Download PDF
Exp Clin Endocrinol Diabetes 2002; 110(5): 223-229
DOI: 10.1055/s-2002-33071
Articles

© Johann Ambrosius Barth

Relations among serum ferritin, C282Y and H63D mutations in the HFE gene and type 2 diabetes mellitus in the Czech population

K. Kaňková1 , E. H. J. M Jansen2 , I. Márová3 , A. Stejskalová1 , L. Pácal1 , J. Mužík1 , J. Vácha1
  • 1 Department of Pathophysiology, Faculty of Medicine, Masaryk University Brno, Czech Republic
  • 2 Laboratory for Health Effects Research, National Institute of Public Health and Environment, Bilthoven, The Netherlands
  • 3 Department of Food Chemistry and Biotechnology, Faculty of Chemistry, Technical University, Brno, Czech Republic
Further Information

Publication History

received 16 October 2001 first decision 26 November 2001

accepted 4 March 2002

Publication Date:
30 July 2002 (online)

Also available at
    Permissions and Reprints

Summary

Aims of the study were: (i) to determine the prevalence of mutations C282Y and H63D in the HFE gene causing hereditary hemochromatosis in patients with type 2 diabetes mellitus and non-diabetics, (ii) to investigate the relationship among HFE genotypes, serum ferritin and glucose intolerance and (iii) to assess possible association of HFE mutations with the susceptibility to develop late diabetic complications in the Czech population. Two approaches were employed - the case-control study comprising diabetics and non-diabetic controls (n = 326) and the cross-sectional study comprising subjects with a previously unknown defect of glucose tolerance (n = 113, oral glucose tolerance test performed in each subject). Allele frequencies of C282Y and H63D did not differ between diabetic and control groups nor among subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes. Ferritin levels significantly differed between diabetic and non-diabetic women (P<1.10-3) and among subjects with NGT, IGT and diabetes (P<0.05). Differences in ferritin levels related to particular genotypes of C282Y and H63D were not detected. Prevalence of diabetes in the first and second quartiles of ferritin distribution differed highly significantly from the prevalence in the third and fourth quartiles in women (P = 0.000037), OR = 3.50 (95% CI, 1.89-6.48). The extent of diabetic late complications did not correlate with ferritin plasma levels.

Key words:

Type 2 diabetes mellitus - Ferritin - Hereditary hemochromatosis - HFE - Diabetic complications - Iron

