No Association Between Factor V Leiden and C282Y Mutation in the Hereditary Hemochromatosis Gene

To the Editor:

In a preliminary paper in Blood, Xie et al1 have reported on a surprising observation that documented a highly significant association between the heterozygous states for the factor 5 Leiden and the HFE C282Y mutations in a population referred for a molecular study of hyper coagulability.1 In this population composed of 87 patients, the carrier frequency for the HFE C282Y mutation was 18.7%, compared with 6% in their normal population. The C282Y mutation is the most common mutation in the hereditary hemochromatosis gene (HH). Hemochromatosis is an autosomal-recessive iron-metabolism disorder with a high prevalence, 2 to 5 of 1,000, in the white population. The gene responsible for the disease was cloned 2 years ago and designated as HFE.2 A very prevalent mutation, cys 282 Tyr, was detected in 80% to 90% of patients and a second mutation resulting in a change from histidine to aspartic acid was found also in 5% of patients suffering from hemochromatosis.3,4 The preliminary work of Xie et al was based on the fact that thromboembolism events are caused by a combination of genetic and environmental factors; therefore, they suggested that the C282Y mutation in the HFE gene could be a genetic cofactor in addition to the factor 5 Leiden mutation (R506Q). As we have had the opportunity of confirming or infirming these data from our population under study, we report on our results determined from a large cohort of 481 patients, all diagnosed for venous thrombosis and all positive for the factor 5 Leiden mutation. This population issued from the western part of Brittany (France) is characterized by an 8% allele frequency for the C282Y mutation, which constitutes one of the highest frequencies recorded in European populations. Thus, we are in charge of a large cohort of more than 500 hemochromatosis patients.5 

In this population of 481 factor 5–positive patients, we found 82 patients heterozygous for the C282Y mutation and 2 who were homozygous. This corresponds to a carrier frequency of 17% and to an allelic frequency of 8.89% among this group of individuals, whereas the allelic frequency was 8% in our control population from the same ethnic origin; these frequencies between patients and controls are not statistically significant.

Our observations based on a large cohort of factor 5–positive patients with venous thrombosis did not enable us to confirm an association between the heterozygous state for the factor 5 Leiden and the C282Y mutation. Consequently, the hypothesis of an influence of HFE C282Y mutation on the risk of venous thrombotic event does not seem to be relevant.