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Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients
  1. C A McCune1,
  2. D Ravine2,
  3. K Carter3,
  4. H A Jackson4,
  5. D Hutton5,
  6. J Hedderich6,
  7. M Krawczak5,
  8. M Worwood3
  1. 1Bristol Royal Infirmary, Malborough St, Bristol, UK
  2. 2Western Australian Institute for Medical Research, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
  3. 3Department of Haematology, School of Medicine, Cardiff University, Heath Park, Cardiff, UK
  4. 4Royal Gwent Hospital, Newport, UK
  5. 5The Welsh Blood Service, Ely Valley Road, Talbot Green, Pontyclun, UK
  6. 6Institut für Medizinische Informatik und Statistik, Christian-Albrechts-Universität, Kiel, Germany
  1. Correspondence to:
    Dr A McCune
    Bristol Royal Infirmary, Malborough St, Bristol BS2 8HW, UK; anne.mccune{at}


Background and aims: Although most cases of hereditary haemochromatosis are associated with homozygosity for the C282Y mutation of the HFE gene, clinical penetrance varies and other genes may modify disease expression. If so, relatives from clinically affected families, by inheriting such genes, may accumulate more iron. To seek evidence for this, we compared iron status and morbidity in unselected first degree relatives of two groups of index cases from South Wales, namely asymptomatic C282Y homozygotes identified by genetic screening of blood donors (n = 56) and C282Y homozygous haemochromatosis patients presenting clinically (n = 60).

Methods: All participating relatives had a structured interview, clinical assessment, and laboratory investigations. Health related quality of life was measured (SF-36 version 2).

Results: In total, 92% of 180 eligible first degree relatives were interviewed in the “screened” family group and 85% of 143 eligible relatives in the “patient” group. Of 59 relatives homozygous for C282Y, 76% of men and 32% of women had the “iron phenotype” (raised transferrin saturation and serum ferritin). Logistic regression modelling of the iron phenotype risk showed that 42% of the initial model deviance could be explained by homozygosity for C282Y, another 6% by lifestyle factors, and 6% by being male. Family group membership was not a significant risk factor. Morbidity and SF-36 scores did not differ significantly either between C282Y homozygotes and relatives lacking C282Y, or between C282Y homozygotes from the “screened” and “patient” groups. Serious morbidity (including cirrhosis) was low in both groups of relatives.

Conclusions:HFE C282Y homozygosity has a high penetrance for iron accumulation but a low clinical penetrance. Lack of excess morbidity among C282Y homozygous relatives of index cases who presented clinically suggests that residual unknown genetic or environmental factors do not greatly influence clinical outcome among C282Y homozygotes.

  • AST, aspartate aminotransferase
  • Hb, haemoglobin
  • HH, hereditary haemochromatosis
  • MCH, mean cell haemoglobin
  • MCV, mean corpuscular volume
  • PCP, physical component score
  • QOL, quality of life
  • sFe, serum iron concentration
  • sFn, serum ferritin concentration
  • TIBC, total iron binding capacity
  • UIBC, unsaturated iron binding capacity
  • TS, transferrin saturation
  • haemochromatosis
  • iron metabolism
  • clinical penetrance
  • HFE
  • genetic modifiers

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  • Published online first 23 September 2005

  • Conflict of interest: None declared