title: Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia.
abstract: beta-Thalassemia and sickle cell disease both display a great deal of phenotypic heterogeneity, despite being generally thought of as simple Mendelian diseases. The reasons for this are not well understood, although the level of fetal hemoglobin (HbF) is one well characterized ameliorating factor in both of these conditions. To better understand the genetic basis of this heterogeneity, we carried out genome-wide scans with 362,129 common SNPs on 4,305 Sardinians to look for genetic linkage and association with HbF levels, as well as other red blood cell-related traits. Among major variants affecting HbF levels, SNP rs11886868 in the BCL11A gene was strongly associated with this trait (P < 10(-35)). The C allele frequency was significantly higher in Sardinian individuals with elevated HbF levels, detected by screening for beta-thalassemia, and patients with attenuated forms of beta-thalassemia vs. those with thalassemia major. We also show that the same BCL11A variant is strongly associated with HbF levels in a large cohort of sickle cell patients. These results indicate that BCL11A variants, by modulating HbF levels, act as an important ameliorating factor of the beta-thalassemia phenotype, and it is likely they could help ameliorate other hemoglobin disorders. We expect our findings will help to characterize the molecular mechanisms of fetal globin regulation and could eventually contribute to the development of new therapeutic approaches for beta-thalassemia and sickle cell anemia.
authors.affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Uda
authors.forename: Renzo
authors.initials: R
authors.lastname: Galanello
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
authors.forename: Vijay G
authors.initials: VG
authors.lastname: Sankaran
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.forename: Gianluca
authors.initials: G
authors.lastname: Usala
authors.forename: Fabio
authors.initials: F
authors.lastname: Busonero
authors.forename: Andrea
authors.initials: A
authors.lastname: Maschio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Albai
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Piras
authors.forename: Natascia
authors.initials: N
authors.lastname: Sestu
authors.forename: Sandra
authors.initials: S
authors.lastname: Lai
authors.forename: Mariano
authors.initials: M
authors.lastname: Dei
authors.forename: Antonella
authors.initials: A
authors.lastname: Mulas
authors.forename: Laura
authors.initials: L
authors.lastname: Crisponi
authors.forename: Silvia
authors.initials: S
authors.lastname: Naitza
authors.forename: Isadora
authors.initials: I
authors.lastname: Asunis
authors.forename: Manila
authors.initials: M
authors.lastname: Deiana
authors.forename: Ramaiah
authors.initials: R
authors.lastname: Nagaraja
authors.forename: Lucia
authors.initials: L
authors.lastname: Perseu
authors.forename: Stefania
authors.initials: S
authors.lastname: Satta
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Cipollina
authors.forename: Carla
authors.initials: C
authors.lastname: Sollaino
authors.forename: Paolo
authors.initials: P
authors.lastname: Moi
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.forename: Antonio
authors.initials: A
authors.lastname: Cao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis* / Q000378:metabolism*; D005787:Gene Frequency; D008040:Genetic Linkage; D015894:Genome, Human; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins; D017086:beta-Thalassemia / Q000175:diagnosis*
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D005319:Fetal Hemoglobin