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Role of HAMP Genetic Variants on Pathophysiology of Iron Deficiency Anemia

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Abstract

Hepcidin is a 25-amino acid peptide hormone produced by hepatocytes and plays a key role in body iron metabolism. Hepcidin deficiency is the cause of iron overload in hereditary hemochromatosis, iron-loading anemia, and its excess is associated with anemia of inflammation, chronic disease and iron deficiency anemia (IDA). The aims of this study was to evaluate HAMP gene mutation, namely IVS2 + 1(–G) (c.148–150 + 1del) and Gly71 Asp (c.212G > A (rs104894696) association with iron status in IDA conditions. Our study participants were 500 IDA patients and 550 age and sex-matched healthy controls. Hepcidin, ferritin and CRP analysis was done by ELISA method while ESR analysis was done according to Wintrobe method. CBC analysis was done by auto-analyzer. Two mutations in the HAMP genes were analysed by PCR RFLP method. Among the IDA patients, 7 were heterozygous for Met50del IVS2 + 1(–G) mutation. Nine IDA patients were heterozygous for G71D G–A mutation and homozygous were not identified in both mutations.Controls were showing heterozygous frequency 1.8 and 2.1% of Met50del IVS2 + 1(–G) and G71D G–A mutations respectively. Mutation of HAMP (Met50del IVS2 + 1(–G) and G71D G–A) were clinically associated with IDA and act as modulator of disease.

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References

  1. Maria AM, Milena C, Rita C, Gabriella S, Susanna B, Antonio C, et al. A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. Haematologica. 2008;93:1473–9.

    Article  Google Scholar 

  2. Hunter HN, Fulton DB, Ganz T, Vogel HJ. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem. 2002;277(40):37597–603.

    Article  CAS  Google Scholar 

  3. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102(3):783–8.

    Article  CAS  Google Scholar 

  4. Kemna EH, Tjalsma H, Willems HL, Swinkels DW. Hepcidin: from discovery to differential diagnosis. Haematologica. 2008;93(1):90–7.

    Article  CAS  Google Scholar 

  5. Bregman DB, Morris D, Koch TA, He A, Goodnough LT. Hepcidin levels predict no responsiveness to oral iron therapy in patients with iron deficiency anemia. Am J Hematol. 2013;88(2):97–101.

    Article  CAS  Google Scholar 

  6. Gardenghi S, Ramos P, Marongiu MF, Melchiori L, Breda L, Guy E, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice. J Clin Invest. 2010;120(12):4466–77.

    Article  CAS  Google Scholar 

  7. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, et al. A new mouse liver specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is over expressed during iron overload. J Biol Chem. 2001;276:7811–9.

    Article  CAS  Google Scholar 

  8. Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci. 2001;98:8780–5.

    Article  CAS  Google Scholar 

  9. Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci. 2002;99:4596–601.

    Article  CAS  Google Scholar 

  10. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110:1037–44.

    Article  CAS  Google Scholar 

  11. Bridle KR, Frazer DM, Wilkins SJ, Dixon JL, Purdie DM, Crawford DH, et al. Disrupted hepcidin regulation in HFE-associated hemochromatosis and the liver as a regulator of body iron homeostasis. Lancet. 2003;361:669–73.

    Article  CAS  Google Scholar 

  12. Gehrke SG, Kulaksiz H, Herrmann T, Riedel HD, Bents K, Veltkamp C, et al. Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron. Blood. 2003;102:371–6.

    Article  CAS  Google Scholar 

  13. Ahmad KA, Ahmann JR, Migas MC, Waheed A, Britton RS, Bacon BR, et al. Decreased liver hepcidin expression in the HFEknockout mouse. Blood Cells Mol Dis. 2002;29:361–6.

    Article  CAS  Google Scholar 

  14. Muckenthaler M, Roy CN, Custodio AO, Miñana B, deGraaf J, Montross LK, et al. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet. 2003;34:102–7.

