Abstract for presentation at 11th International Congress of Human Genetics

Type I hereditary hemochromatosis: dominating role of the environmental factors on the appearance of biological signs in patients C282Y/H63D

  • Virginie Scotet, INSERM U 613 (INSERM - UBO - EFS), Brest, France
  • Gérald Le Gac, Etablissement Français du Sang-Bretagne, Site de Brest, France
  • Marie-Christine Mérour, Etablissement Français du Sang-Bretagne, Site de Brest, France
  • Anne-Yvonne Mercier, Etablissement Français du Sang-Bretagne, Site de Brest, France
  • Brigitte Chanu, Etablissement Français du Sang-Bretagne, Site de Brest, France
  • Chandran Ka, Université de Bretagne Occidentale, Brest, France
  • Catherine Mura, Université de Bretagne Occidentale, Brest, France
  • Claude Férec, INSERM U 613 (INSERM - UBO - EFS), Brest, France

    • Hereditary hemochromatosis (HH) is a complex disorder of iron metabolism whose main form (type I) is usually associated with missense mutations in the HFE gene. The penetrance of the main C282Y/C282Y genotype is incomplete and influenced by genetic and environmental factors. Most of the non-C282Y homozygous patients carry the C282Y/H63D genotype, which has a lower penetrance and leads to more moderate iron overloads. It is therefore probable that, in this genotypic group, the environmental factors play a dominating role in the appearance of the first signs of the disease. This study aimed to determine and compare the role of two environmental factors (overweight and excessive alcohol consumption) on the phenotypic expression of these two genotypes. The study included all the C282Y/C282Y (n=400) and C282Y/H63D (n=71) patients enrolled in a phlebotomy program at the blood centre of Brest (western Brittany, France). The proportion of overweight patients (BMI≥25 kg/m²) was significantly higher among the C282Y/H63D patients (66.2 vs. 34.8%, p<0.0001), this being observed for males (70.0 vs. 39.9%, p=0.0001) as for females (57.1 vs. 29.2%, p=0.0090). Excessive alcohol consumption (≥60 g/day) was also significantly more frequent in this group (19.7 vs. 7.7%, p=0.0056). At least one of these environmental factors was present in 67.2% of the C282Y/H63D patients versus in 39.4% of the other patients (p<0.0001). Serum ferritin was significantly higher in homozygous patients, but increased with the degree of overweight in both genotypic groups. A multiple linear regression model was used to determine the effect of BMI on the degree of iron overload measured by the serum ferritin; it showed that after adjustment the role of BMI on degree of iron overload remained significant only in the group of C282Y/H63D patients (p=0,017). This study highlights that the environmental factors, which modulate the severity of the phenotypic expression among the C282Y/C282Y patients, play a major role in the appearance of biological signs among the C282Y/H63D patients, especially the overweight. This study contributes to explain a part of the phenotypic heterogeneity observed in this complex disease.

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