{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T11:46:32Z","timestamp":1766058392847,"version":"3.48.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Yozgat Bozok University Scientific Research Projects Coordination Unit","award":["6602c-TF\/19-281"],"award-info":[{"award-number":["6602c-TF\/19-281"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med Genomics"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\u03b2-Thalassemia is a hereditary blood disorder with a highly variable clinical presentation that is partly influenced by genetic modifiers that regulate fetal hemoglobin levels. Elevated HbF can ameliorate the clinical symptoms of \u03b2-thalassemia, making the identification of HbF-modifying loci crucial for understanding disease variability and developing potential therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, we evaluated the distribution and effect of known HbF-associated single nucleotide polymorphisms within the\n                      <jats:italic>BCL11A<\/jats:italic>\n                      ,\n                      <jats:italic>HMIP<\/jats:italic>\n                      , and\n                      <jats:italic>XmnI-HBG2<\/jats:italic>\n                      loci in \u03b2-thalassemia patients. Our investigation was initiated by a hypothesis based on genomic data from the K562 cell line, which indicated the presence of a specific\n                      <jats:italic>LRF<\/jats:italic>\n                      \/\n                      <jats:italic>ZBTB7A<\/jats:italic>\n                      variant. In addition, we explored the role of\n                      <jats:italic>LRF<\/jats:italic>\n                      \/\n                      <jats:italic>ZBTB7A<\/jats:italic>\n                      , a transcription factor implicated in globin gene regulation, through Sanger sequencing and in silico analyses. A hypothetical Genetic Modifier Score was devised to quantify the cumulative effect of the five major HbF-associated QTLs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      While we confirmed the previously reported associations of the common SNPs with HbF levels, we also identified novel rare variants in\n                      <jats:italic>LRF<\/jats:italic>\n                      \/\n                      <jats:italic>ZBTB7A<\/jats:italic>\n                      (p.Pro241Leu, p.Asp344Asp, p.Glu277del) that may influence HbF expression.\n                      <jats:italic>XmnI-HBG2<\/jats:italic>\n                      accounted for a small yet significant proportion (7%) of HbF variability. A significant positive correlation was found between the Genetic Modifier Score and HbF levels, yet the model explained only\u2009~\u200914% of the variance, highlighting a substantial role for other modifiers such as the novel\n                      <jats:italic>LRF<\/jats:italic>\n                      \/\n                      <jats:italic>ZBTB7A<\/jats:italic>\n                      variants identified here.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These results suggest\n                      <jats:italic>LRF\/ZBTB7A<\/jats:italic>\n                      is a novel modifier of HbF. The discovery of the variants, against a backdrop of modest QTL effects, underscores its potential and warrants further functional investigation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12920-025-02275-5","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T11:43:42Z","timestamp":1766058222000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel LRF\/ZBTB7A variants and known HbF-modulating SNPs in transfusion-dependent \u03b2-thalassemia"],"prefix":"10.1186","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5585-6795","authenticated-orcid":false,"given":"Yunus","family":"Arikan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3341-9513","authenticated-orcid":false,"given":"Tugba Karaman","family":"Mercan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0490-7828","authenticated-orcid":false,"given":"Merve","family":"Embel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6867-6053","authenticated-orcid":false,"given":"Erdal","family":"Kurtoglu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"key":"2275_CR1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/1750-1172-5-11","volume":"5","author":"R Galanello","year":"2010","unstructured":"Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11.","journal-title":"Orphanet J Rare Dis"},{"key":"2275_CR2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a011643","volume":"3","author":"VG Sankaran","year":"2013","unstructured":"Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med. 2013;3:a011643.","journal-title":"Cold Spring Harb Perspect Med"},{"key":"2275_CR3","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1182\/hematology.2021000313","volume":"2021","author":"AL Langer","year":"2021","unstructured":"Langer AL, Esrick EB. \u03b2-Thalassemia: evolving treatment options beyond transfusion and iron chelation. Hematology. 