title: Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients.
abstract: Fetal hemoglobin (HbF) level has emerged as an important prognostic factor in sickle-cell disease (SCD) and can be measured by the proportion of HbF-containing erythrocytes (F-cells). Recently, BCL11A (zinc-finger protein) was identified as a regulator of HbF, and the strongest association signals were observed either directly for rs766432 or for correlated single-nucleotide polymorphisms (SNPs). To identify additional independently associated genetic variants, we performed a genome-wide association study (GWAS) on the proportion of F-cells in individuals of African ancestry with SCD from the Silent Infarct Transfusion (SIT) Trial cohort. Our study not only confirms the association of rs766432 (P-value <3.32 × 10(-13)), but also identifies an independent novel intronic SNP, rs7606173, associated with F-cells (P-value <1.81 × 10(-15)). The F-cell variances explained independently by these two SNPs are ∼13% (rs7606173) and ∼11% (rs766432), whereas, together they explain ∼16%. Additionally, in men, we identify a novel locus on chromosome 17, glucagon-like peptide-2 receptor (GLP2R), associated with F-cell regulation (rs12103880; P-value <3.41 × 10(-8)). GLP2R encodes a G protein-coupled receptor and involved in proliferative and anti-apoptotic cellular responses. These findings highlight the importance of denser genetic screens and suggest further exploration of the BCL11A and GLP2R loci to gain additional insight into HbF/F-cell regulation.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Pallav
authors.initials: P
authors.lastname: Bhatnagar
authors.forename: Shirley
authors.initials: S
authors.lastname: Purvis
authors.forename: Emily
authors.initials: E
authors.lastname: Barron-Casella
authors.forename: Michael R
authors.initials: MR
authors.lastname: DeBaun
authors.forename: James F
authors.initials: JF
authors.lastname: Casella
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Keefer
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics*; D001499:Bayes Theorem; D044383:Black People / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D015331:Cohort Studies; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000378:metabolism*; D005319:Fetal Hemoglobin / Q000032:analysis*; D055106:Genome-Wide Association Study; D005838:Genotype; D000067757:Glucagon-Like Peptide-1 Receptor; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018027:Receptors, Glucagon / Q000235:genetics; D012097:Repressor Proteins
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D009687:Nuclear Proteins; D018027:Receptors, Glucagon; D012097:Repressor Proteins; D005319:Fetal Hemoglobin