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9 - Heterozygosity for HFE C282Y

Published online by Cambridge University Press:  01 June 2011

James C. Barton ,
Corwin Q. Edwards ,
Pradyumna D. Phatak ,
Robert S. Britton  and
Bruce R. Bacon
By
James C. Barton ,
Corwin Q. Edwards ,
Pradyumna D. Phatak ,
Robert S. Britton  and
Bruce R. Bacon
James C. Barton
Affiliation:
University of Alabama, Birmingham
Corwin Q. Edwards
Affiliation:
University of Utah Medical Center
Pradyumna D. Phatak
Affiliation:
University of Rochester Medical Center, New York
Robert S. Britton
Affiliation:
St Louis University, Missouri
Bruce R. Bacon
Affiliation:
St Louis University, Missouri
James C. Barton
Affiliation:
University of Alabama, Birmingham
Corwin Q. Edwards
Affiliation:
University of Utah School of Medicine, Salt Lake City
Pradyumna D. Phatak
Affiliation:
University of Rochester Medical Center, New York
Robert S. Britton
Affiliation:
St Louis University, Missouri
Bruce R. Bacon
Affiliation:
St Louis University, Missouri
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Summary

The C282Y polymorphism of the HFE gene on chromosome 6p21.3 is the most common known human mutation that has a marked effect on iron absorption and homeostasis. Approximately 12% of Caucasians of northern or western European descent living in Europe or in derivative countries such as the US, Canada, Australia, or New Zealand are simple heterozygotes for C282Y, and they outnumber C282Y homozygotes in these populations by approximately 25:1. In the US alone, approximately 20 million whites are C282Y heterozygotes. If iron-related organ injury or another deleterious allele on C282Y-bearing chromosome 6p haplotypes were to occur in C282Y heterozygotes, the number of individuals at potential risk is great. This has led to an interest in defining: (a) the iron phenotype and any related iron or liver morbidity of C282Y heterozygotes and their management; (b) the optimal means to identify C282Y heterozygotes and to estimate their prevalence in populations; and (c) the association of C282Y with various non-iron-related disorders.

History

The HFE C282Y mutation arose in northwestern Europe, perhaps in the Neolithic Age. The original C282Y mutation probably occurred on a chromosome 6 haplotype characterized by human leukocyte antigens (HLA)-A*03, B*07, and by the marker allele D6S105(8). C282Y spread with various population movements, especially Viking migrations. Many C282Y homozygotes alive today have one or two copies of the ancestral haplotype. Likewise, all C282Y heterozygotes have inherited a common HFE polymorphism, but also much or all of an ancestral chromosome with its other component genes and alleles, the effects of which must be considered in understanding fully the effects of C282Y heterozygosity.

Type
Chapter
Information
Handbook of Iron Overload Disorders , pp. 149 - 159
Publisher: Cambridge University Press
Print publication year: 2010

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References

Lucotte, G, Dieterlen, F. A European allele map of the C282Y mutation of hemochromatosis: Celtic versus Viking origin of the mutation? Blood Cells Mol Dis 2003; 31: 262.CrossRefGoogle ScholarPubMed
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: 2699.CrossRefGoogle ScholarPubMed
