Genetic predisposition to iron overload: Prevalence and phenotypic expression of hemochromatosis-associated HFE-C282Y gene mutation

Scandinavian Journal of Clinical and Laboratory Investigation

Volumn 66, Issue 2, 2006, Pages 83-100

  Distante, S ^a  

^a OSLO UNIVERSITY HOSPITAL   (Norway)

Author keywords

[No Author keywords available]

Indexed keywords

CD71 ANTIGEN; CERULOPLASMIN; FERRITIN; FERROPORTIN 1; HFE PROTEIN; IRON; TRANSFERRIN; TUMOR NECROSIS FACTOR ALPHA;

ABORIGINE; ASIAN; AUSTRALIA; CLINICAL FEATURE; DIAGNOSTIC TEST; DISEASE SEVERITY; DNA DETERMINATION; ENTERIC FEEDING; EUROPE; GENE EXPRESSION; GENE FREQUENCY; GENE IDENTIFICATION; GENE MUTATION; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC POLYMORPHISM; GENETIC PREDISPOSITION; GENETIC REGULATION; GENETIC SCREENING; GENETIC SIMILARITY; GENOTYPE PHENOTYPE CORRELATION; GEOGRAPHIC ORIGIN; HEALTH CARE COST; HEMOCHROMATOSIS; HEPATITIS C; HETEROZYGOSITY; HOMOZYGOSITY; HUMAN; IMMUNE RESPONSE; IMMUNOGENETICS; IRON ABSORPTION; IRON BINDING CAPACITY; IRON BLOOD LEVEL; IRON INTAKE; IRON OVERLOAD; IRON STORAGE; LIVER CIRRHOSIS; LIVER FIBROSIS; LIVER HEMOSIDEROSIS; MUTATION RATE; NEGRO; NEW ZEALAND; NORWAY; NUTRITIONAL DEFICIENCY; PARENTERAL NUTRITION; PHENOTYPE; POPULATION GENETICS; PREVALENCE; PRIORITY JOURNAL; REVIEW; SCANDINAVIA; SOUTH AFRICA; STATISTICAL SIGNIFICANCE; UNITED STATES;

CYSTEINE; GENETIC PREDISPOSITION TO DISEASE; HEMOCHROMATOSIS; HISTOCOMPATIBILITY ANTIGENS CLASS I; HUMANS; IRON OVERLOAD; MEMBRANE PROTEINS; MUTATION; PREVALENCE; SCANDINAVIA; TYROSINE;

HEPATITIS C VIRUS;

EID: 33645009910     PISSN: 00365513     EISSN: 15027686     Source Type: Journal    
DOI: 10.1080/00365510500495616     Document Type: Review

References (88)

