16p13·3) (P = 6·04 × 10(-07) ). This association was validated by targeted genotyping in a fourth independent cohort. The HBA1/HBA2 regulatory elements, hypersensitive sites (HS)-33, HS-40 and HS-48 are located in introns of NPRL3. Rs7203560 was in perfect linkage disequilibrium (LD) with rs9926112 (r(2)  = 1) and in strong LD with rs7197554 (r(2)  = 0·75) and rs13336641 (r(2)  = 0·77); the latter is located between HS-33 and HS-40 sites and next to a CTCF binding site. The minor allele for rs7203560 was associated with the -∝(3·7) thalassaemia gene deletion. When adjusting for HbF and ∝ thalassaemia, the association of NPRL3 with the haemolytic score was significant (P = 0·00375) and remained significant when examining only cases without gene deletion∝ thalassaemia (P = 0·02463). Perhaps by independently down-regulating expression of the HBA1/HBA2 genes, variants of the HBA1/HBA2 gene regulatory loci, tagged by rs7203560, reduce haemolysis in sickle cell anaemia.
Authors:
Jacqueline N Milton; Helen Rooks; Emma Drasar; Elizabeth L McCabe; Clinton T Baldwin; Efi Melista; Victor R Gordeuk; Mehdi Nouraie; Gregory R Kato; Gregory J Kato; Caterina Minniti; James Taylor; Andrew Campbell; Lori Luchtman-Jones; Sohail Rana; Oswaldo Castro; Yingze Zhang; Swee Lay Thein; Paola Sebastiani; Mark T Gladwin; ; Martin H Steinberg
Publication Detail:
Type:  Clinical Trial; Journal Article; Multicenter Study; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-14
Journal Detail:
Title:  British journal of haematology     Volume:  161     ISSN:  1365-2141     ISO Abbreviation:  Br. J. Haematol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-04     Completed Date:  2013-05-23     Revised Date:  2014-09-09    
Medline Journal Info:
Nlm Unique ID:  0372544     Medline TA:  Br J Haematol     Country:  England    
Other Details:
Languages:  eng     Pagination:  270-8     Citation Subset:  IM    
Copyright Information:
© 2013 Blackwell Publishing Ltd.
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Aged
Aged, 80 and over
Alleles*
Anemia, Sickle Cell / genetics*,  metabolism
Child
Cohort Studies
Female
Genetic Loci*
Hemoglobin A, Glycosylated / genetics,  metabolism
Hemoglobins, Abnormal / genetics,  metabolism
Hemolysis / genetics*
Humans
Introns / genetics
Linkage Disequilibrium
Male
Middle Aged
Nuclear Proteins / genetics*,  metabolism
Polymorphism, Single Nucleotide*
Response Elements*
Grant Support
ID/Acronym/Agency:
2M01 RR10284-10/RR/NCRR NIH HHS; 2R25 HL003679-8/HL/NHLBI NIH HHS; 5T32 HL007501/HL/NHLBI NIH HHS; G0001249 ID 56477//Medical Research Council; P01HL103455/HL/NHLBI NIH HHS; R01 HL079912/HL/NHLBI NIH HHS; R01 HL87681/HL/NHLBI NIH HHS; R01HL096973/HL/NHLBI NIH HHS; R01HL098032/HL/NHLBI NIH HHS; RC2 L101212/RC/CCR NIH HHS; T32 GM074905/GM/NIGMS NIH HHS; ZIA HL005116-06/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/C16orf35 protein, human; 0/Hemoglobin A, Glycosylated; 0/Hemoglobins, Abnormal; 0/Nuclear Proteins
Investigator
Investigator/Affiliation:
D B Badesch / ; R J Barst / ; O L Castro / ; J S R Gibbs / ; R E Girgis / ; M T Gladwin / ; J C Goldsmith / ; V R Gordeuk / ; K L Hassell / ; G J Kato / ; L Krishnamurti / ; S Lanzkron / ; J A Little / ; R F Machado / ; C R Morris / ; M Nouraie / ; O Onyekwere / ; E B Rosenzweig / ; V Sachdev / ; D E Schraufnagel / ; M A Waclawiw / ; R Woolson / ; N A Yovetich /
Comments/Corrections
Erratum In:
Br J Haematol. 2014 Aug;166(3):468
Note: Kato, Gregory R [corrected to Kata, Gregory J]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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