Haemochromatosis and HLA--H

The recently identified can didate gene, HLA-H, for haemochromatosis (HH) by Feder et al. generated considerable scientific interest coupled with a degree of uncertainty about the likely involvement of this gene in this common iron metabolism disorder, Feder et al. found a single point mutation resulting in an amino acid substitution (C282Y) that was homozygous in 148 (83%) of their patients, heterozygous in 9 patients (5%) but completely absent in 21 patients (12%). They proposed that the lack of a causative mutation in HLA-H in 12% of their patients was because these cases were not linked to chromosome 6p. A significant weakness in this argument is that all familial studies of the disorder so far have concluded that HH is due to a single major HLA-linked gene5-7. The ultimate test for a candidate gene is the clear segregation of a mutation with the disorder in all patients. Thus, some of the uncertainty surrounding the role of HLA-H in HH may be resolved by the identification of complete concordance of the C282Y mutation (or some other mutation) in HLA H with disease status in HH families. One potential problem in the design of such an experimental analysis is that a number of studies have shown the presence of a predominant ancestral haplotype in all HH populations examined: Australian, French, Italian, UK and US Thus in the analysis of a putative causative mutation, it is important to include families with...

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10−8) loci, some including known iron-related genes (​HFE, ​SLC40A1, ​TF, ​TFR2, ​TFRC, ​TMPRSS6) and others novel (​ABO, ​ARNTL, ​FADS2, ​NAT2, ​TEX14). SNPs at ​ARNTL, ​TF, and ​TFR2 affect iron markers in ​HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.

Genetic testing for haemochromatosis in patients with chondrocalcinosis

Hereditary haemochromatosis (HH) is the most common lethal monogenic human disease, affecting roughly 1 in 300 white northern Europeans. Homozygosity for the C282Y polymorphism within the HFE gene causes more than 80% of cases, with compound heterozygosity of the C282Y and H63D polymorphism also increasing susceptibility to disease. The aim of this study was to determine the frequency of the C282Y and H63D polymorphisms in the disease, and to assess the risk of HH in heterozygotes for the C282Y polymorphism. 128 patients were recruited because of either radiographic chondrocalcinosis (at least bicompartmental knee disease or joints other than the knee involved) or CPPD pseudogout. Genotyping of the HFE C282Y and H63D mutations was performed using PCR/SSP and genotypes for the C282Y polymorphism confirmed by PCR/RFLP. Historical white European control data were used for comparison. Two previously undiagnosed C282Y homozygotes (1.6%), and 16 C282Y heterozygotes (12.5%), including four (3.1%) C282Y/ H63D compound heterozygotes were identified. This represents a significant overrepresentation of C282Y homozygotes (relative risk 3.4, p-0.037), but the number of heterozygotes was not significantly increased. At a cost per test of £1 for each subject, screening all patients with chondrocalcinosis using the above ascertainment criteria costs only £64 for each case of haemochromatosis identified, clearly a highly cost effective test given the early mortality associated with untreated haemochromatosis. Routine screening for haemochromatosis in patients with appreciable chondrocatcinosis is recommended.