Naugler, C. Hemochromatosis: a Neolithic adaptation to cereal grain diets. Med Hypotheses 2008; 70: 691–2.CrossRefGoogle ScholarPubMed
Fairbanks, VF. Hemochromatosis: population genetics. In: Barton, JC, Edwards, CQ, eds. Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, Cambridge University Press. 2000; 420.CrossRefGoogle Scholar
Feder, JN, Gnirke, A, Thomas, W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996; 13: 399–408.CrossRefGoogle ScholarPubMed
Gruen, JR, Weissman, SM. Evolving views of the major histocompatibility complex. Blood 1997; 90: 4252–65.Google ScholarPubMed
Datz, C, Haas, T, Rinner, H, Sandhofer, F, Patsch, W, Paulweber, B. Heterozygosity for the C282Y mutation in the hemochromatosis gene is associated with increased serum iron, transferrin saturation, and hemoglobin in young women: a protective role against iron deficiency?Clin Chem 1998; 44: 2429–32.Google ScholarPubMed
Rossi, E, Olynyk, JK, Cullen, DJ, et al. Compound heterozygous hemochromatosis genotype predicts increased iron and erythrocyte indices in women. Clin Chem 2000; 46: 162–6.Google ScholarPubMed
Chavarro, JE, Rich-Edwards, JW, Rosner, BA, Willett, WC. Iron intake and risk of ovulatory infertility. Obstet Gynecol 2006; 108: 11452.CrossRefGoogle ScholarPubMed
Braekeleer, M. A prevalence and fertility study of haemochromatosis in Saguenay-Lac-Saint-Jean. Ann Hum Biol 1993; 20: 501.CrossRefGoogle ScholarPubMed
Nelson, RL, Persky, V, Davis, F, Becker, E. Is hereditary hemochromatosis a balanced polymorphism: an analysis of family size among hemochromatosis heterozygotes. Hepatogastroenterology 2001; 48: 523–6.Google ScholarPubMed
Rochette, J, Pointon, JJ, Fisher, CA, et al. Multicentric origin of hemochromatosis gene (HFE) mutations. Am J Hum Genet 1999; 64: 1056–62.CrossRefGoogle ScholarPubMed
Bullen, JJ. Bacterial infections in hemochromatosis. In: Barton, JC, Edwards, CQ, eds. Hemochromatosis: Genetics, Pathophysiology, Diagnosis, and Treatment. Cambridge, Cambridge University Press. 2000; 381–6.CrossRefGoogle Scholar
Bulaj, ZJ, Griffen, LM, Jorde, LB, Edwards, CQ, Kushner, JP. Clinical and biochemical abnormalities in people heterozygous for hemochromatosis. N Engl J Med 1996; 335: 1799–805.CrossRefGoogle ScholarPubMed
Edwards, CQ, Griffen, LM, Bulaj, ZJ, Ajioka, RS, Kushner, JP. The iron phenotype of hemochromatosis heterozygotes. In: Barton, JC, Edwards, CQ, eds. Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, Cambridge University Press. 2000; 411–18.CrossRefGoogle Scholar
Edwards, CQ, Griffen, LM, Goldgar, D, Drummond, C, Skolnick, MH, Kushner, JP. Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 1988; 318: 1355–62.CrossRefGoogle ScholarPubMed
McLaren, CE, Gordeuk, VR, Looker, AC, et al. Prevalence of heterozygotes for hemochromatosis in the white population of the United States. Blood 1995; 86: 2021.Google ScholarPubMed
Hunt, JR, Zeng, H. Iron absorption by heterozygous carriers of the HFE C282Y mutation associated with hemochromatosis. Am J Clin Nutr 2004; 80: 924–31.CrossRefGoogle ScholarPubMed
Bassett, ML, Halliday, JW, Powell, LW. HLA typing in idiopathic hemochromatosis: distinction between homozygotes and heterozygotes with biochemical expression. Hepatology 1981; 1: 120–6.CrossRefGoogle ScholarPubMed
