title: The genetics of hemoglobin A2 regulation in sickle cell anemia.
abstract: Hemoglobin A2 , a tetramer of α- and δ-globin chains, comprises less than 3% of total hemoglobin in normal adults. In northern Europeans, single nucleotide polymorphisms (SNPs) in the HBS1L-MYB locus on chromosome 6q and the HBB cluster on chromosome 11p were associated with HbA2 levels. We examined the genetic basis of HbA2 variability in sickle cell anemia using genome-wide association studies. HbA2 levels were associated with SNPs in the HBS1L-MYB interval and SNPs in BCL11A. These effects are mediated by the association of these loci with γ-globin gene expression and fetal hemoglobin (HbF) levels. The association of polymorphisms downstream of the β-globin gene (HBB) cluster on chromosome 11 with HbA2 was not mediated by HbF. In sickle cell anemia, levels of HbA2 appear to be modulated by trans-acting genes that affect HBG expression and perhaps also elements within the β-globin gene cluster. HbA2 is expressed pancellularly and can inhibit HbS polymerization. It remains to be seen if genetic regulators of HbA2 can be exploited for therapeutic purposes.
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Griffin
authors.forename: Paola
authors.initials: P
authors.lastname: Sebastiani
authors.forename: Heather
authors.initials: H
authors.lastname: Edward
authors.forename: Clinton T
authors.initials: CT
authors.lastname: Baldwin
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
authors.forename: David H K
authors.initials: DH
authors.lastname: Chui
authors.forename: Martin H
authors.initials: MH
authors.lastname: Steinberg
mesh_terms: D001741:Black or African American / Q000235:genetics; D000367:Age Factors; D000755:Anemia, Sickle Cell / Q000378:metabolism*; D044466:Asian People / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D015331:Cohort Studies; D005060:Europe / Q000208:ethnology; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D020570:Genes, myb; D055106:Genome-Wide Association Study; D005838:Genotype; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006443:Hemoglobin A2 / Q000096:biosynthesis / Q000235:genetics*; D006451:Hemoglobin, Sickle / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D010445:Peptide Elongation Factors / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins; D015534:Trans-Activators / Q000235:genetics; D044465:White People / Q000235:genetics; D017085:alpha-Thalassemia / Q000235:genetics; D055544:beta-Globins / Q000235:genetics; D055546:delta-Globins / Q000235:genetics; D055545:gamma-Globins / Q000235:genetics
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; D006451:Hemoglobin, Sickle; D009687:Nuclear Proteins; D010445:Peptide Elongation Factors; D012097:Repressor Proteins; D015534:Trans-Activators; D055544:beta-Globins; D055546:delta-Globins; D055545:gamma-Globins; D006443:Hemoglobin A2; D005319:Fetal Hemoglobin; D019204:GTP-Binding Proteins; C000628258:HBS1L protein, human