{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T13:45:43Z","timestamp":1787060743371,"version":"build-2736575974"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["#186159"],"award-info":[{"award-number":["#186159"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Canada Research Chair program","award":["R01HL68959"],"award-info":[{"award-number":["R01HL68959"]}]},{"name":"Canada Research Chair program","award":["R01HL079915"],"award-info":[{"award-number":["R01HL079915"]}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sickle cell disease (SCD) is the most common monogenic disease in the world and is caused by mutations in the \u03b2-globin gene (HBB). Notably, SCD is characterized by extreme clinical heterogeneity. Inter-individual variation in fetal hemoglobin (HbF) levels strongly contributes to this patient-to-patient variability, with high HbF levels associated with decreased morbidity and mortality. Genetic association studies have identified and replicated HbF levels-associated variants at three loci: BCL11A, HBS1L-MYB, and HBB. In SCD patients, genetic variation at these three loci accounts for ~\u200950% of HbF heritability. Genome-wide association studies (GWAS) in non-anemic and SCD patients of multiple ancestries have identified 20 new HbF-associated variants. However, these genetic associations have yet to be replicated in independent SCD cohorts. Here, we validated the association between HbF levels and variants at five of these new loci (ASB3, BACH2, PFAS, ZBTB7A, and KLF1) in up to 3740 SCD patients. By combining CRISPR inhibition and single-cell transcriptomics, we also showed that sequences near non-coding genetic variants at BACH2 (rs4707609) and KLF1 (rs2242514, rs10404876) can control the production of the \u03b2-globin genes in erythroid HUDEP-2 cells. Finally, we analyzed whole-exome sequence data from 1354 SCD patients but could not identify rare genetic variants of large effect on HbF levels. Together, our results confirm five new HbF-associated loci that can be functionally studied to develop new strategies to induce HbF expression in SCD patients.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf015","type":"journal-article","created":{"date-parts":[[2025,1,25]],"date-time":"2025-01-25T23:20:06Z","timestamp":1737847206000},"page":"699-710","source":"Crossref","is-referenced-by-count":8,"title":["A replication study of novel fetal hemoglobin-associated genetic variants in sickle cell disease-only cohorts"],"prefix":"10.1093","volume":"34","author":[{"given":"Yann","family":"Ilboudo","sequence":"first","affiliation":[{"name":"Montreal Heart Institute , 5000 B\u00e9langer Street, Montr\u00e9al, Qu\u00e9bec, H1T 1C8 ,","place":["Canada"]},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al , 2900 Boul. \u00c9douard-Montpetit, Montr\u00e9al, Qu\u00e9bec, H3T 1J4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Brosseau","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute , 5000 B\u00e9langer Street, Montr\u00e9al, Qu\u00e9bec, H1T 1C8 ,","place":["Canada"]},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al , 2900 Boul. \u00c9douard-Montpetit, Montr\u00e9al, Qu\u00e9bec, H3T 1J4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken Sin","family":"Lo","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute , 5000 B\u00e9langer Street, Montr\u00e9al, Qu\u00e9bec, H1T 1C8 ,","place":["Canada"]},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al , 2900 Boul. \u00c9douard-Montpetit, Montr\u00e9al, Qu\u00e9bec, H3T 1J4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hicham","family":"Belhaj","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute , 5000 B\u00e9langer Street, Montr\u00e9al, Qu\u00e9bec, H1T 1C8 ,","place":["Canada"]},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al , 2900 Boul. \u00c9douard-Montpetit, Montr\u00e9al, Qu\u00e9bec, H3T 1J4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Moutereau","sequence":"additional","affiliation":[{"name":"Red Blood Cell Laboratory, Department of Biochemistry-Pharmacology, H\u00f4pital Universitaire Henri Mondor, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 Paris Est , IMRB - U955 - \u00c9quipe no 2, Cr\u00e9teil ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwesi","family":"Marshall","sequence":"additional","affiliation":[{"name":"Tropical Metabolism Research