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To study genetic elements that effect HbF expression in the AI haplotype we completed whole genome sequencing in 14 Saudi AI haplotype sickle hemoglobin homozygotes\u2014seven selected for low HbF (8.2%\u2009\u00b1\u20091.3%) and seven selected for high HbF (23.5%\u2009\u00b1\u20092.6%). An intronic single nucleotide polymorphism (SNP) in <jats:italic>ANTXR1,<\/jats:italic> an anthrax toxin receptor (chromosome 2p13), was associated with HbF. These results were replicated in two independent Saudi AI haplotype cohorts of 120 and 139 patients, but not in 76 Saudi Benin haplotype, 894 African origin haplotype and 44 AI haplotype patients of Indian origin, suggesting that this association is effective only in the Saudi AI haplotype background. <jats:italic>ANTXR1<\/jats:italic> variants explained 10% of the HbF variability compared with 8% for <jats:italic>BCL11A<\/jats:italic>. These two genes had independent, additive effects on HbF and together explained about 15% of HbF variability in Saudi AI sickle cell anemia patients. <jats:italic>ANTXR1<\/jats:italic> was expressed at mRNA and protein levels in erythroid progenitors derived from induced pluripotent stem cells (iPSCs) and CD34<jats:sup>+<\/jats:sup> cells. As CD34<jats:sup>+<\/jats:sup> cells matured and their HbF decreased <jats:italic>ANTXR1<\/jats:italic> expression increased; as iPSCs differentiated and their HbF increased, <jats:italic>ANTXR1<\/jats:italic> expression decreased. Along with elements in cis to the HbF genes, <jats:italic>ANTXR1<\/jats:italic> contributes to the variation in HbF in Saudi AI haplotype sickle cell anemia and is the first gene in trans to <jats:italic>HBB<\/jats:italic> that is associated with HbF only in carriers of the Saudi AI haplotype. Am. J. Hematol. 91:1118\u20131122, 2016. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/ajh.24527","type":"journal-article","created":{"date-parts":[[2016,8,8]],"date-time":"2016-08-08T12:51:35Z","timestamp":1470660695000},"page":"1118-1122","source":"Crossref","is-referenced-by-count":16,"title":["A candidate transacting modulator of fetal hemoglobin gene expression in the Arab\u2014Indian haplotype of sickle cell anemia"],"prefix":"10.1002","volume":"91","author":[{"given":"Vinod","family":"Vathipadiekal","sequence":"first","affiliation":[{"name":"Department of Medicine Boston University School of Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Farrell","sequence":"additional","affiliation":[{"name":"Department of Medicine Boston University School of Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Boston University School of Public Health Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather L.","family":"Edward","sequence":"additional","affiliation":[{"name":"Department of Medicine Boston University School of Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Shappell","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Boston University School of Public Health Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.M.","family":"Al\u2010Rubaish","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine College of Medicine, University of Dammam Dammam Kingdom of Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahad","family":"Al\u2010Muhanna","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine College of Medicine, University of Dammam Dammam Kingdom of Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z.","family":"Naserullah","sequence":"additional","affiliation":[{"name":"Al\u2010Omran Scientific Chair for Hematological Diseases King Faisal University Al\u2010Ahsa Kingdom of Saudi Arabia"},{"name":"Department of Pediatrics Maternity and Child Hospital Dammam Kingdom of Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Alsuliman","sequence":"additional","affiliation":[{"name":"Alomran Scientific Chair King Faisal University, King Fahd Hospital Hafof Al\u2010Ahsa Kingdom of Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatem Othman","family":"Qutub","sequence":"additional","affiliation":[{"name":"Alomran Scientific Chair King Faisal University  Al\u2010Ahsa Kingdom of Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Simkin","sequence":"additional","affiliation":[{"name":"Department of Medicine Boston University School of Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay A.","family":"Farrer","sequence":"additional","affiliation":[{"name":"Department of Medicine Boston University School of Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Medicine Boston University School of Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Yuan","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Medicine Boston University School of Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengwen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medicine Boston University School of Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Mostoslavsky","sequence":"additional","affiliation":[{"name":"Department of Medicine Boston University School of Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George J.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Medicine Boston University School of Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep K.","family":"Patra","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Pt. 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