Morrison, ED, Brandhagen, DJ, Phatak, PD, et al. Serum ferritin level predicts advanced hepatic fibrosis among US patients with phenotypic hemochromatosis. Ann Intern Med 2003; 138: 627–33.CrossRefGoogle Scholar
Rossi, E, Bulsara, MK, Olynyk, JK, Cullen, DJ, Summerville, L, Powell, LW. Effect of hemochromatosis genotype and lifestyle factors on iron and red cell indices in a community population. Clin Chem 2001; 47: 202–8.Google Scholar
George, DK, Goldwurm, S, MacDonald, GA, et al. Increased hepatic iron concentration in non-alcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998; 114: 311–18.CrossRefGoogle Scholar
Beutler, E, Felitti, V, Gelbart, T, Ho, N. The effect of HFE genotypes on measurements of iron overload in patients attending a health appraisal clinic. Ann Intern Med 2000; 133: 329–37.CrossRefGoogle ScholarPubMed
Barton, JC, Bertoli, LF, Rothenberg, BE. Peripheral blood erythrocyte parameters in hemochromatosis: evidence for increased erythrocyte hemoglobin content. J Lab Clin Med 2000; 135: 96–104.CrossRefGoogle ScholarPubMed
Beutler, E, Felitti, V, Gelbart, T, Waalen, J. Haematological effects of the C282Y HFE mutation in homozygous and heterozygous states among subjects of northern and southern European ancestry. Br J Haematol 2003; 120: 887–93.CrossRefGoogle ScholarPubMed
McLaren, CE, Barton, JC, Gordeuk, VR, et al. Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study. Am J Hematol 2007; 82: 898–905.CrossRefGoogle ScholarPubMed
Jacobs, P, Finch, CA. Iron for erythropoiesis [abstract]. Blood 1971; 37: 220.Google Scholar
Cazzola, M, Huebers, HA, Sayers, MH, MacPhail, AP, Eng, M, Finch, CA. Transferrin saturation, plasma iron turnover, and transferrin uptake in normal humans. Blood 1985; 66: 935–9.Google ScholarPubMed
Feeney, GP, Carter, K, Masters, GS, Jackson, HA, Cavil, I, Worwood, M. Changes in erythropoiesis in hereditary hemochromatosis are not mediated by HFE expression in nucleated red cells. Haematologica 2005; 90: 180.Google Scholar
Goodnough, LT. Erythropoietin and iron-restricted erythropoiesis. Exp Hematol 2007; 35: 1672.CrossRefGoogle ScholarPubMed
Iliadou, A, Evans, DM, Zhu, G, et al. Genome-wide scans of red cell indices suggest linkage on chromosome 6q23. J Med Genet 2007; 44: 24–30.CrossRefGoogle Scholar
Lin, JP, O'Donnell, CJ, Levy, D, Cupples, . Evidence for a gene influencing haematocrit on chromosome 6q23–24: genome-wide scan in the Framingham Heart Study. J Med Genet 2005; 42: 75–9.CrossRefGoogle Scholar
Garner, C, Mitchell, J, Hatzis, T, Reittie, J, Farrall, M, Thein, SL. Haplotype mapping of a major quantitative-trait locus for fetal hemoglobin production, on chromosome 6q23. Am J Hum Genet 1998; 62: 14684.CrossRefGoogle Scholar
Adams, PC, Reboussin, DM, Barton, JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005; 352: 17698.CrossRefGoogle Scholar
Roe, MA, Spinks, C, Heath, AL, et al. Serum prohepcidin concentration: no association with iron absorption in healthy men; and no relationship with iron status in men carrying HFE mutations, hereditary haemochromatosis patients undergoing phlebotomy treatment, or pregnant women. Br J Nutr 2007; 97: 544–9.CrossRefGoogle ScholarPubMed
Rivard, SR, Mura, C, Simard, H, et al. Clinical and molecular aspects of juvenile hemochromatosis in Saguenay-Lac-Saint-Jean (Quebec, Canada). Blood Cells Mol Dis 2000; 26: 10–14.CrossRefGoogle Scholar
