Disease penetrance, cancer incidence and life-expectancy in p.C282Y homozygotes in Tyrol

Objective  Hemochromatosis is characterized by progressive iron overload and can cause cirrhosis and hepatocellular carcinoma. The most common disease-associated genotype is p.C282Y homozygosity in HFE. The reported incidence of iron overload in patients who are compound heterozygous for p.C282Y and p.H63D as well as for p.H63D homozygous individuals varies widely. We assessed the penetrance of iron overload for these genotypes.

Materials and Methods  8839 individuals from the Austrian region of Tyrol were genotyped for the p.C282Y and p.H63D variant between 1997 and 2021. Demographic, laboratory parameters, cancer incidence, survival and causes of death were assessed. Results were compared to a simulated cohort using agent-based modelling and matched using date of birth and sex.

Results  Median age at genotyping in 542 p.C282Y homozygous individuals was 47.8 years (64% male) and the prevalence of biochemical iron overload at time of genotyping was 55%. Among all expected Tyrolean residents with p.C282Y homozygosity, biochemical iron overload was 15.8% of men as compared to 8.9% of women aged 60 years. In 301 p.H63D homozygotes and 507 p.C282Y/p.H63D compound heterozygotes lower bounds of lifetime disease penetrance were 8.45% for males and 3.23% for females. In p.H63D males, penetrance was 3.36% and 0.96% for males and females respectively. There was no significant difference in cancer incidence, including hepatocellular carcinoma.

Conclusion  Penetrance of iron overload of those p.C282Y homozygotes referred for testing was high but low on a population level. Survival was reduced compared to a simulated control cohort. Age at diagnosis and sex are the strongest modifiers of disease penetrance.

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Artikel online veröffentlicht:
24. Mai 2023