Genetic determinants of haemolysis in sickle cell anaemia

Jacqueline N. Milton, Helen Rooks, Emma Drasar, Elizabeth L. McCabe, Clinton T. Baldwin, Efi Melista, Victor R. Gordeuk, Mehdi Nouraie, Gregory R. Kato, Caterina Minniti, James Taylor, Andrew Campbell, Lori Luchtman-Jones, Sohail Rana, Oswaldo Castro, Yingze Zhang, Swee Lay Thein, Paola Sebastiani, Mark T. Gladwin, D. B. BadeschR. J. Barst, O. L. Castro, J. S.R. Gibbs, R. E. Girgis, J. C. Goldsmith, K. L. Hassell, G. J. Kato, L. Krishnamurti, S. Lanzkron, J. A. Little, R. F. Machado, C. R. Morris, O. Onyekwere, E. B. Rosenzweig, V. Sachdev, D. E. Schraufnagel, M. A. Waclawiw, R. Woolson, N. A. Yovetich, Martin H. Steinberg

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)270-278
Number of pages9
JournalBritish Journal of Haematology
Volume161
Issue number2
DOIs
StatePublished - Apr 1 2013

Keywords

  • Genetic analysis
  • Haemolysis
  • Haemolytic anaemia
  • Sickle cell anaemia
  • Thalassaemia

ASJC Scopus subject areas

  • Hematology

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    Milton, J. N., Rooks, H., Drasar, E., McCabe, E. L., Baldwin, C. T., Melista, E., Gordeuk, V. R., Nouraie, M., Kato, G. R., Minniti, C., Taylor, J., Campbell, A., Luchtman-Jones, L., Rana, S., Castro, O., Zhang, Y., Thein, S. L., Sebastiani, P., Gladwin, M. T., ... Steinberg, M. H. (2013). Genetic determinants of haemolysis in sickle cell anaemia. British Journal of Haematology, 161(2), 270-278. https://doi.org/10.1111/bjh.12245