1. Andrews NC. Disorders of iron metabolism. N Engl J Med 1999;341:1986-95.
2. Marx JJ. Iron deficiency in developed countries: prevalence, influence of lifestyle factors and hazards of prevention. Eur J Clin Nutr 1997;51:491-4.
3. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102:783-8.
4. Pietrangelo A. Hereditary hemochromatosis: a new look at an old disease. N Engl J Med 2004;350:2383-97.
5. Adams PC, Kertesz AE, Valberg LS. Clinical presentation of hemochromatosis: a changing scene. Am J Med 1991;90:445-9.
6. Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996;110:1107-19.
7. Adams P, Brissot P, Powell LW. EASL International Consensus Conference on Haemochromatosis. J Hepatol 2000;33:485-504.
8. Powell LW, Halliday JW, Cowlishaw JL. Relationship between serum ferritin and total body iron stores in idiopathic haemochromatosis. Gut 1978;19:538-42.
9. Åsberg A, Hveem K, Thorstensen K, Ellekjter E, Kannelonning K, Fjosne U, et al. Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons. Scand J Gastroenterol 2001;36:1108-5.
10. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005;352:1769-78.
11. Simon M, Bourel M, Fauchet R, Genetet B. Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut 1976;17:332-4.
12. 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;13:399-408.
13. Pointon JJ, Wallace D, Merryweather-Clarke AT, Robson KJ. Uncommon mutations and polymorphisms in the hemochromatosis gene. Genet Test 2000;4:151-61.
14. Burke W, Thomson E, Khoury MJ, McDonnell SM, Press N, Adams PC, et al. Hereditary hemochromatosis: gene discovery and its implications for population-based screening. JAMA 1998;280:172-8.
15. Bacon BR, Powell LW, Adams PC, Kresina TF, Hoofnagle JH. Molecular medicine and hemochromatosis: at the crossroads. Gastroenterology 1999;116:193-207.
16. Piperno A, Sampietro M, Pietrangelo A, Arosio C, Lupica L, Montosi G, et al. Heterogeneity of hemochromatosis in Italy. Gastroenterology 1998;114:996-1002.
17. Hanson EH, Imperatore G, Burke W. HFE gene and hereditary hemochromatosis: a HuGE review. Human genome epidemiology. Am J Epidemiol 2001;154:193-206.
18. Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative haemochromatosis mutations. J Med Genet 1997;34:275-8.
19. Merryweather-Clarke AT, Pointon JJ, Jouanolle AM, Rochette J, Robson KJ. Geography of HFE C282Y and H63D mutations. Genet Test 2000;4:183-98.
20. Distante S, Berg JP, Lande K, Haug E, Bell H. High prevalence of the hemochromatosis-associated Cys282Tyr HFE gene mutation in a healthy Norwegian population in the city of Oslo, and its phenotypic expression. Scand J Gastroenterol 1999;34:529-34.
21. Distante S, Berg JP, Lande K, Haug E, Bell H. HFE gene mutation (C282Y) and phenotypic expression among a hospitalised population in a high prevalence area of haemochromatosis. Gut 2000;47:575-9.
22. Distante S, Robson KJ, Graham-Campbell J, Rnaiz-Villena A, Brissot P, Worwood M. The origin and spread of the HFE-C282Y haemochromatosis mutation. Hum Genet 2004;115:269-79.
23. Simon M, Alexandre A, Fauchet R, Genetet B, Bourel M. The genetics of hemochromatosis. In: Steinberg AG, Bearn AG, Motulsky AG, Childs B, editors. Progress in medical genetics. Philadelphia: W.B. Saunders; 1980. pp 135-68.
24. Olsson KS, Ritter B. Idiopatisk hemokromatose. Tidsskrift for Nor Laegeforen 1981;29:101. Ref Type: Generic.
25. Raha-Chowdhury R, Gruen JR. Localisation, alleleic heterogeneity, and origins of the hemochromatosis gene. In: Barton JC, Edwards CQ, editors. Hemochromatosis: genetics, pathophysiology, diagnosis and treatment. Cambridge: Cambridge University Press; 2000. pp 75-90.
