Annals of Hematology

, 88:341 | Cite as

Does the SLC40A1 gene modify HFE-related haemochromatosis phenotypes?

  • Albert Altès
  • Vanessa Bach
  • Angels Ruiz
  • Anna Esteve
  • Angel F. Remacha
  • M. Pilar Sardà
  • Jordi Felez
  • Montserrat Baiget
Original Article

Abstract

Most hereditary haemochromatosis patients are homozygous for the C282Y mutation of the HFE gene. However, the phenotypic expression and clinical aggressiveness of the disease differs considerably from patient to patient. The main objective of this work was to study the role of variants in the SLC40A1 gene in the severity of iron overload and his clinical consequences in 100 Spanish probands homozygous for the C282Y mutation of the HFE gene. We performed automated sequencing of the coding regions, including intron–exon junctions of the SLC40A1 gene. We studied the association between polymorphisms in the SLC40A1 gene and median values of iron removed, taking into account statistical corrections for multiple comparisons. No pathogenic mutations in the SLC40A1 were detected. Five known single nucleotide polymorphisms (SNPs) were identified, and two of them were associated with phenotypic characteristics. IVS1-24 C>G was associated with the amount of iron removed and presence of liver disease: Of the 83 patients finally studied for this SNP, the amount of iron removed was above the median in 36 of 56 (64.3%) for C/C, in nine of 23(39.1%) for C/G and in zero of four (0%) for G/G patients (P = 0.01). Liver damage was observed in 34 of 56 patients (60.7%) for C/C, in eight of 23 (34.8%) for C/G and in zero of four (0%) for G/G (P = 0.01). Both associations remained significant at multivariate analysis (P = 0.011 and P = 0.023, respectively). IVS1-24 C>G on the ferroportin gene seems to be a genetic modifier for clinical aggressiveness of HFE1 haemochromatosis.

