Russian Heart Failure Journal 2011year HFE genotypes in patients with heart failure: clinical and genetic aspects and prognosis

To access this material please log in or register

Register Authorize

HFE genotypes in patients with heart failure: clinical and genetic aspects and prognosis

Pushkareva A. E., Khusainov R. I., Khusnutdinova N. N., Khusnutdinova E. K.

Keywords: HFE genotypes, clinical picture, prognosis, CHF

DOI: 10.18087/rhfj.2011.6.1591

Relevance. Despite achieved successes in treatment of chronic HF, the prognosis of this pathology is still most unfavorable, that is why possibilities of early diagnostics and preventive approaches in treatment are still extremely relevant. Purpose. The study of clinical genetic aspects of hemochromatosis (HFE) gene mutation effects on CHF development with different heart remodeling types. Materials and methods. 203 patients with CHF (170 male and 33 female, average age 51.5±4.2 years) were studied. Genotype identification was performed by RFLP analysis of PCR products. The reference group comprised 240 people (178 male and 62 female, average age 52.6±4.6 years), who had no data proven signs of cardiovascular pathologies. Results. During the study C282Y, H63D and S65C mutations were revealed in 34,97 % patients with CHF from the Republic of Bashkortostan, 37.65 % male and 24.24 % female. And frequency rate of three studied mutations amounted 43.53 % patients with eccentric LV hypertrophy in comparison to the patients with concentric LV hypertrophy, in 28.81 % of them HFE mutations were detected. Mutation rate increase is observed both in female (50 %) and in male patients with eccentric LV hypertrophy (43.59 %). Rather high frequency rate of three studied HFE mutations in our patients with CHF allows an assumption that HFE mutation carriage effects myocardium remodeling processes during HF development in patients with cardiovascular pathology of working age in the Republic of Bashkortostan.
  1. Kohgo Y, Ikuta K, Ohtake T et al. Body iron metabolism and pathophysio­logy of iron overload. Int J Hematol. 2008;88 (1):7–15.
  2. Bridle KR, Frazer DM, Wilkins SJ et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet. 2003;361 (9358):669–673.
  3. Harrison, s Advances in Cardiology / [edited by] Eugene Braunwald. Chapter 100. Hereditary Hemochromatosis: A Risk Factor for Cardiovascular Disease. Mark Roest, Yvonne T. Marx and J. J. M Marx. 2003. – Printed in the USA by The McGraw -Hill Medical Publishing Division. – p. 623–628.
  4. Panjrath GS, Patel V, Valdiviezo CI et al. Potentiation of Doxorubicin Cardiotoxicity by Iron Loading in a Rodent Model. J Am Coll Cardiol. 2007;49 (25):2457–2464.
  5. Miranda CJ, Makui H, Soares RJ et al. Hfe deficiency increases susceptibi­lity to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin. Blood. 2003;102 (7):2574–2580.
  6. Allen KJ, Gurrin LC, Constantine CC et al. Iron-overload-related di­sease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358 (3):221–230.
  7. Dunn T, Blankenship D, Beal N et al. HFE mutations in heart disease. Heart Vessels. 2008;23 (5):348–355.
  8. 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 (1):177–188.
  9. Baer DM, Simons JL, Staples RL et al. Hemochromatosis screening in asymptomatic ambulatory men 30 years of age and older. Am J Med. 1995;98 (5):464–468.
  10. Balan V, Baldus W, Fairbanks V et al. Screening for hemochromatosis: a cost-effectiveness study based on 12258 patients. Gastroenterology. 1994;107 (2):453–459.
  11. Duffy SJ, Biegelsen ES, Holbrook M et al. Iron chelation improves endothelial function in patients with coronary artery disease. Circulation. 2001;103 (23):2799–2804.
  12. Feber L. N, Gnirke A, Thomas W et al. A novel MHC class I-like gene is mutated in patients with hereditary hemochromatosis. Nat Genet. 1996;13 (4):399–408.
  13. De Valk Bl. Biological expression of heterozygous hereditary hemochromatosis. Eur J Intern Med. 2000;11:317.
  14. Rasmussen ML, Folsom AR, Catellier DJ et al. A prospective study of coronary heart disease and the hemochromatosis gene (HFE) C282Y mutation: the Atherosclerosis Risk in Communities (ARIC) study. Atherosclerosis. 2001;154 (3):739–746.
  15. Van Aken MO, De Craen AJ, Gussekloo J et al. No increase in mortality and morbidity among carriers of the C282Y mutation of the hereditary haemochromatosis gene in the oldest old: the Leiden 85‑plus study. Eur J Clin Invest. 2002;32 (10):750–754.
  16. Hannuksela J, Leppilampi M, Peuhkurinen K et al. Hereditary hemochromatosis gene (HFE) mutations C282Y, H63D and S65C in patients with idiopathic dilated cardiomyopathy. Eur J Heart Fail. 2005;7 (1):103–108.
  17. Mahon NG, Coonar AS, Jeffery S et al. Haemochromatosis gene mutations in idiopathic dilated cardiomyopathy. Heart. 2000;84 (5):541–547.
  18. Pereira AC, Cuoco MA, Mota GF et al. Hemochromatosis gene variants in patients with cardiomyopathy. Am J Cardiol. 2001;88 (4):388–391.
  19. Шарандак А. П, Кириченко Л. Л, Королев А. П, Юнусов М. А. Специфическая кардиомиопатия у больных гемохроматозом. Кардио­логия. 2005;45 (6):96–100.
