BCL11A is a major HbF quantitative trait locus in three different populations with β-hemoglobinopathies

Abstract

Increased HbF levels or F-cell (HbF containing erythrocyte) numbers can ameliorate the disease severity of β-thalassemia major and sickle cell anemia. Recent genome wide association studies reported that single nucleotide polymorphisms (SNPs) in BCL11A gene on chromosome 2p16.1 were correlated with F-cells among healthy northern Europeans, and HbF among Sardinians with β-thalassemias. In this study, we showed that SNPs in BCL11A were associated with F-cell numbers in Chinese with β-thalassemia trait, and with HbF levels in Thais with either β-thalassemia or HbE trait and in African Americans with sickle cell anemia. Taken together, the data suggest that the functional motifs responsible for modulating F-cells and HbF levels reside within a 3 kb region in the second intron of BCL11A.

A genetic score for the prediction of beta-thalassemia severity

“…Third, even if the populations in which these variants were successfully associated represent all the main ethnic groups, not all the populations have been tested and some particular linkage disequilibrium structures might render the model less accurate in untested populations. [7][8][9][10][14][15][16][17][18] However, considering only countries with efficient health systems and screening programs, this retrospective study is a robust tool against mortality-driven bias. In such a context, mortality rates before ten years old are negligible (0 in our cohort), while over 90% of study patients were diagnosed, followed-up and treated before this age.…”

“…3,4 More recently genome-wide association studies contributed to the definition of very important trans-acting modifiers of the production of fetal hemoglobin such as the BCL11A gene and the HBS1L-MYB intergenic region. [5][6][7][8][9][10] Previous studies investigated the contribution of known genetic modifiers to the major-intermedia phenotypic classification demonstrating that a great proportion of this status is effectively genetically determined. 11,12 This condition makes b-thalassemia one of the few diseases with complex phenotype that could be accurately predicted on a genetic basis, opening the path for the clinical application of genetic prediction to many other diseases.…”

Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6

“…More specifically, genome-wide association studies (GWAS) led to the identification of a new HbF-associated locus on chromosome 2, located within the gene BCL11A Thein et al 2007; Lettre et al 2008;Sedgewick et al 2008;So et al 2008;Uda et al 2008;). Subsequently, the gene BCL11A (also known as Evi9, Ctip1), encoding a zinc finger transcription factor, was shown to function as a regulator of HbF expression .…”

Variantes genéticas asociadas con niveles de hemoglobina fetal muestran diversos orígenes étnicos en pacientes colombianos con anemia falciforme

“…The BCL11A locus is represented by SNP rs11886868, where the high-HbF (and protective) allele is 'C' in all populations studied so far (22,(25)(26)(27). In the Colombian samples, the two alleles have a nearly equal frequency (T=0.492 and C=0.508) (table 2).…”