2021;2021:600\u20136.","journal-title":"Hematology"},{"key":"2275_CR4","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-48204-2","author":"S Mettananda","year":"2019","unstructured":"Mettananda S, Yasara N, Fisher CA, Taylor S, Gibbons R, Higgs D. Synergistic silencing of \u03b1-globin and induction of \u03b3-globin by histone deacetylase inhibitor, Vorinostat as a potential therapy for \u03b2-thalassaemia. Sci Rep. 2019. https:\/\/doi.org\/10.1038\/s41598-019-48204-2.","journal-title":"Sci Rep"},{"key":"2275_CR5","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/j.omtm.2020.03.015","volume":"17","author":"C Brendel","year":"2020","unstructured":"Brendel C, Negre O, Rothe M, et al. Preclinical evaluation of a novel lentiviral vector driving lineage-specific BCL11A knockdown for sickle cell gene therapy. Molecular Therapy - Methods & Clinical Development. 2020;17:589\u2013600.","journal-title":"Molecular Therapy - Methods & Clinical Development"},{"key":"2275_CR6","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1056\/NEJMoa2117175","volume":"386","author":"J Kanter","year":"2022","unstructured":"Kanter J, Walters MC, Krishnamurti L, et al. Biologic and clinical efficacy of lentiglobin for sickle cell disease. N Engl J Med. 2022;386:617\u201328.","journal-title":"N Engl J Med"},{"key":"2275_CR7","doi-asserted-by":"publisher","first-page":"1839","DOI":"10.1126\/science.1165409","volume":"322","author":"VG Sankaran","year":"2008","unstructured":"Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Van Handel B, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008;322:1839\u201342.","journal-title":"Science"},{"key":"2275_CR8","doi-asserted-by":"publisher","first-page":"2845","DOI":"10.1182\/blood-2012-11-292037","volume":"121","author":"A Lunardi","year":"2013","unstructured":"Lunardi A, Guarnerio J, Wang G, Maeda T, Pandolfi PP. Role of LRF\/Pokemon in lineage fate decisions. Blood. 2013;121:2845\u201353.","journal-title":"Blood"},{"key":"2275_CR9","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1126\/science.aad3312","volume":"351","author":"T Masuda","year":"2016","unstructured":"Masuda T, Wang X, Maeda M, et al. Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science. 2016;351:285\u20139.","journal-title":"Science"},{"key":"2275_CR10","doi-asserted-by":"publisher","DOI":"10.3389\/fgeed.2023.1204536","author":"A Finotti","year":"2023","unstructured":"Finotti A, Gambari R. Combined approaches for increasing fetal hemoglobin (HbF) and de novo production of adult hemoglobin (HbA) in erythroid cells from \u03b2-thalassemia patients: treatment with HbF inducers and CRISPR-Cas9 based genome editing. Front Genome Ed. 2023. https:\/\/doi.org\/10.3389\/fgeed.2023.1204536.","journal-title":"Front Genome Ed"},{"key":"2275_CR11","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/j.ymthe.2024.01.023","volume":"32","author":"V Rajendiran","year":"2024","unstructured":"Rajendiran V, Devaraju N, Haddad M, et al. Base editing of key residues in the BCL11A-XL-specific zinc finger domains derepresses fetal globin expression. Mol Ther. 2024;32:663\u201377.","journal-title":"Mol Ther"},{"key":"2275_CR12","doi-asserted-by":"publisher","first-page":"8","DOI":"10.3390\/molecules29010008","volume":"29","author":"C Zuccato","year":"2023","unstructured":"Zuccato C, Cosenza LC, Tupini C, Finotti A, Sacchetti G, Simoni D, et al. New synthetic isoxazole derivatives acting as potent inducers of fetal hemoglobin in erythroid precursor cells isolated from \u03b2-thalassemic patients. Molecules. 2023;29:8.","journal-title":"Molecules"},{"key":"2275_CR13","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1182\/bloodadvances.2017009811","volume":"2","author":"K Gardner","year":"2018","unstructured":"Gardner K, Fulford T, Silver N, et al. G(HbF): a genetic model of fetal hemoglobin in sickle cell disease. Blood Adv. 2018;2:235\u20139.","journal-title":"Blood Adv"},{"key":"2275_CR14","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1038\/ng2108","volume":"39","author":"S Menzel","year":"2007","unstructured":"Menzel S, Garner C, Gut I, et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet. 2007;39:1197\u20139.","journal-title":"Nat Genet"},{"key":"2275_CR15","doi-asserted-by":"publisher","first-page":"198","DOI":"10.3109\/03630269.2016.1160920","volume":"40","author":"E Keyhani","year":"2016","unstructured":"Keyhani E, Jafari Vesiehsari M, Talebi Kakroodi S, Darabi E, Zamani F, Karimlou M, et al. The impact ofXmnI-HBG2, BCL11Aand HBS1L-MYB single nucleotide polymorphisms on hb F variation of hematologically normal Iranian individuals. Hemoglobin. 