Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia.
نویسندگان
چکیده
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.
منابع مشابه
Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of -thalassemia
Manuela Uda*, Renzo Galanello†, Serena Sanna*, Guillaume Lettre‡§, Vijay G. Sankaran‡¶, Weimin Chen , Gianluca Usala*, Fabio Busonero*, Andrea Maschio*, Giuseppe Albai*, Maria Grazia Piras*, Natascia Sestu*, Sandra Lai*, Mariano Dei*, Antonella Mulas*, Laura Crisponi*, Silvia Naitza*, Isadora Asunis*, Manila Deiana*, Ramaiah Nagaraja**, Lucia Perseu*, Stefania Satta†, Maria Dolores Cipollina†, ...
متن کاملبررسی ارتباط پلی‌مورفیسم ژن BCL11A با میزان بیان ژن گاما گلوبین و مقدار هموگلوبین F در افراد مبتلا به بیماری بتا تالاسمی اینترمدیا در جمعیت اصفهان
Background: A Thalassemia intermedium is an autosomal recessive disease that from clinical and also genotypic view contains a very heterogeneous group of hemoglobinopathies and severity of disease is placed between thalassemia major and minor. High levels of fetal hemoglobin have a major impact on the severity of this disease, so that increased production of HbF, reduces these veritie...
متن کاملA genetic score for the prediction of beta-thalassemia severity.
Clinical and hematologic characteristics of beta(β)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and fetal hemoglobin production modulators (HBG2:g.-158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A). We characterized 54 genetic variants at these five loci robustly associated with the a...
متن کاملControl of fetal hemoglobin: new insights emerging from genomics and clinical implications.
Increased levels of fetal hemoglobin (HbF, alpha(2)gamma(2)) are of no consequence in healthy adults, but confer major clinical benefits in patients with sickle cell anemia (SCA) and beta thalassemia, diseases that represent major public health problems. Inter-individual HbF variation is largely genetically controlled, with one extreme caused by mutations involving the beta globin gene (HBB) co...
متن کاملHuman fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A.
Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here, we examine BCL11A as a potential regulator of HbF expression. The high-HbF BCL11A genotype is associated with reduced BCL11...
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ورودعنوان ژورنال:
- Proceedings of the National Academy of Sciences of the United States of America
دوره 105 5 شماره
صفحات -
تاریخ انتشار 2008