Keywords
iron metabolism disorders
C282Y
H63D
S65C
How to Cite
Abstract
Introduction: The HFE protein, encoded by the HFE gene, participates in iron homeostasis regulation.
Three allelic variants of the HFE gene have been correlated with hereditary hemochromatosis: C282Y, H63D and S65C. Objectives: The purpose of this study was to establish the prevalence of the most frequent mutations in the HFE gene in an apparently healthy population of northwestern Argentina, and to study its relationship with iron metabolism. Materials and Methods: Sixty-nine individuals (48 women and 21 men) were analyzed during the period September 2015-August 2018 in Tucumán, Argentina.
Total blood count and iron parameters were measured. Mutations in the HFE gene were determined by real-time PCR. Results: The prevalence was 28% (19/69; CI95%= 18-39%). Nine percent (9%, 6/69) had a heterozygous C282Y mutation, and 19% showed an H63D mutation (13/69; 11 heterozygous and 2 homozygous). The S65C mutation was not detected. Red blood cell parameters and iron analysis were higher in wild-type men than in wild-type women (p<0.05). No significant differences in iron metabolism were found between healthy volunteers and C282Y and H63D carriers (p>0.05). Conclusions: This is the first study to show the frequency of the three hemochromatosis gene variants in the northwest region of Argentina, and to determine that the H63D mutation was the most prevalent. This HFE mutation did not result in significant biochemical iron overload.
References
Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annu Rev Med 2011; 62:347-60.
Silva B, Faustino P. An overview of molecular basis of iron metabolism regulation and the associated pathologies. Biochim Biophys Acta 2015;1852(7):1347-59.
Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13(4):399-408.
Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab 2009;9(3):217-27.
Barton JC, Edwards CQ, Acton RT. HFE gene: Structure, function, mutations, and associated iron abnormalities. Gene 2015;574(2):179-92.
Feder JN, Penny DM, Irrinki A, Lee VK, Lebrón JA, Watson N, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U S A 1998;95(4):1472-7.
Wu XG, Wang Y, Wu Q, Cheng WH, Liu W, Zhao Y, et al. HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression. Blood 2014;124(8):1335-43.
Hollerer I, Bachmann A, Muckenthaler MU. Pathophysiological consequences and benefits of HFE mutations: 20 years of research. Haematologica 2017;102(5):809-17.
Distante S, Robson KJ, Graham-Campbell J, Arnaiz-Villena A, Brissot P, Worwood M. The origin and spread of the HFE-C282Y haemochromatosis mutation. Hum Genet 2004;115(4):269-79.
Heath KM, Axton JH, McCullough JM, Harris N. The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic. Am J Phys Anthropol 2016;160(1):86-101.
Lucotte G. Frequency analysis and allele map in favor of the celtic origin of the C282Y mutation of hemochromatosis. Blood Cells Mol Dis 2001;27(2):549-56.
Rochette J, Pointon JJ, Fisher CA, Perera G, Arambepola M, Arichchi DS, et al. Multicentric origin of hemochromatosis gene (HFE) mutations. Am J Hum Genet 1999;64(4):1056-62.
Pietrangelo A. Genetics, genetic testing, and management of hemochromatosis: 15 years since hepcidin. Gastroenterology 2015;149(5):1240-51.
Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, et al. Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005;352(17):1769-78.
Soria NW, Cossy Isasi S, Chaig MR, Gerez de Burgos NM. Analysis of C282Y and H63D mutations of the hemochromatosis gene (HFE) in blood donors from Córdoba, Argentina. Ann Hematol 2009;88(1):77-9.
Parellada ME, Cervera M, Lazarte S, Issé B, Mónaco ME. Optimización de una técnica de PCR en tiempo real para la detección de mutaciones en el gen HFE. J Basic Applied Genetics 2014;XXV Suppl.(1):143.