References

  • 1 Baynes J W. Role of oxidative stress in development of complications in diabetes.  Diabetes. 1991;  4 405-412
    PubMedGoogle Scholar
  • 2 Baynes J W, Thorpe S R. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm.  Diabetes. 1999;  1 1-9
    PubMedGoogle Scholar
  • 3 Byrnes V, Ryan E, Barrett S, Kenny P, Mayne P, Crowe J. Genetic hemochromatosis, a Celtic disease: is it now time for population screening?.  Genet Test. 2001;  5 127-130
    CrossrefPubMedGoogle Scholar
  • 4 Carella M, D'Ambrosio L, Totaro A, Grifa A, Valentino M A, Piperno A, Girelli D, Roetto A, Franco B, Gasparini P, Camaschella C. Mutation analysis of the HLA-H gene in Italian hemochromatosis patients.  Am J Hum Genet. 1997;  4 828-832
    PubMedGoogle Scholar
  • 5 Conte D, Manachino D, Colli A, Guala A, Aimo G, Andreoletti M, Cornetti M, Fraquelli M. Prevalence of genetic hemochromatosis in a cohort of Italian patients with diabetes mellitus.  Ann Intern Med. 1998;  5 370-373
    PubMedGoogle Scholar
  • 6 David V, Jouanolle A M, Fergelot P, Brissot P, Deugnier Y, Le Gall J Y. Molecular genetics of hemochromatosis.  Ann Endocrinol (Paris). 1999;  3 204-209
    PubMedGoogle Scholar
  • 7 Dubois-Laforgue D, Caillat-Zucman S, Djilali-Saiah I, Larger E, Mercadier A, Boitard C, Bach J F, Timsit J. Mutations in HFE, the hemochromatosis candidate gene, in patients with NIDDM.  Diabetes Care. 1998;  8 1371-1372
    PubMedGoogle Scholar
  • 8 Dubois-Laforgue D, Caillat-Zucman S, Boitard C, Timsit J. Clinical characteristics of type 2 diabetes in patients with mutations of HFE.  Diabetes Metab. 2000;  1 65-68
    PubMedGoogle Scholar
  • 9 Ellervik C, Mandrup-Poulsen T, Nordestgaard B G, Larsen L E, Appleyard M, Frandsen M, Petersen P, Schlichting P, Saermark T, Tybjaerg-Hansen A, Birgens H. Prevalence of hereditary aemochromatosis in late-onset type 1 diabetes mellitus: a retrospective study.  Lancet. 2001;  358 1405-1409
    CrossrefPubMedGoogle Scholar
  • 10 Eshed I, Elis A, Lishner M. Plasma ferritin and type 2 diabetes mellitus: a critical review.  Endocr Res. 2001;  27 91-97
    CrossrefPubMedGoogle Scholar
  • 11 Feder J N, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy D A, Basava A, Dormishian F, Domingo R, Ellis M C, Fullan A, Hinton L M, Jones N L, Kimmel B E, Kronmal G S, Lauer P, Lee V K, Loeb D B, Mapa F A, McClelland E, Meyer N C, Mintier G A, Moeller N, Moore T, Morikang E, Prass C E, Quintana L, Starnes S M, Schatzman R C, Brunke K J, Drayna D T, Rischl N J, Bacon B R, Wolff R K. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.  Nat Genet. 1996;  4 399-408
    PubMedGoogle Scholar
  • 12 Feder J N, Penny D M, Irrinki A, Lee V K, Lebron J A, Watson N, Tsuchihashi Z, Sigal E, Bjorkman P J, Schatzman R C. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.  Proc Natl Acad Sci USA. 1998;  4 1472-1477
    PubMedGoogle Scholar
  • 13 Fernandez-Real J M, Ricart-Engel W, Arroyo E, Balanca R, Casamitjana-Abella R, Cabrero D, Fernandez-Castaner M, Soler J. Serum ferritin as a component of the insulin resistance syndrome.  Diabetes Care. 1998;  1 62-68
    PubMedGoogle Scholar
  • 14 Fernandez-Real J M, Vendrell J, Baiget M, Gimferrer E, Ricart W. C282Y and H63D mutations of the hemochromatosis candidate gene in type 2 diabetes.  Diabetes Care. 1999;  3 525-526
    PubMedGoogle Scholar
  • 15 Ford E S, Cogswell M E. Diabetes and serum ferritin concentration among U.S. adults.  Diabetes Care. 1999;  12 1978-1983
    PubMedGoogle Scholar
  • 16 Frayling T, Ellard S, Grove J, Walker M, Hattersley A T. C282Y mutation in HFE (haemochromatosis) gene and type 2 diabetes.  Lancet. 1998;  9120 1933-1934
    PubMedGoogle Scholar
  • 17 Gochee P A, Powell L W. What's new in hemochromatosis.  Curr Opin Hematol. 2001;  2 98-104
    PubMedGoogle Scholar
  • 18 Griffiths W J, Kelly A L, Smith S J, Cox T M. Localization of iron transport and regulatory proteins in human cells.  QJM. 2000;  9 575-587
    PubMedGoogle Scholar
  • 19 Griffiths W J, Sly W S, Cox T M. Intestinal iron uptake determined by divalent metal transporter is enhanced in HFE-deficient mice with hemochromatosis.  Gastroenterology. 2001;  6 1420-1429
    PubMedGoogle Scholar
