Association of mutations in the hemochromatosis gene with shorter life expectancy

Background: To investigate whether the frequency of carriers of mutations i n the HFE gene associated with hereditary hemochromatosis diminishes with a ge as an indication that HFE mutations are associated with increased mortal ity, it is of value in the debate concerning screening for hereditary hemoc hromatosis to determine the significance of heterozygosity. Methods: Genotyping for mutations in exons 2 and 4 of the HFE gene using de naturing gradient gel electrophoresis in 1784 participants aged 45 to 100 y ears from 4 population-based studies: all 183 centenarians from the Danish Centenarian Study, 601 people aged 92 to 93 years from the Danish 1905 Coho rt, 400 aged 70 to 94 years from the Longitudinal Study of Aging Danish Twi ns, and 600 aged 45 to 67 years from a study of middle-aged Danish twins. Results: All participants (N=1784) were screened for mutations in exon 4, a nd a trend toward fewer heterozygotes for the C282Y mutation-the mutation m ost often associated with hereditary hemochromatosis-was found. This was si gnificant for the whole population (P=.005) and for women (P=.004) but not for men (P=.26). A group of 599 participants was screened for mutations in exon 2, and there was no variation in the distribution of mutations in exon 2 in the different age groups. Conclusions: In a high-carrier frequency population like Denmark, mutations in HFE show an age-related reduction in the frequency of heterozygotes for C282Y, which suggests that carrier status is associated with shorter life expectancy.