Genetic determinants of haemolysis in sickle cell anaemia

Authors

Jacqueline N. Milton, Boston University
Helen Rooks, Faculty of Life Sciences & Medicine
Emma Drasar, Faculty of Life Sciences & Medicine
Elizabeth L. McCabe, Boston University
Clinton T. Baldwin, Boston University School of Medicine
Efi Melista, Boston University
Victor R. Gordeuk, The Center For Sickle Cell Disease
Mehdi Nouraie, The Center For Sickle Cell Disease
Gregory R. Kato, National Heart, Lung, and Blood Institute (NHLBI)
Caterina Minniti, National Heart, Lung, and Blood Institute (NHLBI)
James Taylor, National Heart, Lung, and Blood Institute (NHLBI)
Andrew Campbell, University of Michigan, Ann Arbor
Lori Luchtman-Jones, Childrens National Health System
Sohail Rana, The Center For Sickle Cell Disease
Oswaldo Castro, National Heart, Lung, and Blood Institute (NHLBI)
Yingze Zhang, University of Pittsburgh
Swee Lay Thein, Faculty of Life Sciences & Medicine
Paola Sebastiani, Boston University
Mark T. Gladwin, University of Pittsburgh
D. B. Badesch, University of Colorado Anschutz Medical Campus
R. J. Barst, Columbia University
O. L. Castro, Howard University
J. S.R. Gibbs, National Heart and Lung Institute
R. E. Girgis, Johns Hopkins University
J. C. Goldsmith, National Heart, Lung, and Blood Institute (NHLBI)
K. L. Hassell, University of Colorado Anschutz Medical Campus
G. J. Kato, National Heart, Lung, and Blood Institute (NHLBI)
L. Krishnamurti, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
S. Lanzkron, Johns Hopkins University
J. A. Little, Albert Einstein College of Medicine of Yeshiva University
R. F. Machado, University of Illinois at Chicago
C. R. Morris, UCSF Benioff Children's Hospital Oakland
O. Onyekwere, Howard University
E. B. Rosenzweig, Columbia University

Document Type

Article

Publication Date

4-1-2013

Abstract

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 (r2 = 1) and in strong LD with rs7197554 (r2 = 0·75) and rs13336641 (r2 = 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 -∝3·7thalassaemia 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. © 2013 Blackwell Publishing Ltd.

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