title: A candidate transacting modulator of fetal hemoglobin gene expression in the Arab-Indian haplotype of sickle cell anemia.
abstract: Fetal hemoglobin (HbF) levels are higher in the Arab-Indian (AI) β-globin gene haplotype of sickle cell anemia compared with African-origin haplotypes. 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-seven selected for low HbF (8.2% ± 1.3%) and seven selected for high HbF (23.5% ± 2.6%). An intronic single nucleotide polymorphism (SNP) in ANTXR1, 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. ANTXR1 variants explained 10% of the HbF variability compared with 8% for BCL11A. These two genes had independent, additive effects on HbF and together explained about 15% of HbF variability in Saudi AI sickle cell anemia patients. ANTXR1 was expressed at mRNA and protein levels in erythroid progenitors derived from induced pluripotent stem cells (iPSCs) and CD34+cells. As CD34+cells matured and their HbF decreased ANTXR1 expression increased; as iPSCs differentiated and their HbF increased, ANTXR1 expression decreased. Along with elements in cis to the HbF genes, ANTXR1 contributes to the variation in HbF in Saudi AI haplotype sickle cell anemia and is the first gene in trans to HBB that is associated with HbF only in carriers of the Saudi AI haplotype. Am. J. Hematol. 91:1118-1122, 2016. © 2016 Wiley Periodicals, Inc.
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors: Vinod
authors: V
authors: Vathipadiekal
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors: John J
authors: JJ
authors: Farrell
authors: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
authors: Shuai
authors: S
authors: Wang
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors: Heather L
authors: HL
authors: Edward
authors: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
authors: Heather
authors: H
authors: Shappell
authors: Department of Internal Medicine, College of Medicine, University of Dammam, Dammam, Kingdom of Saudi Arabia.
authors: A M
authors: AM
authors: Al-Rubaish
authors: Department of Internal Medicine, College of Medicine, University of Dammam, Dammam, Kingdom of Saudi Arabia.
authors: Fahad
authors: F
authors: Al-Muhanna
authors: Al-Omran Scientific Chair for Hematological Diseases, King Faisal University, Al-Ahsa, Kingdom of Saudi Arabia.|Department of Pediatrics, Maternity and Child Hospital, Dammam, Kingdom of Saudi Arabia.
authors: Z
authors: Z
authors: Naserullah
authors: Alomran Scientific Chair, King Faisal University, King Fahd Hospital, Hafof, Al-Ahsa, Kingdom of Saudi Arabia.
authors: A
authors: A
authors: Alsuliman
authors: Alomran Scientific Chair, King Faisal University, Al-Ahsa, Kingdom of Saudi Arabia.
authors: Hatem Othman
authors: HO
authors: Qutub
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors: Irene
authors: I
authors: Simkin
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors: Lindsay A
authors: LA
authors: Farrer
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors: Zhihua
authors: Z
authors: Jiang
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors: Hong-Yuan
authors: HY
authors: Luo
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors: Shengwen
authors: S
authors: Huang
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors: Gustavo
authors: G
authors: Mostoslavsky
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors: George J
authors: GJ
authors: Murphy
authors: Department of Biochemistry, Pt. J. N. M. Medical College, Raipur, Chattisgarh, India.
authors: Pradeep K
authors: PK
authors: Patra
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors: David H K
authors: DH
authors: Chui
authors: Sickle Cell Disease Research Center and Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors: Abdulrahman
authors: A
authors: Alsultan
authors: Center for Research and Medical Consultation, University of Dammam, Dammam, Kingdom of Saudi Arabia.
authors: Amein K
authors: AK
authors: Al-Ali
authors: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
authors: Paola
authors: P
authors: Sebastiani
authors: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts. mhsteinb@bu.edu.
authors: Martin H
authors: MH
authors: Steinberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000235:genetics*; D018912:Arabs / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics*; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics; D012097:Repressor Proteins; D044465:White People / Q000235:genetics; D055815:Young Adult; D055544:beta-Globins / Q000235:genetics
chemical_list: C473287:ANTXR1 protein, human; C486563:BCL11A protein, human; D002352:Carrier Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D055544:beta-Globins; D005319:Fetal Hemoglobin