Unit (TMRU), Caribbean Institute for Health Research (CAIHR), University of the West Indies , Mona, Kingston 7 ,","place":["Jamaica"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin","family":"Reid","sequence":"additional","affiliation":[{"name":"Graduate Studies and Research, University of the West Indies , Mona, Kingston 7 ,","place":["Jamaica"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah","family":"Kutlar","sequence":"additional","affiliation":[{"name":"Center for Blood Disorders, Augusta University , Augusta, Georgia 30912 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison E","family":"Ashley-Koch","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center , Durham, NC 27707 ,","place":["USA"]},{"name":"Duke Molecular Physiology Institute, Duke University Medical Center , 300 North Duke Street, Durham, NC 27701 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn J","family":"Telen","sequence":"additional","affiliation":[{"name":"Duke Comprehensive Sickle Cell Center and Division of Hematology, Department of Medicine, Duke University , Durham, NC 27710 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Joly","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Fonctionnelle 34445 \u2018Biochimie des Pathologies \u00c9rythrocytaires\u2019, Laboratoire de Biochimie et Biologie Mol\u00e9culaire Grand-Est, Groupement Hospitalier Est , Hospices Civils de Lyon, Bron ,","place":["France"]},{"name":"Laboratoire Inter-Universitaire de Biologie de la Motricit\u00e9 (LIBM) EA7424, Equipe \u2018Biologie Vasculaire et du Globule Rouge\u2019, Universit\u00e9 Claude Bernard Lyon 1, Comit\u00e9 d\u2019Universit\u00e9s et d\u2019\u00c9tablissements (COMUE) , Lyon ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Galact\u00e9ros","sequence":"additional","affiliation":[{"name":"Red Cell Genetic Disease Unit, H\u00f4pital Henri-Mondor, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 Paris Est , IMRB - U955 - \u00c9quipe no 2, Cr\u00e9teil ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Bartolucci","sequence":"additional","affiliation":[{"name":"Red Cell Genetic Disease Unit, H\u00f4pital Henri-Mondor, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 Paris Est , IMRB - U955 - \u00c9quipe no 2, Cr\u00e9teil ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7740-3399","authenticated-orcid":false,"given":"Guillaume","family":"Lettre","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute , 5000 B\u00e9langer Street, Montr\u00e9al, Qu\u00e9bec, H1T 1C8 ,","place":["Canada"]},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al , 2900 Boul. \u00c9douard-Montpetit, Montr\u00e9al, Qu\u00e9bec, H3T 1J4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,1,31]]},"reference":[{"key":"2025040712175556200_ref1","doi-asserted-by":"crossref","first-page":"e585","DOI":"10.1016\/S2352-3026(23)00118-7","article-title":"Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the global burden of disease study 2021","volume":"10","author":"Collaborators, G.B.D.S.C.D","year":"2023","journal-title":"Lancet Haematol"},{"key":"2025040712175556200_ref2","doi-asserted-by":"crossref","first-page":"18010","DOI":"10.1038\/nrdp.2018.10","article-title":"Sickle cell disease","volume":"4","author":"Kato","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"2025040712175556200_ref3","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1111\/bjh.15038","article-title":"Recent progress in understanding and manipulating haemoglobin switching for the haemoglobinopathies","volume":"180","author":"Vinjamur","year":"2018","journal-title":"Br J Haematol"},{"key":"2025040712175556200_ref4","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1097\/00000441-194804000-00008","article-title":"The significance of the paucity of sickle cells in newborn negro infants","volume":"215","author":"Watson","year":"1948","journal-title":"Am J Med Sci"},{"key":"2025040712175556200_ref5","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/ajh.2830060210","article-title":"Sickle cell anemia as a syndrome: a review of diagnostic features","volume":"6","author":"Huisman","year":"1979","journal-title":"Am J Hematol"},{"key":"2025040712175556200_ref6","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJM199107043250103","article-title":"Pain in sickle cell disease. 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