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. Badesch; R. 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

doi:10.1111/bjh.12245

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 journal › Article › peer-review

39 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 language	English (US)
Pages (from-to)	270-278
Number of pages	9
Journal	British Journal of Haematology
Volume	161
Issue number	2
DOIs	https://doi.org/10.1111/bjh.12245
State	Published - Apr 1 2013
Externally published	Yes

Keywords

Genetic analysis
Haemolysis
Haemolytic anaemia
Sickle cell anaemia
Thalassaemia

ASJC Scopus subject areas

Hematology

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10.1111/bjh.12245

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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

Milton, JN, Rooks, H, Drasar, E, McCabe, EL, Baldwin, CT, Melista, E, Gordeuk, VR, Nouraie, M, Kato, GR, Minniti, C, Taylor, J, Campbell, A, Luchtman-Jones, L, Rana, S, Castro, O, Zhang, Y, Thein, SL, Sebastiani, P, Gladwin, MT, Badesch, DB, Barst, RJ, Castro, OL, Gibbs, JSR, Girgis, RE, Goldsmith, JC, Hassell, KL, Kato, GJ, Krishnamurti, L, Lanzkron, S, Little, JA, Machado, RF, Morris, CR, Onyekwere, O, Rosenzweig, EB, Sachdev, V, Schraufnagel, DE, Waclawiw, MA, Woolson, R, Yovetich, NA & Steinberg, MH 2013, 'Genetic determinants of haemolysis in sickle cell anaemia', British Journal of Haematology, vol. 161, no. 2, pp. 270-278. https://doi.org/10.1111/bjh.12245

@article{a2b9f65989b54102b4deb5fc996091b9,

title = "Genetic determinants of haemolysis in sickle cell anaemia",

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.",

keywords = "Genetic analysis, Haemolysis, Haemolytic anaemia, Sickle cell anaemia, Thalassaemia",

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

year = "2013",

month = apr,

day = "1",

doi = "10.1111/bjh.12245",

language = "English (US)",

volume = "161",

pages = "270--278",

journal = "British Journal of Haematology",

issn = "0007-1048",

publisher = "Wiley-Blackwell",

number = "2",

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TY - JOUR

T1 - Genetic determinants of haemolysis in sickle cell anaemia

AU - Milton, Jacqueline N.

AU - Rooks, Helen

AU - Drasar, Emma

AU - McCabe, Elizabeth L.

AU - Baldwin, Clinton T.

AU - Melista, Efi

AU - Gordeuk, Victor R.

AU - Nouraie, Mehdi

AU - Kato, Gregory R.

AU - Minniti, Caterina

AU - Taylor, James

AU - Campbell, Andrew

AU - Luchtman-Jones, Lori

AU - Rana, Sohail

AU - Castro, Oswaldo

AU - Zhang, Yingze

AU - Thein, Swee Lay

AU - Sebastiani, Paola

AU - Gladwin, Mark T.

AU - Badesch, D. B.

AU - Barst, R. J.

AU - Castro, O. L.

AU - Gibbs, J. S.R.

AU - Girgis, R. E.

AU - Goldsmith, J. C.

AU - Hassell, K. L.

AU - Kato, G. J.

AU - Krishnamurti, L.

AU - Lanzkron, S.

AU - Little, J. A.

AU - Machado, R. F.

AU - Morris, C. R.

AU - Onyekwere, O.

AU - Rosenzweig, E. B.

AU - Sachdev, V.

AU - Schraufnagel, D. E.

AU - Waclawiw, M. A.

AU - Woolson, R.

AU - Yovetich, N. A.

AU - Steinberg, Martin H.

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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.

AB - 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.

KW - Genetic analysis

KW - Haemolysis

KW - Haemolytic anaemia

KW - Sickle cell anaemia

KW - Thalassaemia

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SN - 0007-1048

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SP - 270

EP - 278

JO - British Journal of Haematology

JF - British Journal of Haematology

IS - 2

ER -

Genetic determinants of haemolysis in sickle cell anaemia

Abstract

Keywords

ASJC Scopus subject areas

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