{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T02:33:06Z","timestamp":1787452386031,"version":"build-2736575974"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2024,2,10]],"date-time":"2024-02-10T00:00:00Z","timestamp":1707523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018645","name":"MRC","doi-asserted-by":"publisher","award":["MR\/T013389\/1"],"award-info":[{"award-number":["MR\/T013389\/1"]}],"id":[{"id":"10.13039\/100018645","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000266","name":"EPSRC","doi-asserted-by":"publisher","award":["EP\/X527920\/1"],"award-info":[{"award-number":["EP\/X527920\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"name":"LIBRA"},{"DOI":"10.13039\/100015544","name":"King's College Hospital Charity","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015544","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome Trust Core","award":["203141\/Z\/16\/Z"],"award-info":[{"award-number":["203141\/Z\/16\/Z"]}]},{"name":"NIHR Oxford BRC"},{"name":"UCL Global Engagement Funds","award":["2016\/17"],"award-info":[{"award-number":["2016\/17"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sickle Pan-Africa Research Consortium Nigeria NEtwork","award":["1U01HL156942\u201301-02"],"award-info":[{"award-number":["1U01HL156942\u201301-02"]}]},{"name":"Wellcome Trust Core","award":["203141\/Z\/16\/Z"],"award-info":[{"award-number":["203141\/Z\/16\/Z"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A, HBS1L-MYB, and Xmn1-HBG2) have been reported, but a considerable hidden heritability remains. We conducted a genome-wide association study for HbF levels in 1006 Nigerian patients with SCD (HbSS\/HbS\u03b20), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients). To dissect association signals at the major loci, we performed stepwise conditional and haplotype association analyses and included public functional annotation datasets. Association signals were detected for BCL11A (lead SNP rs6706648, \u03b2\u00a0=\u2009\u22120.39, P\u00a0=\u20094.96\u2009\u00d7\u200910\u221234) and HBS1L-MYB (lead SNP rs61028892, \u03b2\u00a0=\u20090.73, P\u00a0=\u20091.18\u2009\u00d7\u200910\u22129), whereas the variant allele for Xmn1-HBG2 was found to be very rare. In addition, we detected three putative new trait-associated regions. Genetically, dissecting the two major loci BCL11A and HBS1L-MYB, we defined trait-increasing haplotypes (P\u2009&amp;lt;\u20090.0001) containing so far unidentified causal variants. At BCL11A, in addition to a haplotype harbouring the putative functional variant rs1427407-\u2018T\u2019, we identified a second haplotype, tagged by the rs7565301-\u2018A\u2019 allele, where a yet-to-be-discovered causal DNA variant may reside. Similarly, at HBS1L-MYB, one HbF-increasing haplotype contains the likely functional small indel rs66650371, and a second tagged by rs61028892-\u2018C\u2019 is likely to harbour a presently unknown functional allele. Together, variants at BCL11A and HBS1L-MYB SNPs explained 24.1% of the trait variance. Our findings provide a path for further investigation of the causes of variable fetal haemoglobin persistence in sickle cell disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddae014","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T15:18:32Z","timestamp":1705591112000},"page":"919-929","source":"Crossref","is-referenced-by-count":14,"title":["The genetic dissection of fetal haemoglobin persistence in sickle cell disease in Nigeria"],"prefix":"10.1093","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2774-650X","authenticated-orcid":false,"given":"Oyesola O","family":"Ojewunmi","sequence":"first","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences, King\u2019s College London , 123 Coldharbour Lane, London SE5 9NU , United Kingdom"},{"name":"Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine , Keppel Street, London WC1E 7HT , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Titilope A","family":"Adeyemo","sequence":"additional","affiliation":[{"name":"Department of Haematology and Blood Transfusion , College of Medicine, , P.M.B 12003, Lagos , Nigeria"},{"name":"University of Lagos , College of Medicine, , P.M.B 12003, Lagos , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajoke I","family":"Oyetunji","sequence":"additional","affiliation":[{"name":"Sickle Cell Foundation Nigeria , Ishaga Road, Idi-Araba, P.O. Box 3463, Lagos , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bassey","family":"Inyang","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry , College of Health Sciences, , Mohammed Maccido Road, Airport Road, P.M.B 117, Abuja , Nigeria"},{"name":"University of Abuja , College of Health Sciences, , Mohammed Maccido Road, Airport Road, P.M.B 117, Abuja , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afolashade","family":"Akinrindoye","sequence":"additional","affiliation":[{"name":"Sickle Cell Foundation Nigeria , Ishaga Road, Idi-Araba, P.O. Box 3463, Lagos , Nigeria"},{"name":"School of Science, University of Greenwich , Central Avenue, Chatham Maritime, Kent ME4 4TB , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baraka S","family":"Mkumbe","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Muhimbili University of Health and Allied Sciences , P.O. Box 65001, United Nations Rd, Dar es Salaam , Tanzania"},{"name":"Department of Artificial Intelligence and