26. Burt MJ, George PM, Upton JD, Collett JA, Frampton CM, Chapman TM, et al. The significance of haemochromatosis gene mutations in the general population: implications for screening. Gut 1998;43:830-6.
27. Yaouanq J. Human leucocyte antigen (HLA) association and typing in hemochromatosis. In: Barton JC, Edwards CQ, editors. Hemochromatosis. Cambridge: Cambridge University Press; 2000. pp 63-74.
28. Smith JM, Haigh J. The hitch-hiking effect of a favourable gene. Genet Res 1974;23:23-35.
29. Moalem S, Percy ME, Kruck TP, Gelbart RR. Epidemic pathogenic selection: an explanation for hereditary hemochromatosis? Med Hypotheses 2002;59:325-9.
30. De Sousa M, Porto G. The immunological system in hemochromatosis. J Hepatol 1998;28 Suppl 1:1-7.
31. Farid NR, Sampson L, Noel P, Barnard JM, Davis AJ, Hillman DA. HLA-D-related (DRw) antigens in juvenile diabetes mellitus. Diabetes 1979;28:552-7.
32. Bell H, Thordal C, Raknerud N, Hansen T, Bosnes V, Halvorsen R, et al. Prevalence of hemochromatosis among first-time and repeat blood donors in Norway. J Hepatol 1997;26:272-9.
33. Olsson KS, Eriksson K, Ritter B, Heedman PA. Screening for iron overload using transferrin saturation. Acta Med Scand 1984;215:105-12.
34. Karlsson M, Ikkala E, Reunanen A, Takkunen H, Vuori E, Makinen J. Prevalence of hemochromatosis in Finland. Acta Med Scand 1988;224:385-90.
35. Beckman LE, Sjoberg K, Eriksson S, Beckman L. Haemochromatosis gene mutations in Finns, Swedes and Swedish Saamis. Hum Hered 2001;52:110-2.
36. 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.
37. Moirand R, Guyader D, Mendler MH, Jouanolle AM, Le Gall JY, David V, et al. HFE based re-evaluation of heterozygous hemochromatosis. Am J Med Genet 2002;111:356-61.
38. Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999;341:718-24.
39. Deugnier Y, Jouanolle AM, Chaperon J, Moirand R, Pithois C, Meyer JF, et al. Gender-specific phenotypic expression and screening strategies in C282Y-linked haemochromatosis: a study of 9396 French people. Br J Haematol 2002;118:1170-8.
40. Adams PC, Kertesz AE, McLaren CE, Barr R, Bamford A, Chakrabarti S. Population screening for hemochromatosis: a comparison of unbound iron-binding capacity, transferrin saturation, and C282Y genotyping in 5,211 voluntary blood donors. Hepatology 2000;31:1160-4.
41. 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 Aug; 114:474-84.
42. McDonnell SM, Hover A, Gloe D, Ou CY, Cogswell ME, Grummer-Strawn L. Population-based screening for hemochromatosis using phenotypic and DNA testing among employees of health maintenance organizations in Springfield, Missouri. Am J Med 1999;107:30-7.
43. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G- > A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002;359:211-8.
44. McCune CA, Al Jader LN, May A, Hayes SL, Jackson HA, Worwood M. Hereditary haemochromatosis: only 1 % of adult HFEC282Y homozygotes in South Wales have a clinical diagnosis of iron overload. Hum Genet 2002;111:538-43.
45. Olynyk JK, Knuiman MW, Divitini ML, Bartholomew HC, Cullen DJ, Powell LW. Effects of HFE gene mutations and alcohol on iron status, liver biochemistry and morbidity. J Gastroenterol Hepatol 2005;20:1435-41.
46. Whitfield JB, Cullen LM, Jazwinska EC, Powell LW, Heath AC, Zhu G, et al. Effects of HFE C282Y and H63D polymorphisms and polygenic background on iron stores in a large community sample of twins. Am J Hum Genet 2000;66:1246-58.
47. Levy JE, Montross LK, Andrews NC. Genes that modify the hemochromatosis phenotype in mice. J Clin Invest 2000;105:1209-16.
48. Lee PL, Gelbart T, West C, Halloran C, Felitti V, Beutler E. 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 2001;27:783-802.