  20. Mura C, Raguenes O, Férec C. HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood. 1999;93 (8):2502–2505.
  21. Beutler E, Gelbart T, West C et al. Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis. 1996;22 (2):187–194
  22. StatSoft, Inc. STATISTICA for Windows (Computer program manual). Tulsa, OK: StatSoft, Inc, 1999. Available at: http: \\
  23. Смолянинов А. Б. Клеточные и генные технологии в кардиологии. – СПб.:Спецлит, 2009. – 111с.
  24. Schuchter LM, Hensley ML, Meropol NJ, Winer EP. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2002;20 (12):2895–2903.
  25. Roest M, van der Schouw YT, de Valk B et al. Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women. Circulation. 1999;100 (12):1268–1273.
  26. Tuomainen TP, Kontula K, Nyyssonen K et al. Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cys282Tyr mutation: a prospective cohort study in men in eastern Finland. Circulation. 1999;100 (12):1274–1279.
  27. Ellervik C, Tybjaerg-Hansen A, Grande P, Appleyard M, Nordestgaard BG. Hereditary hemochromatosis and risk of ischemic heart disease: a prospective study and a case-control study. Circulation. 2005;112 (2):185–193.
  28. Fox CJ, Cullen DJ, Knuiman MW et al. Effects of body iron stores and haemochromatosis genotypes on coronary heart disease outcomes in the Busselton health study. J Cardiovasc Risk. 2002;9 (5):287–293.
  29. Gunn IR, Maxwell FK, Gaffney Det al. Haemochromatosis gene mutations and risk of coronary heart disease: a west of Scotland coronary prevention study (WOSCOPS) substudy. Heart. 2004;90 (3):304–306.
  30. Annichino-Bizzacchi JM, Saad ST, Arruda VR et al. C282Y mutation in the HLAH gene is not a risk factor for patients with myocardial infarction. J Cardiovasc Risk. 2000;7 (1):37–40.
  31. Battiloro E, Ombres D, Pascale E et al. Haemochromatosis gene mutations and risk of coronary artery disease. Eur J Hum Genet. 2000;8 (5):389–392.
  32. Bozzini C, Girelli D, Tinazzi E et al. Biochemical and genetic markers of iron status and the risk of coronary artery disease: an angiography-based study. Clin Chem. 2002;48 (4):622–628.
  33. Calado RT, Franco RF, Pazin-Filho A et al HFE gene mutations in coronary atherothrombotic disease. Braz J Med Biol Res. 2000;33 (3):301–306.
  34. Campbell S, George DK, Robb SD et al. The prevalence of haemochromatosis gene mutations in the West of Scotland and their relation to ischaemic heart disease. Heart. 2003;89 (9):1023–1026.
  35. Claeys D, Walting M, Julmy F et al. Haemochromatosis mutations and ferritin in myocardial infarction: a case-control study. Eur J Clin Invest. 2002;32 (Suppl 1):3–8.
  36. Margaglione M, Di Castelnuovo A, Totaro A et al. Risk of myocardial infarction in carriers of mutations in the hemochromatosis-associated gene. Thromb Haemost. 2000;84 (4):726–727.
  37. Rossi E, McQuillan BM, Hung J et al. Serum ferritin and C282Y mutation of the hemochromatosis gene as predictors of asymptomatic carotid athe­rosclerosis in a community population. Stroke. 2000;31 (12):3015–3020.
  38. Surber R, Sigusch HH, Kuehnert H, Figulla HR. Haemochromatosis (HFE) gene C282Y mutation and the risk of coronary artery disease and myocardial infarction: a study in 1279 patients undergoing coronary angiography. J Med Genet. 2003;40 (5):e58.
  39. McLaren CE, Gordeuk VR, Looker AC, Hasselblad V, Edwards CQ, Griffen LM, Kushner JP, Brittenham GM. Prevalence of heterozygotes for hemochromatosis in the white population of the United States. Blood. 1995;86 (5):2021–2027.
  40. Velati C, Piperno A, Fargion S, Colombo S, Fiorelli G. Prevalence of idiopathic hemochromatosis in Italy: study of 1301 blood donors. Haematologica. 1990;75 (4):309–312.
  41. Waheed A, Parkkila S, Zhou XY et al. Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β2‑microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci U S A. 1997;94 (23):12384–12389.
  42. Waalen J, Felitti V, Gelbart T et al. Prevalence of coronary heart disease associated with HFE mutations in adults attending a health appraisal center. Am J Med. 2002;113 (6):472–479.
  43. Ellervik C, Birgens H, Tybjaerg-Hansen A, Nordestgaard BG. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-ana­lyses including 66,000 cases and 226,000 controls. Hepatology. 2007;46 (4):1071–1080.
  44. Gurrin LC, Bertalli NA, Dalton GW et al. HFE C282Y / H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity. Hepatology. 2009;50 (1):94–101.
  45. Njajou OT, Houwing-Duistermaat JJ, Osborne RH et al. A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism. Eur J Hum Genet. 2003;11 (3):225–231.
  46. Whitfield JB, Cullen LM, Jazwinska EC 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 (4):1246–1258.
Pushkareva A.E., Khusainov R.I., Khusnutdinova N.N. et al. HFE genotypes in patients with heart failure: clinical and genetic aspects and prognosis. Russian Heart Failure Journal. 2011;12(6):356-361.

To access this material please log in or register

Register Authorize
Ru En