Innovative Medicine, Tohoku University Graduate School of Medicine , 980-8573, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Gardner","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences, King\u2019s College London , 123 Coldharbour Lane, London SE5 9NU , United Kingdom"},{"name":"Clinical Haematology, Haematology and Oncology Directorate, Guy\u2019s Hospital , Great Maze Pond, London SE1 9RT , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Rooks","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences, King\u2019s College London , 123 Coldharbour Lane, London SE5 9NU , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Brewin","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences, King\u2019s College London , 123 Coldharbour Lane, London SE5 9NU , United Kingdom"},{"name":"Department of Haematological Medicine, King's College Hospital , London SE5 9RS , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamel","family":"Patel","sequence":"additional","affiliation":[{"name":"NIHR BioResource Centre Maudsley , NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) and Institute of Psychiatry, Psychology and Neuroscience (IoPPN), , 16 De Crespigny Park, London SE5 8AB , United Kingdom"},{"name":"King\u2019s College London , NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) and Institute of Psychiatry, Psychology and Neuroscience (IoPPN), , 16 De Crespigny Park, London SE5 8AB , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Hyuck","family":"Lee","sequence":"additional","affiliation":[{"name":"NIHR BioResource Centre Maudsley , NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) and Institute of Psychiatry, Psychology and Neuroscience (IoPPN), , 16 De Crespigny Park, London SE5 8AB , United Kingdom"},{"name":"King\u2019s College London , NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) and Institute of Psychiatry, Psychology and Neuroscience (IoPPN), , 16 De Crespigny Park, London SE5 8AB , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Chung","sequence":"additional","affiliation":[{"name":"NIHR BioResource Centre Maudsley , NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) and Institute of Psychiatry, Psychology and Neuroscience (IoPPN), , 16 De Crespigny Park, London SE5 8AB , United Kingdom"},{"name":"King\u2019s College London , NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) and Institute of Psychiatry, Psychology and Neuroscience (IoPPN), , 16 De Crespigny Park, London SE5 8AB , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5542-6891","authenticated-orcid":false,"given":"Sara","family":"Rashkin","sequence":"additional","affiliation":[{"name":"St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guolian","family":"Kang","sequence":"additional","affiliation":[{"name":"St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reuben","family":"Chianumba","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Sickle Cell Disease Research and Training (CESRTA), University of Abuja , Mohammed Maccido Road, Airport Road, P.M.B 117, Abuja , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Sangeda","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Microbiology, Muhimbili University of Health and Allied Sciences , P.O. Box 65001, Dar es Salaam , Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liberata","family":"Mwita","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Microbiology, Muhimbili University of Health and Allied Sciences , P.O. Box 65001, Dar es Salaam , Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hezekiah","family":"Isa","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Sickle Cell Disease Research and Training (CESRTA), University of Abuja , Mohammed Maccido Road, Airport Road, P.M.B 117, Abuja , Nigeria"},{"name":"Department of Haematology and Blood Transfusion, University of Abuja Teaching Hospital , Gwagwalada, P.M.B. 228, Gwagwalada, FCT Abuja , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uche-Nnebe","family":"Agumadu","sequence":"additional","affiliation":[{"name":"Department of Paediatrics , College of Health Sciences, , Mohammed Maccido Road, Airport Road, P.M.B 117, Abuja , Nigeria"},{"name":"University of Abuja , College of Health Sciences, , Mohammed Maccido Road, Airport Road, P.M.B 117, Abuja , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary","family":"Ekong","sequence":"additional","affiliation":[{"name":"Research Department of Genetics , Evolution and Environment, , Gower Street, London WC1E 6BT , United Kingdom"},{"name":"University College London , Evolution and Environment, , Gower Street, London WC1E 6BT , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1070-8531","authenticated-orcid":false,"given":"Jamilu A","family":"Faruk","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Ahmadu Bello University\/Ahmadu Bello University Teaching Hospital , P.M.B 006, Zaria , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bello Y","family":"Jamoh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ahmadu Bello University\/Ahmadu Bello University Teaching Hospital , P.M.B 006, Zaria , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niyi M","family":"Adebiyi","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Ahmadu Bello University\/Ahmadu Bello University Teaching Hospital , P.M.B 006, Zaria , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail