Drs. Gladwin and Steinberg contributed equally to this manuscript.
Genetic determinants of haemolysis in sickle cell anaemia
Article first published online: 14 FEB 2013
© 2013 Blackwell Publishing Ltd
British Journal of Haematology
Volume 161, Issue 2, pages 270–278, April 2013
How to Cite
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., the Walk-PHAAST Investigators and Steinberg, M. H. (2013), Genetic determinants of haemolysis in sickle cell anaemia. British Journal of Haematology, 161: 270–278. doi: 10.1111/bjh.12245
For the Walk-PHAAST Investigators detail see Appendix I.
- Issue published online: 3 APR 2013
- Article first published online: 14 FEB 2013
- Manuscript Accepted: 29 DEC 2012
- Manuscript Received: 23 OCT 2012
- National Institutes of Health. Grant Numbers: R01 HL87681 MHS, RC2 L101212 MHS, 5T32 HL007501 JNM, 2R25 HL003679-8 VRG, R01 HL079912 VRG, 2M01 RR10284-10 VRG, R01HL098032 MTG, R01HL096973 MTG, P01HL103455 MTG
- Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania (MTG). Grant Number: G0001249 ID 56477 SLT
Vol. 166, Issue 3, 468, Article first published online: 9 JUL 2014
- sickle cell anaemia;
- haemolytic anaemia;
- genetic analysis;
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.