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

Abstract

Increased HbF levels or F-cell (HbF containing erythrocyte) numbers can ameliorate the disease severity of beta-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 beta-thalassemias. In this study, we showed that SNPs in BCL11A were associated with F-cell numbers in Chinese with beta-thalassemia trait, and with HbF levels in Thais with either beta-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.

Figures

Figure 1

Box plots showing the complete distribution of F-cells, expressed as 109 F-cells per liter of blood in log scale, on the y-axis among Chinese adult β-thalassemia heterozygotes, excluding those who were heterozygotes for the β-globin gene promoter nt −28 A>G β+-thalassemia mutation and those who were heterozygous for the C>T polymorphism (rs7482144) at the HBG2 promoter nt −158 bp. AA, AC, and CC represent the SNP genotypes at rs766432. Each rectangle shows the data between the 25th and 75th quartiles, and the bar in each rectangle is the median value for the F-cells in log scale.

Figure 2

Hematological findings of Chinese adult β-thalassemia heterozygotes, with SNP re766432 genotypes of either AA (n=113) or CC (n=12). Subjects who were heterozygotes for the β-globin gene promoter nt −28 A>G β+-thalassemia mutation and those who were heterozygous for the C>T polymorphism (rs7482144) at the HBG2 promoter nt −158 bp were excluded from these anlyses.

Figure 3

Linkage disequilibrium plots incorporating all 6 SNPs presented in Table 1, plus 3 SNPs which were previously reported [6,7]. These plots were generated using HapMap data with the program HaploView 4.0. Each square reports the value of D', with the standard LD color scheme: white D'