Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia

Abstract

␤-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 ␤-thalassemia, and patients with attenuated forms of ␤-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 ␤-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 ␤-thalassemia and sickle cell anemia.globin gene regulation ͉ polymorphism ͉ sickle cell anemia

Thalassemia 2016: Modern medicine battles an ancient disease

“…More recently, the technique of genome wide association studies (GWAS) has been used to confirm the importance of 2 previously identified loci. One of these is the BCL11A intron 2 polymorphism at chromosome 2p16, and the other is the HBS1L-MYB intergenic polymorphism at chromosome 6q23 [24]. The advantage of genome wide association studies is that it enables pinpointing the specific gene involved more precisely than linkage studies and furthermore, this methodology can potentially reveal associations which were not previously revealed using linkage.…”

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

“…The association of SNP alleles with HbF levels was evaluated by linear regression, with age and sex as covariates. Association was also tested with a joint 'SNP score' (22). Allele frequencies between populations were compared using chi-square test.…”

Fetal hemoglobin chemical inducers for treatment of hemoglobinopathies

“…These observations have been confirmed through the analysis of single nucleotide polymorphisms at the level of the 2p15 locus and F-cell production in a population of Sardinian β-thalassemic patients. Particularly, it was observed that the SNP rs11886868 variant is significantly associated with Hb [39].…”