2016;40:198\u2013201.","journal-title":"Hemoglobin"},{"key":"2275_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-00169-x","author":"P Hariharan","year":"2021","unstructured":"Hariharan P, Gorivale M, Sawant P, Mehta P, Nadkarni A. Significance of genetic modifiers of hemoglobinopathies leading towards precision medicine. Sci Rep. 2021. https:\/\/doi.org\/10.1038\/s41598-021-00169-x.","journal-title":"Sci Rep"},{"key":"2275_CR17","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1182\/blood-2016-01-694331","volume":"127","author":"A Perkins","year":"2016","unstructured":"Perkins A, Xu X, Higgs DR, Patrinos GP, Arnaud L, Bieker JJ, Philipsen S, KLF1 Consensus Workgroup. Kr\u00fcppeling erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants. Blood. 2016;127:1856\u201362.","journal-title":"Blood"},{"key":"2275_CR18","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s10038-019-0690-5","volume":"65","author":"A Ohishi","year":"2020","unstructured":"Ohishi A, Masunaga Y, Iijima S, Yamoto K, Kato F, Fukami M, et al. De novo ZBTB7A variant in a patient with macrocephaly, intellectual disability, and sleep apnea: implications for the phenotypic development in 19p13.3 microdeletions. J Hum Genet. 2020;65:181\u20136.","journal-title":"J Hum Genet"},{"key":"2275_CR19","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1002\/ajmg.a.62492","volume":"188","author":"C Von Der Lippe","year":"2022","unstructured":"Von Der Lippe C, Tveten K, Prescott TE, et al. Heterozygous variants in <Emphasis Type=\"ItalicSmallCaps\">ZBTB7A<\/Emphasis>cause a neurodevelopmental disorder associated with symptomatic overgrowth of pharyngeal lymphoid tissue, macrocephaly, and elevated fetal hemoglobin. Am J Med Genet A. 2022;188:272\u201382.","journal-title":"Am J Med Genet A"},{"key":"2275_CR20","doi-asserted-by":"publisher","DOI":"10.1186\/s40246-018-0177-z","author":"V Chondrou","year":"2018","unstructured":"Chondrou V, Stavrou EF, Markopoulos G, et al. Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea. Hum Genomics. 2018. https:\/\/doi.org\/10.1186\/s40246-018-0177-z.","journal-title":"Hum Genomics"},{"key":"2275_CR21","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.1038\/s41591-022-01906-z","volume":"28","author":"B Fu","year":"2022","unstructured":"Fu B, Liao J, Chen S, et al. CRISPR\u2013Cas9-mediated gene editing of the BCL11A enhancer for pediatric \u03b20\/\u03b20 transfusion-dependent \u03b2-thalassemia. Nat Med. 2022;28:1573\u201380.","journal-title":"Nat Med"},{"key":"2275_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-66309-x","author":"A Lamsfus-Calle","year":"2020","unstructured":"Lamsfus-Calle A, Daniel-Moreno A, Antony JS, et al. Comparative targeting analysis of KLF1, BCL11A, and HBG1\/2 in CD34\u2009+\u2009HSPCs by CRISPR\/Cas9 for the induction of fetal hemoglobin. Sci Rep. 2020. https:\/\/doi.org\/10.1038\/s41598-020-66309-x.","journal-title":"Sci Rep"},{"key":"2275_CR23","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1056\/NEJMoa2215643","volume":"389","author":"A Sharma","year":"2023","unstructured":"Sharma A, Boelens J-J, Cancio M, et al. CRISPR-Cas9 editing of the HBG1 and HBG2 promoters to treat sickle cell disease. N Engl J Med. 2023;389:820\u201332.","journal-title":"N Engl J Med"},{"key":"2275_CR24","doi-asserted-by":"publisher","first-page":"25580","DOI":"10.1038\/s41598-025-10791-8","volume":"15","author":"C Wongborisuth","year":"2025","unstructured":"Wongborisuth C, Innachai P, Saisawang C, et al. Disrupting ZBTB7A or BCL11A binding sites reactivates fetal hemoglobin in erythroblasts from healthy and \u03b20-thalassemia\/HbE individuals. Sci Rep. 2025;15:25580.","journal-title":"Sci Rep"},{"key":"2275_CR25","doi-asserted-by":"publisher","unstructured":"Liu J, Shen Z, Park S-Y et al. Discovery of A small molecule non-IMiD degrader of ZBTB7A for the treatment of \u03b2-hemoglobinopathies.\u00a02025. https:\/\/doi.org\/10.1101\/2025.09.17.676148","DOI":"10.1101\/2025.09.17.676148"}],"container-title":["BMC Medical Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-025-02275-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12920-025-02275-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-025-02275-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T11:43:49Z","timestamp":1766058229000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12920-025-02275-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,18]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2275"],"URL":"https:\/\/doi.org\/10.1186\/s12920-025-02275-5","relation":{},"ISSN":["1755-8794"],"issn-type":[{"value":"1755-8794","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,18]]},"assertion":[{"value":"5 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The local ethical committee (Yozgat Bozok University, Clinical Research Ethical Committee) approved the current prospective study (protocol number: KAEK-189_2019.03.13_12). Written informed consent was given by all participants in accordance with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent was obtained from all participants for the publication of the data included in this study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The authors declare that they have no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"194"}}