Merryweather-Clarke, AT, Pointon, JJ, Jouanolle, AM, Rochette, J, Robson, KJ. Geography of HFE C282Y and H63D mutations. Genet Test 2000; 4: 183–98.CrossRefGoogle ScholarPubMed
Mortimore, M, Merryweather-Clarke, AT, Robson, KJ, Powell, LW. The haemochromatosis gene: a global perspective and implications for the Asia-Pacific region. J Gastroenterol Hepatol 1999; 14: 838–43.CrossRefGoogle ScholarPubMed
Porto, G, Sousa, M. Variation of hemochromatosis prevalence and genotype in national groups. In: Barton, JC, Edwards, CQ, eds. Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, Cambridge University Press. 2000; 51–62.CrossRefGoogle Scholar
Acton, RT, Barton, JC, Snively, BM, et al. Geographic and racial/ethnic differences in HFE mutation frequencies in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Ethn Dis 2006; 16: 815–21.Google ScholarPubMed
Barton, JC, Patton, MA, Edwards, CQ, et al. Blood lead concentrations in hereditary hemochromatosis. J Lab Clin Med 1994; 124: 193–8.Google ScholarPubMed
Nelson, RL, Davis, FG, Persky, V, Becker, E. Risk of neoplastic and other diseases among people with heterozygosity for hereditary hemochromatosis. Cancer 1995; 76: 875–9.3.0.CO;2-Q>CrossRefGoogle ScholarPubMed
Waalen, J, Beutler, E. No age-related decrease in frequency of heterozygotes for the HFE C282Y haemochromatosis mutation. J Hepatol 2004; 40: 1044.CrossRefGoogle ScholarPubMed
Oliva, R, Novials, A, Sanchez, M, et al. The HFE gene is associated to an earlier age of onset and to the presence of diabetic nephropathy in diabetes mellitus type 2. Endocrine 2004; 24: 111–14.CrossRefGoogle Scholar
Zamboni, P, Tognazzo, S, Izzo, M, et al. Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration. J Vasc Surg 2005; 42: 309–14.CrossRefGoogle ScholarPubMed
Fracanzani, AL, Fargion, S, Stazi, MA, et al. Association between heterozygosity for HFE gene mutations and hepatitis viruses in hepatocellular carcinoma. Blood Cells Mol Dis 2005; 35: 27–32.CrossRefGoogle ScholarPubMed
Pacal, L, Husa, P, Znojil, V, Kankova, K. HFE C282Y gene variant is a risk factor for the progression to decompensated liver disease in chronic viral hepatitis C subjects in the Czech population. Hepatol Res 2007; 37: 740.CrossRefGoogle ScholarPubMed
Nahon, P, Sutton, A, Rufat, P, et al. Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis. Gastroenterology 2008; 134: 102–10.CrossRefGoogle ScholarPubMed
Lauret, E, Rodriguez, M, Gonzalez, S, et al. HFE gene mutations in alcoholic and virus-related cirrhotic patients with hepatocellular carcinoma. Am J Gastroenterol 2002; 97: 1016–21.CrossRefGoogle ScholarPubMed
Barton, JC, McDonnell, SM, Adams, PC, et al. Management of hemochromatosis. Hemochromatosis Management Working Group. Ann Intern Med 1998; 129: 932–9.CrossRefGoogle ScholarPubMed
Bonkovsky, HL, Poh-Fitzpatrick, M, Pimstone, N, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in north America. Hepatology 1998; 27: 1661–9.CrossRefGoogle ScholarPubMed
Stuart, KA, Busfield, F, Jazwinska, EC, et al. The C282Y mutation in the haemochromatosis gene (HFE) and hepatitis C virus infection are independent cofactors for porphyria cutanea tarda in Australian patients. J Hepatol 1998; 28: 404–9.CrossRefGoogle ScholarPubMed