Keywords

SLC 40A1 Ferroportin Haemochromatosis Genetic penetrance Iron metabolism 

References

  1. 1.
    Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators et al (2005) Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 352:1769–1778 doi:10.1056/NEJMoa041534 PubMedCrossRefGoogle Scholar
  2. 2.
    Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ et al (2008) Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 358:221–230 doi:10.1056/NEJMoa073286 PubMedCrossRefGoogle Scholar
  3. 3.
    Altes A, Ruiz A, Barceló MJ, Remacha AF, Puig T, Maya AJ et al (2004) Prevalence of C282Y, H63D and S65C mutations of HFE gene in 1146 newborns from a region of Northern Spain. Genet Test 8:407–410 doi:10.1089/gte.2004.8.407 PubMedCrossRefGoogle Scholar
  4. 4.
    Altes A, Ruiz A, Martinez C, Esteve A, Vela MD, Remacha AF et al (2007) The relationship between iron overload and clinical characteristics in a Spanish cohort of 100 C282Y homozygous hemochromatosis patients. Ann Hematol 86:831–835 doi:10.1007/s00277-007-0336-0 PubMedCrossRefGoogle Scholar
  5. 5.
    Asberg A, Hveem K, Thorstensen K, Ellekjter E, Kannelønning K, Fjøsne U et al (2001) Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons. Scand J Gastroenterol 36:1108–1115 doi:10.1080/003655201750422747 PubMedCrossRefGoogle Scholar
  6. 6.
    Barry M, Sherlock SA (1971) Measurements of liver-iron concentration in needle-biopsy specimens. Lancet 1:100–103 doi:10.1016/S0140-6736(71)90838-5 PubMedCrossRefGoogle Scholar
  7. 7.
    Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T (2002) Penetrance of 845-A (C282Y) HFE hereditary haemochromatosis mutations in USA. Lancet 359:211–218 doi:10.1016/S0140-6736(02)07447-0 PubMedCrossRefGoogle Scholar
  8. 8.
    Beutler E, Beutler L, Lee PL, Barton JC (2004) The mitochondrial nt 16189 polymorphism and hereditary hemochromatosis. Blood Cells Mol Dis 33:344–345 doi:10.1016/j.bcmd.2004.06.006 PubMedCrossRefGoogle Scholar
  9. 9.
    Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M et al (2000) The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 25:14–15 doi:10.1038/75534 PubMedCrossRefGoogle Scholar
  10. 10.
    De Domenico I, Ward DM, Kaplan J (2007) Hepcidin regulation: ironing out the details. J Clin Invest 117:1755–1758 doi:10.1172/JCI32701 PubMedCrossRefGoogle Scholar
  11. 11.
    De Domenico I, Ward DM, Langelier C, Vaughn MB, Nemeth E, Sundquist WI et al (2007) The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell 18:2569–2578 doi:10.1091/mbc.E07-01-0060 PubMedCrossRefGoogle Scholar
  12. 12.
    Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A et al (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399–408 doi:10.1038/ng0896-399 PubMedCrossRefGoogle Scholar
  13. 13.
    Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C (2004) HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood 103:2835–2840 doi:10.1182/blood-2003-10-3366 PubMedCrossRefGoogle Scholar
  14. 14.
    Le Gac G, Scotet V, Ka C, Gourlaouen I, Bryckaert L, Jacolot S et al (2004) The recently identified type 2A juvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. Hum Mol Genet 13:1913–1918 doi:10.1093/hmg/ddh206 PubMedCrossRefGoogle Scholar
  15. 15.
    Le Gac G, Férec C (2005) The molecular genetics of haemochromatosis. Eur J Hum Genet 13:1172–1185 doi:10.1038/sj.ejhg.5201490 PubMedCrossRefGoogle Scholar
  16. 16.
    Lee PL, Gelbart T, West C, Halloran C, Felitti V, Beutler E (2001) A study of genes that may modulate the expression of hereditary hemochromatosis: transferrin receptor-1, ferroportin, ceruloplasmin, ferritin light and heavy chains, iron regulatory proteins (IRP)-1 and -2, and hepcidin. Blood Cells Mol Dis 27:783–802 doi:10.1006/bcmd.2001.0445 PubMedCrossRefGoogle Scholar
  17. 17.
    Livesey KJ, Wimhurst VL, Carter K, Worwood M, Cadet E, Rochette J et al (2004) The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading. J Med Genet 41:6–10 doi:10.1136/jmg.2003.008805 PubMedCrossRefGoogle Scholar
  18. 18.
    Merryweather-Clarke A, Pointon JJ, Shearman JD, Robson KJH (1997) Global prevalence of putative haemochromatosis mutations. J Med Genet 34:275–278PubMedCrossRefGoogle Scholar
  19. 19.
    Merryweather-Clarke AT, Cadet E, Bomford A, Capron D, Viprakasit V, Miller A et al (2003) Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum Mol Genet 12:2241–2247 doi:10.1093/hmg/ddg225 PubMedCrossRefGoogle Scholar
  20. 20.
    Milet J, Dehais V, Bourgain C, Jouanolle AM, Mosser A, Perrin M et al (2007) Common Variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance. Am J Hum Genet 81:799–807 doi:10.1086/520001 PubMedCrossRefGoogle Scholar
  21. 21.
    Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S et al (2001) Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 108:619–623PubMedGoogle Scholar
  22. 22.
    Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T (2003) Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101:2461–2463 doi:10.1182/blood-2002-10-3235 PubMedCrossRefGoogle Scholar
  23. 23.
    Papanikolaou G, Sauels ME, Ludwig EH, MacDonald MLE, Franchini PL, Dubé MP et al (2004) Mutation in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 36:77–82 doi:10.1038/ng1274 PubMedCrossRefGoogle Scholar
  24. 24.
    Pietrangelo A (2004) Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 350:2383–2397 doi:10.1056/NEJMra031573 PubMedCrossRefGoogle Scholar
  25. 25.
    Pietrangelo A (2004) The ferroportin disease. Blood Cells Mol Diseases 32:131–138 doi:10.1016/j.bcmd.2003.08.003 CrossRefGoogle Scholar
  26. 26.
    Roetto A, Papanikolau G, Politou M, Alberti F, Girelli D, Christakis J et al (2003) Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 33:21–22 doi:10.1038/ng1053 PubMedCrossRefGoogle Scholar
  27. 27.
    Sanchez M, Bruguera M, Bosch J, Rodes J, Ballesta F, Oliva R (1998) Prevalence of the Cys282Tyr and His63Asp HFE gene mutations in Spanish patients with hereditary hemochromatosis and in controls. J Hepatol 29:725–728 doi:10.1016/S0168-8278(98)80252-3 PubMedCrossRefGoogle Scholar
  28. 28.
    Waalen J, Nordestgaard BG, Beutler E (2005) The penetrance of hereditary hemochromatosis. Best Pract Res Clin Haematol 18:203–220 doi:10.1016/j.beha.2004.08.023 PubMedCrossRefGoogle Scholar
  29. 29.
    Wallace DF, Pedersen P, Dixon JL, Stephenson P, Searle JW, Powell LW (2002) Subramaniam VN. Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis. Blood 100:692–694 doi:10.1182/blood.V100.2.692 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Albert Altès
    • 1
  • Vanessa Bach
    • 2
  • Angels Ruiz
    • 1
  • Anna Esteve
    • 1
  • Angel F. Remacha
    • 3
  • M. Pilar Sardà
    • 3
  • Jordi Felez
    • 2
  • Montserrat Baiget
    • 3
  1. 1.Servei Hematologia, ALTHAIAManresaSpain
  2. 2.A.B.S. CanaletesHospital de Sant PauBarcelonaSpain
  3. 3.Hematology and Genetics DepartmentsHospital de Sant PauBarcelonaSpain

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