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 (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: Biostatistics, Boston University School of Medicine, 72 E. Concord St., Boston, MA 02118, USA.
authors: Jacqueline N
authors: JN
authors: Milton
authors: Helen
authors: H
authors: Rooks
authors: Emma
authors: E
authors: Drasar
authors: Elizabeth L
authors: EL
authors: McCabe
authors: Clinton T
authors: CT
authors: Baldwin
authors: Efi
authors: E
authors: Melista
authors: Victor R
authors: VR
authors: Gordeuk
authors: Mehdi
authors: M
authors: Nouraie
authors: Gregory R
authors: GR
authors: Kato
authors: Gregory J
authors: GJ
authors: Kato
authors: Caterina
authors: C
authors: Minniti
authors: James
authors: J
authors: Taylor
authors: Andrew
authors: A
authors: Campbell
authors: Lori
authors: L
authors: Luchtman-Jones
authors: Sohail
authors: S
authors: Rana
authors: Oswaldo
authors: O
authors: Castro
authors: Yingze
authors: Y
authors: Zhang
authors: Swee Lay
authors: SL
authors: Thein
authors: Paola
authors: P
authors: Sebastiani
authors: Mark T
authors: MT
authors: Gladwin
authors: Martin H
authors: MH
authors: Steinberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000755:Anemia, Sickle Cell / Q000235:genetics* / Q000378:metabolism; D002648:Child; D015331:Cohort Studies; D005260:Female; D020690:GTPase-Activating Proteins; D056426:Genetic Loci; D006442:Glycated Hemoglobin / Q000235:genetics / Q000378:metabolism; D006455:Hemoglobins, Abnormal / Q000235:genetics / Q000378:metabolism; D006461:Hemolysis / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D020218:Response Elements
chemical_list: D020690:GTPase-Activating Proteins; D006442:Glycated Hemoglobin; D006455:Hemoglobins, Abnormal; D009687:Nuclear Proteins; C543618:NPRL3 protein, human