Martinelli, AL, Zago, MA, Roselino, AM, et al. Porphyria cutanea tarda in Brazilian patients: association with hemochromatosis C282Y mutation and hepatitis C virus infection. Am J Gastroenterol 2000; 95: 3516–21.CrossRefGoogle ScholarPubMed
Tannapfel, A, Stolzel, U, Kostler, E, et al. C282Y and H63D mutation of the hemochromatosis gene in German porphyria cutanea tarda patients. Virchows Arch 2001; 439: 1.CrossRefGoogle ScholarPubMed
Egger, NG, Goeger, , Payne, DA, Miskovsky, EP, Weinman, SA, Anderson, KE. Porphyria cutanea tarda: multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrinogen decarboxylase deficiency. Dig Dis Sci 2002; 47: 419–26.CrossRefGoogle ScholarPubMed
Hift, RJ, Corrigall, AV, Hancock, V, Kannemeyer, J, Kirsch, RE, Meissner, PN. Porphyria cutanea tarda: the etiological importance of mutations in the HFE gene and viral infection is population-dependent. Cell Mol Biol (Noisy-le-grand) 2002; 48: 853–9.Google ScholarPubMed
Lamoril, J, Andant, C, Gouya, L, et al. Hemochromatosis (HFE) and transferrin receptor-1 (TFRC1) genes in sporadic porphyria cutanea tarda (sPCT). Cell Mol Biol (Noisy-le-grand) 2002; 48: 33–41.Google Scholar
Chiaverini, C, Halimi, G, Ouzan, D, Halfon, P, Ortonne, JP, Lacour, JP.Porphyria cutanea tarda, C282Y, H63D and S65C HFE gene mutations and hepatitis C infection: a study from southern France. Dermatology 2003; 206: 212–16.CrossRefGoogle ScholarPubMed
Nagy, Z, Koszo, F, Par, A, et al. Hemochromatosis (HFE) gene mutations and hepatitis C virus infection as risk factors for porphyria cutanea tarda in Hungarian patients. Liver Int 2004; 24: 16–20.CrossRefGoogle ScholarPubMed
Toll, A, Celis, R, Ozalla, MD, Bruguera, M, Herrero, C, Ercilla, MG. The prevalence of HFE C282Y gene mutation is increased in Spanish patients with porphyria cutanea tarda without hepatitis C virus infection. J Eur Acad Dermatol Venereol 2006; 20: 1201–6.CrossRefGoogle ScholarPubMed
Kratka, K, Dostalikova-Cimburova, M, Michalikova, H, Stransky, J, Vranova, J, Horak, J. High prevalence of HFE gene mutations in patients with porphyria cutanea tarda in the Czech Republic. Br J Dermatol 2008; 159: 585–90.CrossRefGoogle ScholarPubMed
Brandenberg, JB, Demarmels, BF, Lutz, HU, Wuillemin, WA. Hereditary spherocytosis and hemochromatosis. Ann Hematol 2002; 81: 202–9.Google ScholarPubMed
Montes-Cano, MA, Rodriguez-Munoz, F, Franco-Osorio, R, Nunez-Roldan, A, Gonzalez-Escribano, MF. Hereditary spherocytosis associated with mutations in HFE gene. Ann Hematol 2003; 82: 7692.CrossRefGoogle ScholarPubMed
Valenti, L, Pulixi, EA, Arosio, P, et al. Relative contribution of iron genes, dysmetabolism and hepatitis C virus (HCV) in the pathogenesis of altered iron regulation in HCV chronic hepatitis. Haematologica 2007; 92: 1037–42.CrossRefGoogle ScholarPubMed
Blanc, JF, De, Ledinghen, Bernard, PH, et al. Increased incidence of HFE C282Y mutations in patients with iron overload and hepatocellular carcinoma developed in non-cirrhotic liver. J Hepatol 2000; 32: 805–11.CrossRefGoogle ScholarPubMed
Varkonyi, J, Tarkovacs, G, Karadi, I, et al. High incidence of hemochromatosis gene mutations in the myelodysplastic syndrome: the Budapest Study on 50 patients. Acta Haematol 2003; 109: 64.CrossRefGoogle ScholarPubMed
