{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T18:22:19Z","timestamp":1793730139892,"version":"4.6.1"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"33","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,8,19]]},"abstract":"<jats:p>\n                    Sickle cell disease (SCD) is a debilitating monogenic blood disorder with a highly variable phenotype characterized by severe pain crises, acute clinical events, and early mortality. Interindividual variation in fetal hemoglobin (HbF) expression is a known and potentially heritable modifier of SCD severity. High HbF levels are correlated with reduced morbidity and mortality. Common single nucleotide polymorphisms (SNPs) at the\n                    <jats:italic>BCL11A<\/jats:italic>\n                    and\n                    <jats:italic>HBS1L-MYB<\/jats:italic>\n                    loci have been implicated previously in HbF level variation in nonanemic European populations. We recently demonstrated an association between a\n                    <jats:italic>BCL11A<\/jats:italic>\n                    SNP and HbF levels in one SCD cohort [Uda M,\n                    <jats:italic>et al.<\/jats:italic>\n                    (2008)\n                    <jats:italic>Proc Natl Acad Sci<\/jats:italic>\n                    USA 105:1620\u20131625]. Here, we genotyped additional\n                    <jats:italic>BCL11A<\/jats:italic>\n                    SNPs,\n                    <jats:italic>HBS1L-MYB<\/jats:italic>\n                    SNPs, and an SNP upstream of\n                    <jats:italic>\n                      <jats:sup>G<\/jats:sup>\n                    <\/jats:italic>\n                    \u03b3-\n                    <jats:italic>globin<\/jats:italic>\n                    (\n                    <jats:italic>HBG2<\/jats:italic>\n                    ; the\n                    <jats:italic>Xmn<\/jats:italic>\n                    I polymorphism), in two independent SCD cohorts: the African American Cooperative Study of Sickle Cell Disease (CSSCD) and an SCD cohort from Brazil. We studied the effect of these SNPs on HbF levels and on a measure of SCD-related morbidity (pain crisis rate). We strongly replicated the association between these SNPs and HbF level variation (in the CSSCD,\n                    <jats:italic>P<\/jats:italic>\n                    values range from 0.04 to 2 \u00d7 10\n                    <jats:sup>\u221242<\/jats:sup>\n                    ). Together, common SNPs at the\n                    <jats:italic>BCL11A<\/jats:italic>\n                    ,\n                    <jats:italic>HBS1L-MYB<\/jats:italic>\n                    , and \u03b2-\n                    <jats:italic>globin<\/jats:italic>\n                    (\n                    <jats:italic>HBB<\/jats:italic>\n                    ) loci account for &gt;20% of the variation in HbF levels in SCD patients. We also have shown that HbF-associated SNPs associate with pain crisis rate in SCD patients. These results provide a clear example of inherited common sequence variants modifying the severity of a monogenic disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0804799105","type":"journal-article","created":{"date-parts":[[2008,7,30]],"date-time":"2008-07-30T22:00:34Z","timestamp":1217455234000},"page":"11869-11874","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":508,"title":["DNA polymorphisms at the\n                    <i>BCL11A<\/i>\n                    ,\n                    <i>HBS1L-MYB<\/i>\n                    , and \u03b2-\n                    <i>globin<\/i>\n                    loci associate with fetal hemoglobin levels and pain crises in sickle cell disease"],"prefix":"10.1073","volume":"105","author":[{"given":"Guillaume","family":"Lettre","sequence":"first","affiliation":[{"name":"*Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142;"},{"name":"Divisions of Genetics and Endocrinology and Program in Genomics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay G.","family":"Sankaran","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Children's Hospital Boston, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos Andr\u00e9 C.","family":"Bezerra","sequence":"additional","affiliation":[{"name":"**Funda\u00e7\u00e3o de Hematologia e Hemoterapia de Pernambuco, Hemope, 52011-000 Recife, Brazil;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aderson S.","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"**Funda\u00e7\u00e3o de Hematologia e Hemoterapia de Pernambuco, Hemope, 52011-000 Recife, Brazil;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Uda","sequence":"additional","affiliation":[{"name":"Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c\/o Cittadella Universitaria di Monserrato, Monserrato, 09042 Cagliari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Sanna","sequence":"additional","affiliation":[{"name":"Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c\/o Cittadella Universitaria di Monserrato, Monserrato, 09042 Cagliari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Cao","sequence":"additional","affiliation":[{"name":"Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c\/o Cittadella Universitaria di Monserrato, Monserrato, 09042 Cagliari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Schlessinger","sequence":"additional","affiliation":[{"name":"Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando F.","family":"Costa","sequence":"additional","affiliation":[{"name":"Center of Hemotherapy and Hematology, State University of Campinas, 13083-970 Campinas, Sau Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel N.","family":"Hirschhorn","sequence":"additional","affiliation":[{"name":"*Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142;"},{"name":"Divisions of Genetics and Endocrinology and Program in Genomics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart H.","family":"Orkin","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Children's Hospital Boston, Boston, MA 02115;"},{"name":"Department of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,8,19]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"663","volume-title":"Disease control priorities in developing countries","author":"Weatherall DJ","year":"2006","unstructured":"DJ Weatherall, et al., Inherited disorders of hemoglobin. 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