Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia
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...
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| Published in: | Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 5; p. 1620 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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United States
05.02.2008
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| ISSN: | 1091-6490, 1091-6490 |
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| 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. |
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| AbstractList | 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.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. 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. |
| Author | Sankaran, Vijay G Deiana, Manila Asunis, Isadora Crisponi, Laura Nagaraja, Ramaiah Lai, Sandra Dei, Mariano Orkin, Stuart H Naitza, Silvia Schlessinger, David Hirschhorn, Joel N Sanna, Serena Sollaino, Carla Albai, Giuseppe Busonero, Fabio Sestu, Natascia Satta, Stefania Maschio, Andrea Uda, Manuela Chen, Weimin Cao, Antonio Perseu, Lucia Cipollina, Maria Dolores Piras, Maria Grazia Moi, Paolo Galanello, Renzo Lettre, Guillaume Usala, Gianluca Mulas, Antonella Abecasis, Gonçalo R |
| Author_xml | – sequence: 1 givenname: Manuela surname: Uda fullname: Uda, Manuela organization: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy – sequence: 2 givenname: Renzo surname: Galanello fullname: Galanello, Renzo – sequence: 3 givenname: Serena surname: Sanna fullname: Sanna, Serena – sequence: 4 givenname: Guillaume surname: Lettre fullname: Lettre, Guillaume – sequence: 5 givenname: Vijay G surname: Sankaran fullname: Sankaran, Vijay G – sequence: 6 givenname: Weimin surname: Chen fullname: Chen, Weimin – sequence: 7 givenname: Gianluca surname: Usala fullname: Usala, Gianluca – sequence: 8 givenname: Fabio surname: Busonero fullname: Busonero, Fabio – sequence: 9 givenname: Andrea surname: Maschio fullname: Maschio, Andrea – sequence: 10 givenname: Giuseppe surname: Albai fullname: Albai, Giuseppe – sequence: 11 givenname: Maria Grazia surname: Piras fullname: Piras, Maria Grazia – sequence: 12 givenname: Natascia surname: Sestu fullname: Sestu, Natascia – sequence: 13 givenname: Sandra surname: Lai fullname: Lai, Sandra – sequence: 14 givenname: Mariano surname: Dei fullname: Dei, Mariano – sequence: 15 givenname: Antonella surname: Mulas fullname: Mulas, Antonella – sequence: 16 givenname: Laura surname: Crisponi fullname: Crisponi, Laura – sequence: 17 givenname: Silvia surname: Naitza fullname: Naitza, Silvia – sequence: 18 givenname: Isadora surname: Asunis fullname: Asunis, Isadora – sequence: 19 givenname: Manila surname: Deiana fullname: Deiana, Manila – sequence: 20 givenname: Ramaiah surname: Nagaraja fullname: Nagaraja, Ramaiah – sequence: 21 givenname: Lucia surname: Perseu fullname: Perseu, Lucia – sequence: 22 givenname: Stefania surname: Satta fullname: Satta, Stefania – sequence: 23 givenname: Maria Dolores surname: Cipollina fullname: Cipollina, Maria Dolores – sequence: 24 givenname: Carla surname: Sollaino fullname: Sollaino, Carla – sequence: 25 givenname: Paolo surname: Moi fullname: Moi, Paolo – sequence: 26 givenname: Joel N surname: Hirschhorn fullname: Hirschhorn, Joel N – sequence: 27 givenname: Stuart H surname: Orkin fullname: Orkin, Stuart H – sequence: 28 givenname: Gonçalo R surname: Abecasis fullname: Abecasis, Gonçalo R – sequence: 29 givenname: David surname: Schlessinger fullname: Schlessinger, David – sequence: 30 givenname: Antonio surname: Cao fullname: Cao, Antonio |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/18245381$$D View this record in MEDLINE/PubMed |
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| Snippet | beta-Thalassemia and sickle cell disease both display a great deal of phenotypic heterogeneity, despite being generally thought of as simple Mendelian... |
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| SubjectTerms | Adolescent Adult Aged Aged, 80 and over beta-Thalassemia - diagnosis Carrier Proteins - genetics Cohort Studies Female Fetal Hemoglobin - analysis Fetal Hemoglobin - metabolism Gene Frequency Genetic Linkage Genome, Human Humans Italy Male Middle Aged Nuclear Proteins - genetics Phenotype Polymorphism, Single Nucleotide Repressor Proteins |
| Title | Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia |
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