Adams PC. Epidemiology and diagnostic testing for hemochromatosis and iron overload. Int J Lab Hematol 2015;37 Suppl 1:25-30.
Felipoff AL, Fleischman SJ, Donadío ML, Sebastiano V, Castro M, Vellicce A, et al. [Iron intake and HFE gen in male adults from Buenos Aires]. Medicina (Buenos Aires) 2017;77(6):458-64.
Kaczorowska-Hac B, Luszczyk M, Antosiewicz J, Ziolkowski W, Adamkiewicz-Drozynska E, Mysliwiec M, et al. HFE gene mutations and iron status in 100 healthy polish children. J Pediatr Hematol Oncol 2017;39(5):e240-3.
Alves LN, Santos EV, Stur E, Silva Conforti AM, Louro ID. Molecular epidemiology of HFE gene polymorphic variants (C282Y, H63D and S65C) in the population of Espírito Santo, Brazil. Genet Mol Res 2016;15(2): gmr.15028189.
Aranda N, Viteri FE, Montserrat C, Arija V. Effects of C282Y, H63D, and S65C HFE gene mutations, diet, and life-style factors on iron status in a general Mediterranean population from Tarragona, Spain. Ann Hematol 2010;89(8):767-73.
Adams PC, McLaren CE, Speechley M, McLaren GD, Barton JC, Eckfeldt JH. HFE mutations in Caucasian participants of the Hemochromatosis and Iron Overload Screening study with serum ferritin level <1000 μg/L. Can J Gastroenterol 2013;27(7):390-2.
Ropero P, Briceño O, Mateo M, Polo M, Mora A, González FA, et al. Frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in a cohort of 1,000 neonates in Madrid (Spain). Ann Hematol 2006;85(5):323-6.
Contreras Pérez F. Recluta masiva de emigrantes andaluces y su inserción social en Argentina (siglo XIX). Nuevas notas para su estudio. En: Anuario de Estudios Americanos. Tomo LIII. Sevilla, España: Universidad de Sevilla.1996. p.173-97.
La Gaceta. Hay 4.370 ciudadanos italianos en Tucumán en la actualidad. 2010. Disponible en: http://www.lagaceta.com.ar/nota/381975/actualidad/hay-4370-ciudadanos-italianos-tucuman-actualidad.html?origen=notarel. Consultado el 14/03/22.
Calvo CL, Palacios de Cosiansi L, Naessens SF. Inmigración árabe “otomana” en la provincia de Tucumán, Argentina. 2013. http://paginasarabes.com/2013/05/11/inmigracion-arabe-otomana-en-la-provincia-de-tucuman-argentina/. Consultado el 14/03/22.
Floreani A, Rosa Rizzotto E, Basso D, Navaglia F, Zaninotto M, Petridis I, et al. An open population screening study for HFE gene major mutations proves the low prevalence of C282Y mutation in Central Italy. Aliment Pharmacol Ther 2007;26(4):577-86.
Mahfouz RA, Sarieddine DS, Charafeddine KM, Abdul Khalik RN, Cortas NK, Daher RT. Should we screen for hereditary hemochromatosis in healthy Lebanese: a pilot study. Mol Biol Rep 2012;39(1):753-9.
Worwood M. Iron deficiency anaemia and iron overload. In: Meloni D, Oberle
K, Saltzberg D, editors. Dacie and Lewis Practical Haematology. 10TH ed. Philadelphia: Churchil Livingstone Elsevier; 2006. p.131-60.
Jackson HA, Carter K, Darke C, Guttridge MG, Ravine D, Hutton RD, et al. HFE mutations, iron deficiency and overload in 10,500 blood donors. Br J Haematol 2001;114(2):474-84.
Barton JC, Barton JC, Acton RT. White blood cells and subtypes in HFE p.C282Y and wild-type homozygotes in the hemochromatosis and iron overload screening study. Blood Cells Mol Dis 2017;63:9-14.