High risk of death for individuals with C282Y/C282Y hereditary haemochromatosis and diabetes

Individuals with C282Y/C282Y genotypes, a hereditary cause of haemochromatosis, have an increased risk of diabetes, even if they have normal levels of iron, transferrin saturation, or ferritin. Also, the risk of death is two times higher for C282Y homozygotes than in wildtype individuals with diabetes. These were the main outcomes of a large Danish cohort study.

“There are several genetic variants that can affect hepcidin levels in the context of hereditary haemochromatosis,” explained Dr Mathis Mottelson (Copenhagen University Hospital, Denmark). “Today I will focus on two genotypes: wildtype/wildtype individuals, who have normal hepcidin levels and normal iron uptake, and C282Y/C282Y individuals, who generally show lowered hepcidin levels and increased iron uptake.” Dr Mottelson and colleagues hypothesised that C282Y homozygotes have an increased risk of diabetes and death even with normal levels of iron and transferrin saturation, The study included 132,542 individuals. Plasma iron, transferrin saturation, ferritin, and haemochromatosis genotype were measured for each individual and all participants were followed prospectively for up to 28 years [1].

The risk for diabetes was increased in C282Y homozygotes (n=422) compared with wildtype individuals (n=87,313; HR 1.66; 95% CI 1.20–2.31; P=0.002), even when C282Y homozygotes presented with normal iron levels (HR 1.67; P=0.007), normal transferrin saturation (HR 2.49; P=0.002), or normal ferritin (HR 4.35; P=0.001, all compared with wildtype individuals). While the risk of death for C282Y homozygotes and wildtype individuals was comparable for individuals without diabetes, the risk of death in C282Y homozygotes with diabetes was significantly higher than in wildtype individuals with diabetes (HR 4.39 vs 2.26; P=0.008). Dr Mottelson added that the population-attributable fraction of all deaths of diabetes was 27.3% in the group of C282Y homozygotes with diabetes.

“Future research should focus on how to improve the testing and treatment specifically for individuals with C282Y/C282Y hereditary haemochromatosis,” concluded Dr Mottelson.

1. Mottelson M, et al. Individuals with HFE C282Y homozygosity and diabetes have almost two-fold risk of death compared to non-carriers with diabetes: a prospective study of a 132,542-individual general population cohort. Plenary abstracts session, EHA 2023 Annual Congress, 8─11 June, Frankfurt, Germany.

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Posted on 2 August, 202325 March, 2024