{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:05:36Z","timestamp":1787069136027,"version":"build-2736575974"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T00:00:00Z","timestamp":1659571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"FONSEC","award":["SSA\/IMSS\/ISSSTE-272773"],"award-info":[{"award-number":["SSA\/IMSS\/ISSSTE-272773"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hemoglobin S is caused by a nucleotide change in HBB gene (HBB:c.20A&amp;gt;T, p.Glu6Val), is presented in diverse forms: simple carriers (HbSA), homozygotes (HbSS) also known as sickle cell anemia, and compound heterozygotes with other \u03b2-hemoglobinopathies. It is worldwide distributed, in Mexico, is frequently observed in the southern states Guerrero, Oaxaca and Chiapas. Elevated fetal hemoglobin (HbF) is associated with mild phenotype; single-nucleotide variants (SNVs) in modifier genes, such as BCL11A, HBG2, HBBP1 pseudogene and HBS1L-MYB intergenic region, upregulate HbF synthesis. The aim of this study was to identify HbF regulating genetic variants in HbSS and HbSA Mexican subjects. We studied 39 individuals (HbSS\u2009=\u200924, 61%, HbSA\u2009=\u200915, 39%) from Chiapas (67%) and Guerrero (33%), peripheral blood was collected in ethylenediamine tetraacetic acid (EDTA) for molecular and hematological studies, DNA was isolated by salting-out technic and genotyping was performed through allelic discrimination by real time polymerase chain reaction (RT-PCR) using Taqman\u00ae probes for 15 SNV (in BCL11A: rs6706648, rs7557939, rs4671393, rs11886868, rs766432, rs7599488, rs1427407; HBS1L-MYB: rs28384513, rs7776054, rs9399137, rs4895441, rs9402686, rs1320963; HBG2: rs7482144; and HBBP1: rs10128556). The obtained data were analyzed using IMB SPSS v.22.0 software. All minor alleles were observed in frequencies over 0.05, the most frequent was rs9402686 (0.82), while the less frequent was rs101028556 (0.08). In HbSS group, the mean fetal hemoglobin was 11.9\u2009\u00b1\u20095.9% and was significantly elevated in BCL11A rs11886868 wildtype homozygotes and in carriers of HBS1L-MYB intergenic region rs7776054 (p\u2009=\u20090.04 and p\u2009=\u20090.03, respectively). In conclusion, in HbSS Mexican patients, two SNVs were observed related to increased HbF; BCL11A rs11886868 and HBS1L-MYB rs7776054.<\/jats:p>","DOI":"10.1093\/tropej\/fmac073","type":"journal-article","created":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T16:54:37Z","timestamp":1661878477000},"source":"Crossref","is-referenced-by-count":7,"title":["Fetal hemoglobin regulating genetic variants identified in homozygous (HbSS) and heterozygous (HbSA) subjects from South Mexico"],"prefix":"10.1093","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5482-1611","authenticated-orcid":false,"given":"L C","family":"Rizo-de la Torre","sequence":"first","affiliation":[{"name":"Divisi\u00f3n de Medicina Molecular, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS) , Guadalajara, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F J","family":"Borrayo-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Medicina Molecular, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS) , Guadalajara, Jalisco, Mexico"},{"name":"Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara (UDG) , Guadalajara, Jalisco, Mexico"},{"name":"Divisi\u00f3n de Gen\u00e9tica, CIBO, IMSS , Guadalajara, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F J","family":"Perea-D\u00edaz","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Gen\u00e9tica, CIBO, IMSS , Guadalajara, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Aquino","sequence":"additional","affiliation":[{"name":"Departamento de Hematolog\u00eda, Hospital de Especialidades Pedi\u00e1tricas, Secretar\u00eda de Salud , Tuxtla Guti\u00e9rrez, Chiapas, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Venegas","sequence":"additional","affiliation":[{"name":"Departamento de Hematolog\u00eda, Hospital Regional, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado , Acapulco, Guerrero, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Hern\u00e1ndez-Carbajal","sequence":"additional","affiliation":[{"name":"Departamento de Hematolog\u00eda, Hospital General Regional No. 1, IMSS , Acapulco, Guerrero, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L L","family":"Espinoza-Mata","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Medicina Molecular, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS) , Guadalajara, Jalisco, Mexico"},{"name":"Divisi\u00f3n de Gen\u00e9tica, CIBO, IMSS , Guadalajara, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B","family":"Ibarra-Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica Humana \u201cDr. Enrique Corona Rivera\u201d CUCS, UDG , Guadalajara, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,21]]},"reference":[{"key":"2022092120555687500_fmac073-B1","doi-asserted-by":"crossref","first-page":"3782","DOI":"10.3390\/jcm9113782","article-title":"Fetal hemoglobin in sickle hemoglobinopathies: high HbF genotypes and phenotypes","volume":"9","author":"Steinberg","year":"2020","journal-title":"JCM"},{"key":"2022092120555687500_fmac073-B2","doi-asserted-by":"crossref","first-page":"237","DOI":"10.5144\/0256-4947.1994.237","article-title":"The geography of sickle cell disease: opportunities for understanding its diversity","volume":"14","author":"Serjeant","year":"1994","journal-title":"Ann Saudi Med"},{"key":"2022092120555687500_fmac073-B3","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1056\/NEJMra1510865","article-title":"Sickle