  • 20 Hramiak I M, Finegood D T, Adams P C. Factors affecting glucose tolerance in hereditary hemochromatosis.  Clin Invest Med. 1997;  2 110-118
    PubMedGoogle Scholar
  • 21 Jeffrey G P, Chakrabarti S, Hegele R A, Adams P C. Polymorphism in intron 4 of HFE may cause overestimation of C282Y homozygote prevalence in haemochromatosis.  Nat. Genet.. 1999;  4 325-326
    PubMedGoogle Scholar
  • 22 Kaňková K, Márová I, Záhejský J, Mužík A, Znojil V, Vácha J. Polymorphisms 1704G/T and 2184A/G in the RAGE gene are associated with antioxidant status.  Metabolism. 2001;  10 1152-1160
    PubMedGoogle Scholar
  • 23 Mowri H O, Frei B, Keaney J F. Glucose enhancement of LDL oxidation is strictly metal ion dependent.  Free Radic Biol Med. 2000;  9 814-824
    PubMedGoogle Scholar
  • 24 Nedstrand E, Pertl J, Hammar M. Climacteric symptoms in a postmenopausal Czech population.  Maturitas. 1996;  23 85-89
    CrossrefPubMedGoogle Scholar
  • 25 Orino K, Lehman L, Tsuji Y, Ayaki H, Torti F M. Ferritin and the response to oxidative stress.  Biochem J. 2001;  1 241-247
    PubMedGoogle Scholar
  • 26 Parkkila S, Waheed A, Britton R S, Feder J N, Tsuchihashi Z, Schatzman R C, Bacon B R, Sly W S. Immunohistochemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in gastrointestinal tract.  Proc Natl Acad Sci USA. 1997;  6 2534-2539
    PubMedGoogle Scholar
  • 27 Phelps G, Chapman I, Hall P, Braund W, Mackinnon M. Prevalence of genetic haemochromatosis among diabetic patients.  Lancet. 1989;  8657 33-234
    PubMedGoogle Scholar
  • 28 Qian M, Liu M, Eaton J W. Transition metals bind to glycated proteins forming redox active “glycochelates”: implications for the pathogenesis of certain diabetic complications.  Biochem Biophys Res Commun. 1998;  2 385-389
    PubMedGoogle Scholar
  • 29 Qian M, Eaton J W. Glycochelates and the etiology of diabetic peripheral neuropathy.  Free Radic Biol Med. 2000;  4 652-656
    PubMedGoogle Scholar
  • 30 Rahier J, Loozen S, Goebbels R M, Abrahem M. The haemochromatotic human pancreas: a quantitative immunohistochemical and ultrastructural study.  Diabetologia. 1987;  1 5-12
    PubMedGoogle Scholar
  • 31 Rochette J, Pointon J J, Fisher C A, Perera G, Arambepola M, Arichchi D S, De Silva S, Vandwalle J L, Monti J P, Old J M, Merryweather-Clarke A T, Weatherall D J, Robson K J. Multicentric origin of hemochromatosis gene (HFE) mutations.  Am J Hum Genet. 1999;  4 1056-1062
    PubMedGoogle Scholar
  • 32 Ryab E, O'keane C, Crowe J. Hemochromatosis in Ireland and HFE.  Blood Cells Mol Dis. 1998;  24 428-432
    CrossrefPubMedGoogle Scholar
  • 33 Salonen J T, Tuomainen T P, Nyyssonen K, Lakka H M, Punnonen K. Relation between iron stores and non-insulin dependent diabetes in men: case-control study.  BMJ. 1998;  7160 727
    PubMedGoogle Scholar
  • 34 Sampson M J, Williams T, Heyburn P J, Greenwood R H, Temple R C, Wimperis J Z, Jennings B A, Willis G A. Prevalence of HFE (hemochromatosis gene) mutations in unselected male patients with type 2 diabetes.  J Lab Clin Med. 2000;  2 170-173
    PubMedGoogle Scholar
  • 35 Thorbe S R, Baynes J W. Role of the Maillard reaction in diabetes mellitus and diseases of aging.  Drugs Aging. 1996;  2 69-77
    PubMedGoogle Scholar
  • 36 Tuomainen T P, Nyyssonen K, Salonen R, Tervahauta A, Korpela H, Lakka T, Kaplan G A, Salonen J T. Body iron stores are associated with serum insulin and blood glucose concentrations. Population study in 1,013 eastern Finnish men Diabetes Carey 1997 3: 426-428
    Google Scholar
  • 37 Turnbull A J, Mitchison H C, Peaston R T, Lai L C, Bennett M K, Taylor R, Bassendine M F. The prevalence of hereditary haemochromatosis in a diabetic population.  QJM. 1997;  4 271-275
    PubMedGoogle Scholar
  • 38 Waheed A, Parkkila S, Zhou X Y, Tomatsu S, Tsuchihashi Z, Feder J N, Schatzman R C, Britton R S, Bacon B R, Sly W S. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells.  Proc Natl Acad Sci USA. 1997;  23 12384-12389
    PubMedGoogle Scholar

Kateřina KaňkováMD, PhD 

Masaryk University

Faculty of Medicine

Department of Pathophysiology

Komenského nám. 2

66243 Brno

Czech Republic

Phone: +420-5-42126556

Fax: +420-5-42126550

Email: kankov@med.muni.cz