Hemochromatisis HFE mutations: Penetrance in 451,000 adults of European descent

Abstract

Introduction HFE C282Y mutations account for the majority of hereditary hemochromatosis (HH) in people of European descent. HH is characterised by progressive accumulation of iron, plus chronic pain, exhaustion, arthritis, diabetes, liver cirrhosis and liver cancer. Previous studies (mainly in 20- to 50-year-olds) suggested that development of related disease in those with the mutation was uncommon. As a result of the claimed low penetrance, identification of additional cases within families is advised, but screening is not recommended. Methods We estimated C282Y homozygote associations with morbidity and mortality in 40- to 70-year-old UK Biobank volunteers, from England, Scotland and Wales. We included 451,243 subjects of European descent, and tested baseline and incident disease and mortality associations during follow-up (maximum 9.7 years). Follow-up was through hospital records, cancer registry and death certificates. Odds ratios and Cox hazard ratios were adjusted for age, sex and technical covariates. Results There were n = 2890 C282Y homozygote subjects (0.64% of the 451,243 subjects, or 1 in 156). Excess morbidity was most common in older men (age 60 to 70). C282Y homozygous status was associated with increased presence of hemochromatosis, liver disease, diabetes, arthritis, osteoporosis, pneumonia and polymyalgia rheumatica. Overall, 51.8% of older male C282Y homozygotes had ≥ 1 of the associated diagnoses, compared to 28.6% of those with the wild type (common) genotype: odds ratio = 2.63 95% CI: 2.23 to 3.10, P = 3.1 × 10−31. Increased risks for the associated conditions were also present in older women and younger groups but were less common. There was a modest increase in morbidity in heterozygotes. Conclusion We conclude that HFE C282Y homozygosity has a far higher penetrance than previously reported, and is a major contributor to common disease occurrence, especially with advancing age. The case for systematic early identification of iron overload related to HFE mutations needs to be re-examined.