Nearman, ZP, Szpurka, H, Serio, B, et al. Hemochromatosis-associated gene mutations in patients with myelodysplastic syndromes with refractory anemia with ringed sideroblasts. Am J Hematol 2007; 82: 1076–9.CrossRefGoogle ScholarPubMed
Nelson, JE, Bhattacharya, R, Lindor, KD, et al. HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with non-alcoholic steatohepatitis. Hepatology 2007; 46: 723–9.CrossRefGoogle Scholar
Kushner, JP, Edwards, CQ, Dadone, MM, Skolnick, MH. Heterozygosity for HLA-linked hemochromatosis as a likely cause of the hepatic siderosis associated with sporadic porphyria cutanea tarda. Gastroenterology 1985; 88: 1232–8.CrossRefGoogle ScholarPubMed
Ivanova, A, Ahsen, N, Adjarov, D, Krastev, Z, Oellerich, M, Wieland, E. C282Y and H63D mutations in the HFE gene are not associated with porphyria cutanea tarda in Bulgaria. Hepatology 1999; 30: 1531–2.CrossRefGoogle Scholar
Chitturi, S, Weltman, M, Farrell, GC, et al. HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH with C282Y but not with fibrotic severity. Hepatology 2002; 36: 142–9.CrossRefGoogle Scholar
Bugianesi, E, Manzini, P, D'Antico, S, et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in non-alcoholic fatty liver. Hepatology 2004; 39: 179–87.CrossRefGoogle Scholar
Kallianpur, AR, Hall, LD, Yadav, M, et al. Increased prevalence of the HFE C282Y hemochromatosis allele in women with breast cancer. Cancer Epidemiol Biomarkers Prev 2004; 13: 205–12.CrossRefGoogle ScholarPubMed
Shaheen, NJ, Silverman, LM, Keku, T, et al. Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. J Natl Cancer Inst 2003; 95: 154–9.CrossRefGoogle ScholarPubMed
Dorak, MT, Burnett, AK, Worwood, M. Hemochromatosis gene in leukemia and lymphoma. Leuk Lymphoma 2002; 43: 4677.CrossRefGoogle ScholarPubMed
Dorak, MT, Burnett, AK, Worwood, M, Sproul, AM, Gibson, BE. The C282Y mutation of HFE is another male-specific risk factor for childhood acute lymphoblastic leukemia. Blood 1999; 94: 3957.Google ScholarPubMed
Guerreiro, RJ, Bras, JM, Santana, I, et al. Association of HFE common mutations with Parkinson's disease, Alzheimer's disease, and mild cognitive impairment in a Portuguese cohort. BMC Neurol 2006; 6: 24.CrossRefGoogle Scholar
Kwan, T, Leber, B, Ahuja, S, Carter, R, Gerstein, HC. Patients with type 2 diabetes have a high frequency of the C282Y mutation of the hemochromatosis gene. Clin Invest Med 1998; 21: 251.Google ScholarPubMed
Moczulski, DK, Grzeszczak, W, Gawlik, B. Role of hemochromatosis C282Y and H63D mutations in HFE gene in development of type 2 diabetes and diabetic nephropathy. Diabetes Care 2001; 24: 1187–91.CrossRefGoogle ScholarPubMed
Cauza, E, Hanusch-Enserer, U, Bischof, M, et al. Increased C282Y heterozygosity in gestational diabetes. Fetal Diagn Ther 2005; 20: 3494.CrossRefGoogle ScholarPubMed
Rasmussen, ML, Folsom, AR, Catellier, DJ, Tsai, MY, Garg, U, Eckfeldt, JH. A prospective study of coronary heart disease and the hemochromatosis gene (HFE) C282Y mutation: the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis 2001; 154: 739–46.CrossRefGoogle ScholarPubMed
Pankow, JS, Boerwinkle, E, Adams, PC, et al. HFE C282Y homozygotes have reduced low-density lipoprotein cholesterol: the Atherosclerosis Risk in Communities (ARIC) Study. Transl Res 2008; 152: 3–10.CrossRefGoogle ScholarPubMed

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