49. Walker AP, Wallace DF, Partridge J, Bomford AB, Dooley JS. Atypical haemochromatosis: phenotypic spectrum and beta2-microglobulin candidate gene analysis. J Med Genet 1999;36:537-41.
50. Piperno A, Arosio C, Fargion S, Roetto A, Nicoli C, Girelli D, et al. The ancestral hemochromatosis haplotype is associated with a severe phenotype expression in Italian patients. Hepatology 1996;24:43-6.
51. Sachot S, Moirand R, Jouanolle AM, Mosser J, Fergelot P, Deugnier Y, et al. Low penetrant hemochromatosis phenotype in eight families: no evidence of modifiers in the MHC region. Blood Cells Mol Dis 2001;27:518-29.
52. Van Vlierberghe H, Langlois M, Delanghe J, Horsmans Y, Michielsen P, Henrion J, et al. Haptoglobin phenotype 2-2 overrepresentation in Cys282Tyr hemochromatotic patients. J Hepatol 2001;35:707-11.
53. Beutler E, Gelbart T, Lee P. Haptoglobin polymorphism and iron homeostasis. Clin Chem 2002;48:2232-5.
54. Tolosano E, Fagoonee S, Garuti C, Valli L, Andrews NC, Altruda F, et al. Haptoglobin modifies the hemochromatosis phenotype in mice. Blood 2005 15;105:3353-5.
55. Jacolot S, Le GG, Scotet V, Quere I, Mura C, Ferec C. HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood 2004 1;103:2835-40.
56. Reimao R, Porto G, De Sousa M. Stability of CD4/CD8 ratios in man: new correlation between CD4/CD8 profiles and iron overload in idiopathic haemochromatosis patients. C R Acad Sci III 1991;313:481-7.
57. Barton JC, Wiener HW, Acton RT, Go RC. Total blood lymphocyte counts in hemochromatosis probands with HFE C282Y homozygosity: relationship to severity of iron overload and HLA-A and -B alleles and haplotypes. BMC Blood Disord 2005;5:5.
58. Ten Elshof AE, Brittenham GM, Chorney KA, Page MJ, Gerhard G, Cable EE, et al. Gamma delta intraepithelial lymphocytes drive tumor necrosis factor-alpha responsiveness to intestinal iron challenge: relevance to hemochromatosis. Immunol Rev 1999;167:223-32.
59. Gordeuk VR, Ballou S, Lozanski G, Brittenham GM. Decreased concentrations of tumor necrosis factor-alpha in supernatants of monocytes from homozygotes for hereditary hemochromatosis. Blood 1992;79:1855-60.
60. Fargion S, Valenti L, Dongiovanni P, Scaccabarozzi A, Fracanzani AL, Taioli E, et al. Tumor necrosis factor alpha promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis. Blood 2001;97:3707-12.
61. Cookson S, Constantini PK, Clare M, Underhill JA, Bernal W, Czaja AJ, et al. Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology 1999;30:851-6.
62. Jones DE, Watt FE, Grove J, Newton JL, Daly AK, Gregory WL, et al. Tumour necrosis factor-alpha promoter polymorphisms in primary biliary cirrhosis [comments]. J Hepatol 1999;30:232-6.
63. Distante S, Elmberg M, Foss Haug KB, Ovstebo R, Berg JP, Kierulf P, et al. Tumour necrosis factor alpha and its promoter polymorphisms' role in the phenotypic expression of hemochromatosis. Scand J Gastroenterol 2003;38:871-7.
64. Beutler E, Gelbart T. Tumor necrosis factor alpha promoter polymorphisms and liver abnormalities of homozygotes for the 845G > A(C282Y) hereditary hemochromatosis mutation. Blood 2002;100:2268-9.
65. Donaldson PT. TNF gene polymorphisms in primary biliary cirrhosis: a critical appraisal. J Hepatol 1999;31:366-8.
66. Wilson AG. Genetics of tumour necrosis factor (TNF) in autoimmune liver diseases: red hot or red herring? J Hepatol 1999;30:331-3.
67. Piperno A, Vergani A, Malosio I, Parma L, Fossati L, Ricci A, et al. Hepatic iron overload in patients with chronic viral hepatitis: role of HFE gene mutations. Hepatology 1998;28:1105-9.
68. Thorburn D, Curry G, Spooner R, Spence E, Oien K, Halls D, et al. The role of iron and haemochromatosis gene mutations in the progression of liver disease in chronic hepatitis C. Gut 2002;50:248-52.