    Article  CAS  Google Scholar 

  15. Nicolas G, Viatte L, Lou DQ, Bennoun M, Beaumont C, Kahn A, et al. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet. 2003;34:97–101.

    Article  CAS  Google Scholar 

  16. Merryweather-Clarke AT, Cadet E, Bomford A, Capron D, Viprakasit V, Miller A, et al. Digenic inheritance of mutations in HAMP and HFE results in different types of Haemochromatosis. Hum Mol Genet. 2003;12(17):2241–7.

    Article  CAS  Google Scholar 

  17. Shukla P, Julka S, Bhatia E, Shah S, Nagral A, Aggarwal R. HFE, hepcidin and ferroportin gene mutations are not present in Indian patients with primary haemochromatosis. Natl Med J India. 2006;19:20–3.

    PubMed  Google Scholar 

  18. Nemeth E, Ganz T. Regulation of iron metabolism by hepcidin. Annu Rev Nutr. 2006;26:323–42.

    Article  CAS  Google Scholar 

  19. Antonella R, Filomena D, Paolo P, Roberta C, Cox Timothy M, Cazzola Mario, et al. Screening hepcidin for mutations in juvenile hemochromatosis: identification of a new mutation (C70R). Blood. 2004;103:2407–9.

    Article  Google Scholar 

  20. Silvia P, Arturo G, Joaquín C, Celsa Q, Fernando D. Genetic study of the hepcidin gene (HAMP) promoter and functional analysis of the c.–582A > G variant. BMC Genet. 2010;11:110.

    Google Scholar 

  21. Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. Immunoassay for human serum hepcidin. Blood. 2008;112(10):4292–7.

    Article  CAS  Google Scholar 

  22. Pasricha S, McQuilten Z, Westerman M, Keller A, Nemeth E, Ganz T, et al. Serum hepcidin as a diagnostic test of iron deficiency in premenopausal female blood donors. Haematologica. 2011;96(8):1099–105.

    Article  CAS  Google Scholar 

  23. Galesloot TE, Vermeulen SH, Geurts-Moespot AJ, Klaver SM, Kroot JJ, van Tienoven D, Wetzels JF, Kiemeney LA, Sweep FC, den Heijer M, Swinkels DW. Serum hepcidin: reference ranges and biochemical correlates in the general population. Blood. 2011;117(25):e218–25.

    Article  CAS  Google Scholar 

  24. Island ML, Jouanolle AM, Mosser A, Deugnier Y, David V, Brissot P. A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis. Haematologica. 2009;94:720–4.

    Article  CAS  Google Scholar 

  25. Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood. 2009;113(21):5277–86.

    Article  CAS  Google Scholar 

  26. Swinkels DW, Wetzels JF. Hepcidin: a new tool in the management of anaemia in patients withchronic kidney disease? Nephrol Dial Transplant. 2008;23(8):2450–3.

    Article  CAS  Google Scholar 

  27. Nemeth E, Ganz T. The Role of Hepcidin in Iron Metabolism. Acta Haematol. 2009;122:78–86.

    Article  CAS  Google Scholar 

  28. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012;1823(9):1434–43.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Centre for Biotechnology Studies, Awadhesh Pratap Singh University, Rewa, M.P., 486003, India

    S. Pandey, S. K. Pandey & V. Shah

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  1. S. Pandey
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  2. S. K. Pandey
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  3. V. Shah
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Correspondence to S. Pandey.

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Ethical Standards

Study financially supported by Indian Council of Medical Research (ICMR), New Delhi, India—No. 45/4/2014-Hum/BMS.

Ethical Approval

Study was approved by Awadhesh Pratap Singh University Ethics committee. Samples were collected after taken signed consent from patients.

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Pandey, S., Pandey, S.K. & Shah, V. Role of HAMP Genetic Variants on Pathophysiology of Iron Deficiency Anemia. Ind J Clin Biochem 33, 479–482 (2018). https://doi.org/10.1007/s12291-017-0707-9

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  • DOI: https://doi.org/10.1007/s12291-017-0707-9

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