HFE Gene
HFE Gene (Hereditary Haemochromatosis — C282Y & H63D)
What it is
The HFE gene encodes the haemochromatosis protein (HFE), which regulates hepcidin production — the master hormonal regulator of systemic iron absorption. Hepcidin is produced by the liver and acts on the iron exporter ferroportin (expressed on enterocytes, macrophages, and hepatocytes) to reduce iron release into the circulation. In individuals with functional HFE, hepcidin production responds appropriately to iron loading, suppressing intestinal iron absorption when iron stores are adequate. Two common variants in the HFE gene are clinically significant: the C282Y variant (a cysteine-to-tyrosine substitution at position 282) disrupts the HFE protein's interaction with beta-2-microglobulin, preventing its proper folding and surface expression; the H63D variant (a histidine-to-aspartate substitution at position 63) has a milder effect on HFE function. In C282Y homozygotes (C282Y/C282Y), hepcidin signalling is severely impaired, leading to constitutively unregulated intestinal iron absorption — typically 3–4 mg per day instead of the normal 1–2 mg — and progressive iron accumulation in the liver, heart, pancreas, joints, and pituitary over decades. HFE haemochromatosis is the most common autosomal recessive disorder in populations of northern European descent, affecting approximately 1 in 200 individuals.
Why we measure it
Hereditary haemochromatosis is simultaneously one of the most common, most preventable, and most underdiagnosed serious genetic disorders. Iron accumulation proceeds silently from early adulthood — the liver is the primary storage organ, with subsequent deposition in the heart (causing cardiomyopathy and arrhythmias), pancreas (causing diabetes from beta-cell destruction, termed 'bronze diabetes'), joints (causing arthropathy, particularly of the second and third metacarpophalangeal joints — a characteristic feature), pituitary (causing hypogonadism through gonadotropin suppression), and skin (causing the bronze pigmentation that gives the condition its historical name). By the time these complications are clinically apparent, the organ damage is often advanced and partially irreversible. The critical clinical point is that haemochromatosis is completely preventable through phlebotomy — regular removal of blood (typically 450–500 mL every 1–2 weeks until iron stores are depleted, then maintenance phlebotomy every 3–4 months) — if the genetic diagnosis is established before organ damage occurs. Regular phlebotomy in preclinical haemochromatosis produces normal life expectancy; phlebotomy initiated after cirrhosis has developed does not reverse liver fibrosis, and diabetes from pancreatic iron deposition is often irreversible. Genetic testing at enrollment identifies individuals who require iron studies monitoring (transferrin saturation and ferritin at minimum) — and allows phlebotomy to begin at the point of iron overload, not at the point of organ failure.
Why once at enrollment
HFE genotype is determined at conception and does not change. A single test at enrollment produces a lifetime result. The genotype result determines the iron studies monitoring strategy: C282Y homozygotes require regular iron studies (ferritin and transferrin saturation, already in the Blueprint Pulse draw) and clinical review; heterozygotes (C282Y/H63D compound or simple C282Y carriers) have lower but not zero iron overload risk and benefit from periodic iron studies monitoring.
What movement means
HFE testing produces a categorical genotype result. The C282Y and H63D variants are each reported as wild-type (normal allele), heterozygous (one variant copy), or homozygous (two variant copies).
Non-Carrier (Wild Type)
C282Y wild type / H63D wild type
No HFE variants detected. Hereditary haemochromatosis from HFE variants is not a concern. Ferritin monitoring in the Pulse draw serves its standard inflammation and iron status functions without requiring haemochromatosis-specific interpretation.
Feder JN et al., Nature Genetics, 1996 — doi:10.1038/ng0896-399
Simple Heterozygote
C282Y heterozygous (C282Y/WT) or H63D heterozygous (H63D/WT)
Carrier of one variant allele. Clinically significant iron overload is uncommon in simple heterozygotes; however, elevated transferrin saturation (> 45%) or ferritin warrants the same investigation as in the general population. Awareness of carrier status is relevant for family screening if iron overload is identified.
Bacon BR et al., Hepatology, 2011 — doi:10.1002/hep.24330
Compound Heterozygote
C282Y / H63D (one of each variant)
Compound heterozygosity — one copy of each variant. Moderate iron overload risk, lower than C282Y homozygosity. Approximately 1–2% of compound heterozygotes develop clinically significant haemochromatosis. Iron studies monitoring (transferrin saturation, ferritin) at least annually is appropriate, with referral if either is elevated.
Bacon BR et al., Hepatology, 2011 — doi:10.1002/hep.24330
C282Y Homozygote
C282Y / C282Y (two C282Y variants)
The genotype responsible for classical hereditary haemochromatosis. Approximately 70–80% of C282Y homozygotes will develop iron overload; approximately 25–30% of males and 1–5% of females will develop clinical disease if untreated. Iron studies monitoring (transferrin saturation + ferritin) at each Pulse draw is essential. Transferrin saturation persistently > 45% or ferritin rising above normal warrants phlebotomy therapy and hepatology review.
Feder JN et al., Nature Genetics, 1996 — doi:10.1038/ng0896-399
In the protocol
References
- 1.
Feder JN, Gnirke A, Thomas W, et al.. “A Novel MHC Class I-Like Gene Is Mutated in Patients with Hereditary Haemochromatosis.” Nature Genetics. 1996.
- 2.
Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS. “Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases.” Hepatology. 2011.
- 3.
Pietrangelo A. “Hereditary Hemochromatosis — A New Look at an Old Disease.” New England Journal of Medicine. 2004.
- 4.
Allen KJ, Gurrin LC, Constantine CC, et al.. “Iron-Overload-Related Disease in HFE Hereditary Hemochromatosis.” New England Journal of Medicine. 2008.