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A study by researchers at the University of Tartu shows that the symptoms associated with hereditary iron metabolism disorders vary depending on specific genetic variants.
Hereditary hemochromatosis is a common condition that causes organ damage due to excessive iron accumulation. Although the disease is genetic, it does not manifest in the same way in all carriers of pathogenic variants associated with the disease. Some individuals remain completely symptom‑free, while others develop serious health problems. Symptoms most often affect the liver, heart and joints, and one of the earliest complaints is chronic fatigue.
Estonian researchers set out to understand why this is the case, using data from the Estonian Biobank and the UK Biobank. The study focused on how different hemochromatosis‑related gene variants actually manifest in real life.
Working with two biobanks
Hereditary hemochromatosis caused by defects in the HFE gene is the most common autosomal‑recessive disorder in Northern Europe, affecting an estimated 1 in 150–300 people. According to the researchers, it is likely underdiagnosed, even though treatment exists.
“Hereditary hemochromatosis is a disease with a wide range of symptoms, and predicting how different gene variants will manifest is challenging. We wanted to examine how this condition appears in Estonian Biobank donors who carry at least one of the three main hereditary hemochromatosis variants,” said Miriam Nurm, Junior Research Fellow in Genetics at the Institute of Genomics, University of Tartu.
Various analyses provided insights into which conditions and symptoms are more common among carriers of these variants and which genetic modifiers may influence disease expression. The researchers compared the diagnosis codes of hemochromatosis variant carriers with those of the rest of the biobank, examined potential disease‑related variants, and mapped additional variants that may influence the manifestation of hemochromatosis. The same approach was applied to UK Biobank data to compare results.
The significance of a previously underestimated variant
The study showed that carriers of the HFE variant p.S65C which is generally considered clinically insignificant exhibit more clinical symptoms than controls, particularly those related to the skin and urogenital system. According to Nurm, for example, various prostate‑related problems were diagnosed on average 11 years earlier in individuals carrying two pathogenic variants – at least one of which was S65C – compared with those who did not carry this variant.
“We also identified a new variant (CP rs61733458) that may significantly influence the manifestation and progression of diseases related to both iron and copper metabolism,” Nurm added. To determine this, the researchers conducted a genome‑wide association study to identify variants that affect the level or function of the protein regulating copper and iron metabolism. Nurm noted that this variant has previously been found in patients diagnosed with Parkinson’s disease and non‑alcoholic fatty liver disease.
A comparison of the Estonian Biobank and the UK Biobank highlights the immense value of large biobanks in understanding the true impact of genetic diseases in populations. “They allow us to link genes with associated symptoms and to study rare variants that might otherwise go unnoticed,” Nurm explained.
Researchers from the University of Tartu’s Institute of Genomics who contributed to the study were Miriam Nurm, Tarmo Annilo, Anu Reigo, Reedik Mägi, Urmo Võsa and Neeme Tõnisson. The study was led by Toomas Haller.
We are especially grateful to the donors to the Estonian Biobank.
DOI: https://doi.org/10.1186/s12864-026-12746-3
This article was sent to us by University of Tartu.
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