Hereditary hemochromatosis (HH) is a common disorder of iron overload and over 80% of patients are homozygous for the C282Y mutation in the HFE gene. Clinical manifestations of HH vary widely from non-specific symptoms associated with mild iron overload to severe organ damage due to iron deposition in the liver, heart, joints and pancreas. Penetrance is age-dependent and it is estimated that only about half of all C282Y homozygotes will express clinical disease. A number of factors may modify expression of disease in HH and both genetic and environmental factors are potentially important. There are several promising candidate genes in the iron transport pathway that could modify the effect of HFE mutations. The overall aim of this project is to evaluate genetic modifiers of phenotypic variability in HH. We hypothesize that haplotypes in genes involved in iron transport and storage, and regulation of iron homeostasis, modify iron overload as measured by serum ferritin and transferrin saturation, in HFE mutation carriers. This study will use the resources of an existing unique Australian general population cohort of 41,500 men and women aged 40-69 years at enrollment. Initial HFE mutation testing will be conducted on the entire cohort. Participants have been followed for almost 10 years and extensive epidemiologic and dietary data and a blood specimen were collected at baseline. A sub cohort (n=1,150) that includes all C282Y homozygotes and an age-matched stratified random sample of other HFE genotypes and wild-type individuals will be selected for clinical follow-up. Siblings of C282Y homozygotes will also be invited for clinical follow-up. For this sub-cohort, serum ferritin and transferrin saturation will be measured on follow-up samples as well as on the samples collected at baseline approximately 10 years earlier. Variants in potential modifier genes in the pathways described above will be systematically identified and haplotypes will be determined using a computational algorithm. Individuals in the subcohort will be tested for variants to define these haplotypes and we will look for interaction with HFE mutations using measures of iron overload as the outcome. In addition, we will utilize the epidemiologic and dietary data on the cohort to evaluate whether dietary and lifestyle factors modify HH phenotype and how these factors may interact with the genetic modifiers described above. Finally, the functional significance of variants that are associated with iron overload will be determined. The identification of genetic and environmental modifiers of HH phenotype in this study has potentially important implications for clinical management of genetically susceptible people and for public health decision-making regarding screening for HH. HH is a model disease for studying gene-gene interaction due to the availability of intermediate markers of iron overload and promising candidate modifier genes in iron transport pathways.