69. Bonkovsky HL, Jawaid Q, Tortorelli K, LeClair P, Cobb J, Lambrecht RW, et al. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol 1999;31:421-9.
70. Cauza E, Peck-Radosavljevic M, Ulrich-Pur H, Datz C, Gschwantler M, Schoniger-Hekele M, et al. Mutations of the HFE gene in patients with hepatocellular carcinoma. Am J Gastroenterol 2003;98:442-7.
71. Distante S, Bjoro K, Hellum KB, Myrvang B, Berg JP, Skaug K, et al. Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection. Liver 2002;22:269-75.
72. Olynyk JK, Reddy KR, Di Bisceglie AM, Jeffers LJ, Parker TI, Radick JL, et al. Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology 1995;108:1104-9.
73. Martinelli AL, Franco RF, Villanova MG, Figueiredo JF, Secaf M, Tavella MH, et al. Are haemochromatosis mutations related to the severity of liver disease in hepatitis C virus infection? Acta Haematol 2000;102:152-6.
74. Hezode C, Cazeneuve C, Coue O, Pawlotsky JM, Zafrani ES, Amselem S, et al. Hemochromatosis Cys282Tyr mutation and liver iron overload in patients with chronic active hepatitis C. Hepatology 1998;27:306.
75. Fillebeen C, Rivas-Estilla AM, Bisaillon M, Ponka P, Muckenthaler M, Hentze MW, et al. Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C Virus. J Biol Chem 2005 11;280:9049-57.
76. Bell H, Berg JP, Undlien DE, Distante S, Raknerud N, Heier HE, et al. The clinical expression of hemochromatosis in Oslo, Norway. Excessive oral iron intake may lead to secondary hemochromatosis even in HFE C282Y mutation negative subjects. Scand J Gastroenterol 2000;35:1301-7.
77. Scotet V, Le GG, Merour MC, Mercier AY, Chanu B, Ka C, et al. Impact of HFE genetic testing on clinical presentation of hereditary hemochromatosis: new epidemiological data. BMC Med Genet 2005;6:24.
78. Adams PC. Nonexpressing homozygotes for C282Y hemochromatosis: minority or majority of cases? Mol Genet Metab 2000;71:81-6.
79. Wilson JMG, Junger G. The principles and practice of screening for disease. Public Health Paper no. 34. Geneva: World Health Organisation; 1968.
80. Adams PC. Population screening for hemochromatosis: are we finding people with a disease or a biochemical curiosity? Semin Gastrointest Dis 2002;13:89-94.
81. Asberg A, Hveem K, Kruger O, Bjerve KS. Persons with screening-detected haemochromatosis: as healthy as the general population? Scand J Gastroenterol 2002;37:719-24.
82. Hickman PE, Hourigan LF, Powell LW, Cordingley F, Dimeski G, Ormiston B, et al. Automated measurement of unsaturated iron binding capacity is an effective screening strategy for C282Y homozygous haemochromatosis. Gut 2000;46:405-9.
83. Phatak PD, Guzman G, Woll JE, Robeson A, Phelps CE. Cost-effectiveness of screening for hereditary hemochromatosis. Arch Intern Med 1994;154:769-76.
84. Adams PC, Gregor JC, Kertesz AE, Valberg LS. Screening blood donors for hereditary hemochromatosis: decision analysis model based on a 30-year database. Gastroenterology 1995;109:177-88.
85. Asberg A, Tretli S, Hveem K, Bjerve KS. Benefit of population-based screening for phenotypic hemochromatosis in young men. Scand J Gastroenterol 2002;37:1212-9.
86. Delatycki MB, Allen KJ, Nisselle AE, Collins V, Metcalfe S, du SD, et al. Use of community genetic screening to prevent HFE-associated hereditary haemochromatosis. Lancet 2005;366:314-6.
87. Larsen LE, Ellervik C, Appleyard M, Nordestgaard BG, Birgens H, Tybjaerg-Hansen A. Prevalence of hemochromatosis-associated mutations in the hemochromatosis gene in the Danish population. Ugeskr Laeger 2002;164:4545-7.
88. Sanchez M, Villa M, Ingelmo M, Sanz C, Bruguera M, Ascaso C, et al. Population screening for hemochromatosis: a study in 5370 Spanish blood donors. J Hepatol 2003;38:745-50.