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CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients
Sara Pelucchi1, Raffaella Mariani, Stefano Calza
1Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy.
Insights
Genetic factors influence hereditary hemochromatosis (HH) expression in HFE p.C282Y homozygotes. While CYBRD1 variants show associations, no single polymorphism significantly modifies HH phenotype, suggesting complex genetic interactions.
Area of Science:
- Genetics
- Iron Metabolism
- Human Physiology
Background:
- Hereditary hemochromatosis (HH) is often associated with the HFE p.C282Y mutation in Caucasians.
- Significant variability exists in HH penetrance and expression among individuals with the same HFE genotype.
- Environmental and additional genetic factors likely contribute to HH phenotype variability.
Purpose of the Study:
- To investigate the role of genetic variations in iron metabolism genes on HH phenotype.
- To identify single nucleotide polymorphisms (SNPs) associated with iron overload markers in p.C282Y homozygous Italians.
- To assess the predictive value of these genetic variants for adverse HH phenotypes.
Main Methods:
- Analysis of 214 SNPs in 50 iron metabolism genes.
- Association testing with serum ferritin, iron removed, and transferrin saturation in 296 p.C282Y homozygous Italians.
- Linear regression models adjusted for age, sex, and alcohol consumption.
Main Results:
- Seventeen genetic variants showed potential additive effects on iron overload markers.
- A significant association was found between CYBRD1 SNP rs3806562 and transferrin saturation.
- This SNP (rs3806562) appears to be a marker for a functional variant (rs884409) influencing serum ferritin, but rs3806562 itself lacks direct functional impact.
Conclusions:
- Polymorphisms in iron metabolism genes, particularly CYBRD1, may modulate HH penetrance.
- No single identified polymorphism acts as a major modifier of the HH phenotype.
- The findings support a complex genetic architecture underlying HH phenotype variability.
Background:
Most patients with hereditary hemochromatosis in the Caucasian population are homozygous for the p.C282Y mutation in the HFE gene. The penetrance and expression of hereditary hemochromatosis differ largely among cases of homozygous p.C282Y. Genetic factors might be involved in addition to environmental factors.
Design And Methods:
In the present study, we analyzed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 p.C282Y homozygous Italians. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption.
Results:
We found a series of 17 genetic variants located in different genes with possible additive effects on the studied outcomes. In order to evaluate whether the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction could be achieved by adding genetic information to clinical data. Among the selected polymorphisms, a significant association was observed between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation. This variant belongs to the same haplotype block that contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. A luciferase assay indicated that rs3806562 does not have a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409.
Conclusions:
While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-hereditary hemochromatosis, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of the phenotype of hereditary hemochromatosis.
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