cell disease","volume":"376","author":"Piel","year":"2017","journal-title":"N Engl J Med"},{"key":"2022092120555687500_fmac073-B4","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1056\/NEJMoa1813598","article-title":"Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa","volume":"380","author":"Tshilolo","year":"2019","journal-title":"N Engl J Med"},{"key":"2022092120555687500_fmac073-B5","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1006\/bcmd.2002.0498","article-title":"Analysis of betas and beta genes in a Mexican population with African roots","volume":"28","author":"Maga\u00f1a","year":"2002","journal-title":"Blood Cells Mol Dis"},{"key":"2022092120555687500_fmac073-B6","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1146\/annurev-pathmechdis-012418-012838","article-title":"Pathophysiology of sickle cell disease","volume":"14","author":"Sundd","year":"2019","journal-title":"Annu Rev Pathol"},{"key":"2022092120555687500_fmac073-B7","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/bjh.15021","article-title":"Fetal haemoglobin induction in sickle cell disease","volume":"180","author":"Paikari","year":"2018","journal-title":"Br J Haematol"},{"key":"2022092120555687500_fmac073-B8","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.bcmd.2017.06.001","article-title":"Molecular basis of \u03b2 thalassemia and potential therapeutic targets","volume":"70","author":"Thein","year":"2018","journal-title":"Blood Cells Mol Dis"},{"key":"2022092120555687500_fmac073-B9","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1126\/science.1165409","article-title":"Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A","volume":"322","author":"Sankaran","year":"2008","journal-title":"Science"},{"key":"2022092120555687500_fmac073-B10","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1101\/gad.1897310","article-title":"Transcriptional silencing of \u03b3-globin by BCL11A involves long-range interactions and cooperation with SOX6","volume":"24","author":"Xu","year":"2010","journal-title":"Genes Dev"},{"key":"2022092120555687500_fmac073-B11","doi-asserted-by":"crossref","first-page":"R99","DOI":"10.1093\/hmg\/ddw170","article-title":"Hemoglobin genetics: recent contributions of GWAS and gene editing","volume":"25","author":"Smith","year":"2016","journal-title":"Hum Mol Genet"},{"key":"2022092120555687500_fmac073-B12","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1007\/s00277-020-04079-2","article-title":"Functional polymorphisms of BCL11A and HBS1L-MYB genes affect both fetal hemoglobin level and clinical outcomes in cohort of children with sickle cell anemia","volume":"99","author":"Sales","year":"2020","journal-title":"Ann Hematol"},{"key":"2022092120555687500_fmac073-B13","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1038\/ng.3307","article-title":"Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels","volume":"47","author":"Danjou","year":"2015","journal-title":"Nat Genet"},{"key":"2022092120555687500_fmac073-B14","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1093\/clinchem\/45.7.969","article-title":"Evaluation of cation-exchange HPLC compared with isoelectric focusing for neonatal hemoglobinopathy screening","volume":"45","author":"Campbell","year":"1999","journal-title":"Clin Chem"},{"key":"2022092120555687500_fmac073-B15","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","article-title":"A simple salting out procedure for extracting DNA from human nucleated cells","volume":"16","author":"Miller","year":"1988","journal-title":"Nucleic Acids Res"},{"key":"2022092120555687500_fmac073-B16","doi-asserted-by":"crossref","first-page":"27","DOI":"10.5455\/medarh.2021.75.27-30","article-title":"Sickle cell disease in Jordan: the experience of a major referral center","volume":"75","author":"Oudat","year":"2021","journal-title":"Med Arch"},{"key":"2022092120555687500_fmac073-B17","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1002\/ajh.22221","article-title":"Fetal hemoglobin in sickle cell anemia: molecular characterization of the unusually high fetal hemoglobin phenotype in African Americans","volume":"87","author":"Akinsheye","year":"2012","journal-title":"Am J Hematol"},{"key":"2022092120555687500_fmac073-B18","doi-asserted-by":"crossref","first-page":"567","DOI":"10.3390\/jpm11060567","article-title":"Unique polymorphisms at BCL11A, HBS1L-MYB and HBB loci associated with HbF in Kuwaiti patients with sickle cell disease","volume":"11","author":"Akbulut-Jeradi","year":"2021","journal-title":"JPM"},{"key":"2022092120555687500_fmac073-B19","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1038\/ng2108","article-title":"A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15","volume":"39","author":"Menzel","year":"2007","journal-title":"Nat Genet"},{"key":"2022092120555687500_fmac073-B20","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s40291-018-0370-8","article-title":"Genetic modifiers of fetal haemoglobin in sickle cell disease","volume":"23","author":"Menzel","year":"2019","journal-title":"Mol Diagn Ther"},{"key":"2022092120555687500_fmac073-B21","doi-asserted-by":"crossref","first-page":"20906","DOI":"10.1038\/s41598-021-00169-x","article-title":"Significance of genetic modifiers of hemoglobinopathies leading towards precision medicine","volume":"11","author":"Hariharan","year":"2021","journal-title":"Sci Rep"},{"key":"2022092120555687500_fmac073-B22","doi-asserted-by":"crossref","first-page":"e92506","DOI":"10.1371\/journal.pone.0092506","article-title":"Association