CYBRD1 – Hereditary Hemochromatosis

Hereditary hemochromatosis is an autosomal recessive iron overload disorder most often caused by HFE p.Cys282Tyr homozygosity. Clinical penetrance is variable, suggesting modifier loci influence iron indices. CYBRD1 encodes duodenal cytochrome b, an ascorbate-dependent ferric reductase critical for dietary iron uptake. In a cohort of 863 northern European individuals stratified by HFE genotype, the promoter SNP rs884409 in CYBRD1 was associated with reduced median serum ferritin from 1194 µg/l (N = 27) to 387 µg/l (N = 16) in males and from 357 µg/l (N = 42) to 69 µg/l (N = 12) among C282Y homozygotes (PMID:19673882). A second study of 296 Italian C282Y homozygotes identified rs3806562 in the same haplotype block as a marker for transferrin saturation but found no independent functional effect in luciferase assays (PMID:22773607). Functional assays demonstrated a 30% decrease in basal CYBRD1 promoter activity for the rs884409 allele (P = 0.004), supporting a mechanism of reduced enteric ferrireduction leading to lower iron absorption (PMID:19673882).

Overall, evidence is limited to modifier associations without reports of rare CYBRD1 coding variants segregating with disease. No segregation studies or case reports of monogenic CYBRD1 deficiency in hemochromatosis have been described. Additional large cohorts and functional correlations are required to establish clinical utility.

Key Take-home: CYBRD1 promoter variant rs884409 modestly reduces iron loading in HFE C282Y homozygotes and may inform risk stratification in hereditary hemochromatosis.

References

• British journal of haematology • 2009 • A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis. PMID:19673882
• Haematologica • 2012 • CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients. PMID:22773607

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