A","family":"Umar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry , Faculty of Life Sciences, , Sokoto Road, Samaru, P.M.B 006, Zaria , Nigeria"},{"name":"Ahmadu Bello University , Faculty of Life Sciences, , Sokoto Road, Samaru, P.M.B 006, Zaria , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulaziz","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Haematology and Blood Transfusion, Ahmadu Bello University , Sokoto Road, Samaru, P.M.B 006, Zaria , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Grace","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine , Radcliffe Department of Medicine, , Roosevelt Drive, Oxford OX37BN , United Kingdom"},{"name":"University of Oxford, Centre for Human Genetics , Radcliffe Department of Medicine, , Roosevelt Drive, Oxford OX37BN , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuj","family":"Goel","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine , Radcliffe Department of Medicine, , Roosevelt Drive, Oxford OX37BN , United Kingdom"},{"name":"University of Oxford, Centre for Human Genetics , Radcliffe Department of Medicine, , Roosevelt Drive, Oxford OX37BN , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baba P D","family":"Inusa","sequence":"additional","affiliation":[{"name":"Evelina London Children\u2019s Hospital, Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust , Westminster Bridge Rd, London SE1 7EH , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Falchi","sequence":"additional","affiliation":[{"name":"Department of Twin Research and Genetic Epidemiology, King\u2019s College London, St Thomas\u2019 Hospital , Westminster Bridge Road, London SE1 7EH , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siana","family":"Nkya","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Muhimbili University of Health and Allied Sciences , P.O. Box 65001, United Nations Rd, Dar es Salaam , Tanzania"},{"name":"Tanzania Human Genetics Organisation, Sickle Cell Centre , 1 Kipalapala Street, Dar es Salaam , Tanzania"},{"name":"Sickle Cell Program, Muhimbili University of Health and Allied Sciences , P.O. Box 65001, United Nations Rd, Dar es Salaam , Tanzania"},{"name":"Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science , P.O. Box 65001, Dar es Salaam , Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Makani","sequence":"additional","affiliation":[{"name":"Sickle Cell Program, Muhimbili University of Health and Allied Sciences , P.O. Box 65001, United Nations Rd, Dar es Salaam , Tanzania"},{"name":"Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science , P.O. Box 65001, Dar es Salaam , Tanzania"},{"name":"Centre for Haematology , Department of Immunology & Inflammation, , , United Kingdom"},{"name":"Imperial College London , Department of Immunology & Inflammation, , , United Kingdom"},{"name":"Commonwealth Building, Hammersmith Campus, Du Cane Rd, London W12 0NN , Department of Immunology & Inflammation, , , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hafsat R","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Ahmadu Bello University\/Ahmadu Bello University Teaching Hospital , P.M.B 006, Zaria , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Obiageli","family":"Nnodu","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Sickle Cell Disease Research and Training (CESRTA), University of Abuja , Mohammed Maccido Road, Airport Road, P.M.B 117, Abuja , Nigeria"},{"name":"Department of Haematology and Blood Transfusion, University of Abuja Teaching Hospital , Gwagwalada, P.M.B. 228, Gwagwalada, FCT Abuja , Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Strouboulis","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences, King\u2019s College London , 123 Coldharbour Lane, London SE5 9NU , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Menzel","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences, King\u2019s College London , 123 Coldharbour Lane, London SE5 9NU , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,2,10]]},"reference":[{"key":"2024050512555231700_ref1","doi-asserted-by":"crossref","first-page":"e723","DOI":"10.1016\/S2352-3026(21)00216-7","article-title":"Child mortality from sickle cell disease in Nigeria: a model-estimated, population-level analysis of data from the 2018 demographic and health survey","volume":"8","author":"Nnodu","year":"2021","journal-title":"Lancet Haematol"},{"key":"2024050512555231700_ref2","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1056\/NEJM199406093302303","article-title":"Mortality in sickle cell disease. Life expectancy and risk factors for early death","volume":"330","author":"Platt","year":"1994","journal-title":"N Engl J Med"},{"key":"2024050512555231700_ref3","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1182\/blood.V95.1.342","article-title":"Genetic influences on F cells and other hematologic variables: a twin heritability study","volume":"95","author":"Garner","year":"2000","journal-title":"Blood"},{"key":"2024050512555231700_ref4","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1002\/ajh.23232","article-title":"Genetic modifiers of sickle cell disease","volume":"87","author":"Steinberg","year":"2012","journal-title":"Am J Hematol"},{"key":"2024050512555231700_ref5","first-page":"428","article-title":"Genetic heterogeneity in heterocellular hereditary persistence of fetal 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