of variants at BCL11A and HBS1L-MYB with hemoglobin F and hospitalization rates among sickle cell patients in Cameroon","volume":"9","author":"Wonkam","year":"2014","journal-title":"PLoS One"},{"key":"2022092120555687500_fmac073-B23","doi-asserted-by":"crossref","first-page":"156","DOI":"10.3109\/03630269.2015.1023897","article-title":"Genetic modifiers of sickle cell disease: a genotype-phenotype relationship study in a cohort of 82 children on Mayotte Island","volume":"39","author":"Muszlak","year":"2015","journal-title":"Hemoglobin"},{"key":"2022092120555687500_fmac073-B24","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1080\/10245332.2015.1107275","article-title":"rs11886868 and rs4671393 of BCL11A associated with HbF level variation and modulate clinical events among sickle cell anemia patients","volume":"21","author":"Chaouch","year":"2016","journal-title":"Hematology"},{"key":"2022092120555687500_fmac073-B25","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1172\/JCI71520","article-title":"HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers","volume":"124","author":"Stadhouders","year":"2014","journal-title":"J Clin Invest"},{"key":"2022092120555687500_fmac073-B26","doi-asserted-by":"crossref","first-page":"11869","DOI":"10.1073\/pnas.0804799105","article-title":"DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease","volume":"105","author":"Lettre","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022092120555687500_fmac073-B27","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1080\/03630269.2016.1253586","article-title":"Genetic variants at BCL11A and HBS1L-MYB loci influence Hb F levels in Chinese Zhuang \u03b2-Thalassemia intermedia patients","volume":"40","author":"Lai","year":"2016","journal-title":"Hemoglobin"},{"key":"2022092120555687500_fmac073-B28","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.bcmd.2015.01.001","article-title":"BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia","volume":"54","author":"Sebastiani","year":"2015","journal-title":"Blood Cells Mol Dis"},{"key":"2022092120555687500_fmac073-B29","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1177\/1535370216642047","article-title":"Original Research: A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease","volume":"241","author":"Liu","year":"2016","journal-title":"Exp Biol Med (Maywood)"},{"key":"2022092120555687500_fmac073-B30","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1080\/03630269.2020.1787178","article-title":"The effect of five single nucleotide polymorphisms on Hb F variation of \u03b2-thalassemia traits and hematologically normal individuals in Southeast Turkey","volume":"44","author":"Genc","year":"2020","journal-title":"Hemoglobin"},{"key":"2022092120555687500_fmac073-B31","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/jhg.2011.12","article-title":"Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients","volume":"56","author":"Bhatnagar","year":"2011","journal-title":"J Hum Genet"},{"key":"2022092120555687500_fmac073-B32","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1038\/ng.707","article-title":"Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation","volume":"42","author":"Galarneau","year":"2010","journal-title":"Nat Genet"},{"key":"2022092120555687500_fmac073-B33","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1080\/03630269.2020.1753766","article-title":"Multi-locus models to address Hb F variability in Portuguese \u03b2-thalassemia carriers","volume":"44","author":"Manco","year":"2020","journal-title":"Hemoglobin"},{"key":"2022092120555687500_fmac073-B34","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s12288-020-01270-3","article-title":"Detection of BCL11A and HBS1L-MYB genotypes in sickle cell anemia","volume":"36","author":"Qadah","year":"2020","journal-title":"Indian J Hematol Blood Transfus"},{"key":"2022092120555687500_fmac073-B35","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12881-015-0148-3","article-title":"Genetic association of fetal-hemoglobin levels in individuals with sickle cell disease in Tanzania maps to conserved regulatory elements within the MYB core enhancer","volume":"16","author":"Mtatiro","year":"2015","journal-title":"BMC Med Genet"},{"key":"2022092120555687500_fmac073-B36","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1136\/jmg.2008.060335","article-title":"The HBS1L-MYB intergenic region on chromosome 6q23 is a quantitative trait locus controlling fetal haemoglobin level in carriers of beta-thalassaemia","volume":"45","author":"So","year":"2008","journal-title":"J Med Genet"}],"container-title":["Journal of Tropical Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/tropej\/article-pdf\/68\/5\/fmac073\/45961513\/fmac073.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/tropej\/article-pdf\/68\/5\/fmac073\/45961513\/fmac073.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T17:21:47Z","timestamp":1663780907000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/tropej\/article\/doi\/10.1093\/tropej\/fmac073\/6709334"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,4]]},"references-count":36,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022,8,4]]}},"URL":"https:\/\/doi.org\/10.1093\/tropej\/fmac073","relation":{},"ISSN":["1465-3664"],"issn-type":[{"value":"1465-3664","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,10,1]]},"published":{"date-parts":[[2022,8,4]]},"article-number":"fmac073"}}