medwireNews: A study published in The BMJ reveals that individuals homozygous for the homoeostatic iron regulation (HFE) gene variant C282Y may face a higher risk for diabetes, even if they have normal transferrin saturation or ferritin levels.
Several guidelines recommend genotyping for hemochromatosis only in patients who have increased transferrin saturation or ferritin concentrations, note the researchers, who say that this strategy may “fail to detect some C282Y homozygotes at increased risk for diabetes.”
Moreover, among people with diabetes in the study, those homozygous for C282Y had an increased risk for death compared with non-C282Y carriers.
For the prospective cohort study, Andreas Glenthøj, from the University of Copenhagen in Denmark, and colleagues analyzed data from three Danish general population studies involving 132,542 individuals.
The participants (aged 20–100 years) were genotyped for the HFE gene variants C282Y and H63D using DNA extracted from peripheral blood leukocytes, and then followed-up for a median of 41 years to determine their risk for diabetes, liver disease, or heart disease based on hospital admissions and outpatient data identified from national registers.
The findings showed that 422 individuals who were homozygous for the C282Y variant had a significantly increased risk for diabetes, at a hazard ratio (HR) of 1.72 after adjusting for sex and age, compared with the 87,313 individuals who were noncarriers, with respective rates of 8.5% and 5.8%.
The investigators estimated that the absolute 5-year risk for diabetes in C282Y homozygous women would range from 0.54% in 20–39-year-olds to 4.3% in those aged 80 years and older, compared with 0.37–3.0% in noncarrier women, while the corresponding range for C282Y homozygous and noncarrier men would be 0.86–6.8% versus 0.60–4.8%.
People homozygous for C282Y also had a significantly increased risk for liver disease compared with noncarriers, at an HR of 2.22 and respective rates of 4.3% and 2.1%, but they did not have a significantly increased risk for heart disease.
The researchers note that the risk for diabetes and liver disease was not significantly increased among the 12,154 individuals who were heterozygous C282Y carriers, nor for those who were heterozygous or homozygous for the H63D variant (n=27,820 and 2358, respectively) or for the 2115 H63D/C282Y carriers.
The researchers then stratified the patients according to their plasma iron, transferrin saturation, and ferritin levels based on a single blood sample taken at enrolment. They found that the risk for diabetes among individuals who were homozygous for the C282Y variant and had normal transferrin saturation (10–45% for women aged ≤50 years and 15–45% for women >50 and men regardless of age) or normal ferritin levels (12–200 µg/L for women and 12–300 µg/L for men) was significantly increased 2.00-fold and 3.76-fold, respectively, compared with noncarriers with normal levels. For C282Y homozygous carriers with both normal transferrin saturation and ferritin levels, the risk for diabetes was increased a significant 6.49-fold.
The risk for diabetes among homozygous C282Y carriers with normal iron levels (9–34 µmol/L in men and women) was “less pronounced,” say the investigators.
The researchers also point out that for the 36 individuals who were homozygous for C282Y and had diabetes, the risk for death from any cause was nearly double that for the the 5095 noncarriers with diabetes (HR=1.94), occurring in a respective 44% and 32% of patients. Moreover, 27.3% of deaths in the C282Y homozygous group were potentially attributable to diabetes, compared with 7.8% of deaths among noncarriers with diabetes.
The authors conclude that their findings challenge the assumption "that progressive systemic iron accumulation is the only mechanism causing increased risk of diabetes in C282Y homozygotes," and suggest that screening for diabetes in C282Y homozygotes and initiating therapy should be considered in future clinical guidelines on hereditary hemochromatosis.
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group
