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Most individuals suffering from the iron-overload disease hereditary haemochromatosis carry mutations in both copies of their HFE gene. The two disease-associated mutations that have been identified are known as C282Y and H63D. As the population prevalence of genetically defined hereditary haemochromatosis has been estimated to be between 1 in 200 and 1 in 500, and a relatively straightforward preventive treatment is available (regular phlebotomy), it has often been suggested that population screening for hereditary haemochromatosis should be offered. However, accurate information is lacking on the prevalence and penetrance of haemochromatosis-associated mutations, and on the financial and social consequences of treating people who have a disease susceptibility rather than the disease itself. Steinberg et al contribute an important piece of information to the analysis: population-based estimates of the prevalence of C282Y and H63D mutations in the US population [Steinberg, K et al (2001) JAMA 285, 2216-2222 (Abstract)]. Using DNA from cell lines established as part of the Third National Health and Nutrition Examination Study (NHANES III), they genotyped 5171 individuals who described their race as non-Hispanic white, non-Hispanic black, or Mexican American. They estimate that overall approximately 0.26% (1 in 385) Americans are homozygous for C282Y, 1.89% are homozygous for H63D and 1.97% are compound heterozygotes (i.e. C282Y/H63D). The prevalence of the C282Y allele is significantly higher in non-Hispanic whites than in the other two racial/ethnic groups.

Comment: The results of this study are broadly in line with previous estimates from smaller studies, confirming a relatively high prevalence of genotypes associated with hereditary haemochromatosis in populations of predominantly white European origin. Steinberg et al are currently determining transferrin saturation levels (that is, a phenotypic indication of haemochromatosis) in the NHANES III samples, in an attempt to estimate the penetrance of the mutations. However, as the samples have been irrevocably anonymised, it will presumably not be possible to estimate the penetrance of the genotypes in terms of overt disease.