{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T19:00:11Z","timestamp":1776970811781,"version":"3.51.4"},"reference-count":40,"publisher":"Proceedings of the National Academy of Sciences","issue":"5","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,2,5]]},"abstract":"<jats:p>\n            \u03b2-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\n            <jats:italic>BCL11A<\/jats:italic>\n            gene was strongly associated with this trait (\n            <jats:italic>P<\/jats:italic>\n            &lt; 10\n            <jats:sup>\u221235<\/jats:sup>\n            ). The C allele frequency was significantly higher in Sardinian individuals with elevated HbF levels, detected by screening for \u03b2-thalassemia, and patients with attenuated forms of \u03b2-thalassemia vs. those with thalassemia major. We also show that the same\n            <jats:italic>BCL11A<\/jats:italic>\n            variant is strongly associated with HbF levels in a large cohort of sickle cell patients. These results indicate that\n            <jats:italic>BCL11A<\/jats:italic>\n            variants, by modulating HbF levels, act as an important ameliorating factor of the \u03b2-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 \u03b2-thalassemia and sickle cell anemia.\n          <\/jats:p>","DOI":"10.1073\/pnas.0711566105","type":"journal-article","created":{"date-parts":[[2008,2,2]],"date-time":"2008-02-02T02:07:55Z","timestamp":1201918075000},"page":"1620-1625","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":585,"title":["Genome-wide association study shows\n            <i>BCL11A<\/i>\n            associated with persistent fetal hemoglobin and amelioration of the phenotype of \u03b2-thalassemia"],"prefix":"10.1073","volume":"105","author":[{"given":"Manuela","family":"Uda","sequence":"first","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Renzo","family":"Galanello","sequence":"additional","affiliation":[{"name":"Clinica Pediatrica, Ospedale Microcitemico, Via Jenner s\/n 09121 Cagliari, Dipartimento di Scienze Biomediche e Biotecnologie, Universit\u00e0 degli Studi di Cagliari, 09121Cagliari, Italy;"}]},{"given":"Serena","family":"Sanna","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Guillaume","family":"Lettre","sequence":"additional","affiliation":[{"name":"Children's Hospital of Boston, 300 Longwood Avenue, Boston, MA 02115;"},{"name":"Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142;"}]},{"given":"Vijay G.","family":"Sankaran","sequence":"additional","affiliation":[{"name":"Children's Hospital of Boston, 300 Longwood Avenue, Boston, MA 02115;"},{"name":"Department of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115;"}]},{"given":"Weimin","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Statistical Genetics, Department of Biostatistics, University of Michigan, 1420 Washington Heights, Ann Arbor, MI 48109; and"}]},{"given":"Gianluca","family":"Usala","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Fabio","family":"Busonero","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Andrea","family":"Maschio","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Giuseppe","family":"Albai","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Maria Grazia","family":"Piras","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Natascia","family":"Sestu","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Sandra","family":"Lai","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Mariano","family":"Dei","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Antonella","family":"Mulas","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Laura","family":"Crisponi","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Silvia","family":"Naitza","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Isadora","family":"Asunis","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Manila","family":"Deiana","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Ramaiah","family":"Nagaraja","sequence":"additional","affiliation":[{"name":"**Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224"}]},{"given":"Lucia","family":"Perseu","sequence":"additional","affiliation":[{"name":"*Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042;"}]},{"given":"Stefania","family":"Satta","sequence":"additional","affiliation":[{"name":"Clinica Pediatrica, Ospedale Microcitemico, Via Jenner s\/n 09121 Cagliari, Dipartimento di Scienze Biomediche e Biotecnologie, Universit\u00e0 degli Studi di Cagliari, 09121Cagliari, Italy;"}]},{"given":"Maria Dolores","family":"Cipollina","sequence":"additional","affiliation":[{"name":"Clinica Pediatrica, Ospedale Microcitemico, Via Jenner s\/n 09121 Cagliari, Dipartimento di Scienze Biomediche e Biotecnologie, Universit\u00e0 degli Studi di Cagliari, 09121Cagliari, Italy;"}]},{"given":"Carla","family":"Sollaino","sequence":"additional","affiliation":[{"name":"Clinica Pediatrica, Ospedale Microcitemico, Via Jenner s\/n 09121 Cagliari, Dipartimento di Scienze Biomediche e Biotecnologie, Universit\u00e0 degli Studi di Cagliari, 09121Cagliari, Italy;"}]},{"given":"Paolo","family":"Moi","sequence":"additional","affiliation":[{"name":"Clinica Pediatrica, Ospedale Microcitemico, Via Jenner s\/n 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