rs1799945 — HFE H63D

HFE H63D — The Common Iron Variant

The HFE gene produces a protein that acts as an iron gatekeeper. It sits on the surface of cells in the gut and liver, where it binds to transferrin receptor 1¹¹ transferrin receptor 1
TfR1: the main receptor cells use to take up iron from the blood via iron-loaded transferrin and helps the body sense how much iron is circulating. When iron levels are adequate, HFE triggers production of hepcidin²² hepcidin
A hormone produced by the liver that acts as the master regulator of iron absorption — it blocks the iron exporter ferroportin on gut cells, reducing dietary iron uptake, the master hormone that puts the brakes on iron absorption. The H63D variant (rs1799945) is a C-to-G change in exon 2 that swaps histidine for aspartic acid at position 63, subtly weakening HFE's grip on transferrin receptor 1 and mildly blunting the hepcidin response.

H63D is the second most common HFE variant after C282Y (rs1800562). While C282Y is the primary driver of hereditary hemochromatosis — the most common genetic disorder in people of Northern European descent — H63D has a milder and more nuanced role. It is far more common (carried by roughly one in four Europeans) yet far less likely to cause clinical iron overload on its own.

The Mechanism

The HFE protein is structurally similar to MHC class I molecules³³ MHC class I molecules
Major histocompatibility complex class I: the immune system proteins that display fragments of internal proteins on the cell surface for immune surveillance. It folds with beta-2 microglobulin and competes with iron-loaded transferrin for binding to transferrin receptor 1 (TfR1). When iron levels rise, HFE releases from TfR1 and instead binds TfR2, which triggers a signaling cascade that upregulates hepcidin production. Hepcidin then degrades ferroportin — the only known cellular iron exporter — on intestinal enterocytes, effectively closing the gate on dietary iron absorption.

The H63D substitution sits in the alpha-1 domain of HFE, outside the primary TfR1 binding interface (which involves the alpha-1/alpha-2 groove). It reduces but does not abolish the interaction with TfR1. The result is a modest decrease in hepcidin signaling: enough to slightly increase baseline iron absorption but not enough to cause the dramatic iron loading seen with C282Y, which completely disrupts HFE folding and surface expression.

The Evidence

The HFE gene was discovered in 1996⁴⁴ discovered in 1996
Feder JN et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet, 1996 by Feder and colleagues, who found that 83% of hemochromatosis patients were homozygous for C282Y. In the same study, H63D was identified on chromosomes that carried hemochromatosis but not C282Y.

A pooled analysis of 14 case-control studies⁵⁵ pooled analysis of 14 case-control studies
Burke W et al. Contribution of different HFE genotypes to iron overload disease: a pooled analysis. Genet Med, 2000 quantified the risk by genotype: H63D homozygotes had an OR of 5.7 (95% CI 3.2-10.1) for iron overload, while C282Y/H63D compound heterozygotes had OR 32 (95% CI 18.5-55.4) — still far below C282Y homozygotes at OR 4,383. Simple H63D heterozygotes had only a marginal elevation (OR 1.6, 95% CI 1.0-2.6).

A dedicated study of 170 H63D homozygotes⁶⁶ dedicated study of 170 H63D homozygotes
Kelley M et al. Iron overload is rare in patients homozygous for the H63D mutation. Can J Gastroenterol Hepatol, 2014 found that while 29% had elevated ferritin at baseline, only 6.7% developed documented iron overload at follow-up, and just 1.7% progressed to iron overload-related disease.

For compound heterozygotes (C282Y + H63D), a Newfoundland cohort study of 247 individuals⁷⁷ Newfoundland cohort study of 247 individuals
Power TE et al. C282Y/H63D compound heterozygosity is a low penetrance genotype for iron overload-related disease. J Can Assoc Gastroenterol, 2022 found that only 5.3% developed iron overload-related disease at 10-year follow-up, with men at higher risk (13.5% documented iron overload) than women (4.3%).

Beyond Iron: Hypertension and Athletic Performance

The H63D variant has associations beyond iron storage. The ARIC study⁸⁸ ARIC study
Selvaraj S et al. HFE H63D Polymorphism and the Risk for Systemic Hypertension. Hypertension, 2019 followed 10,902 white participants and found that H63D carriers had higher systolic and diastolic blood pressure, with a 2-4% (heterozygotes) and 4-7% (homozygotes) absolute increase in hypertension risk. However, after 25 years of follow-up, there was no increased risk of adverse cardiovascular events — the iron-mediated blood pressure effect did not translate into heart attacks or strokes.

Intriguingly, the G allele appears to benefit endurance athletes. A meta-analysis of five cohorts⁹⁹ meta-analysis of five cohorts
Semenova EA et al. The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity. Eur J Appl Physiol, 2020 found that CG/GG genotypes were significantly overrepresented among elite endurance athletes (OR 1.96, 95% CI 1.58-2.45; P = 1.7 x 10^-9). Male athletes carrying the G allele also had higher VO2max (66.3 vs 61.8 ml/min/kg). The proposed mechanism: mildly elevated iron stores enhance hemoglobin synthesis, erythropoiesis, and oxygen-carrying capacity — a meaningful edge for endurance performance.

Practical Implications

For CC individuals: your HFE protein functions normally. Iron absorption is properly regulated. No special monitoring or dietary changes are needed.

For CG carriers: you carry one copy of H63D. Your iron absorption may be mildly increased, but the odds of developing clinically significant iron overload from this alone are very low. Simple awareness is appropriate — if iron markers are checked for other reasons, your result is worth noting on the chart.

For GG homozygotes: you carry two copies of H63D. About 29% of H63D homozygotes have elevated ferritin, but fewer than 7% develop documented iron overload. Periodic iron studies are prudent, and you should avoid unnecessary iron supplementation unless blood tests confirm deficiency.

Interactions

The clinically important interaction is between H63D (rs1799945) and C282Y (rs1800562). Compound heterozygotes — one copy of each — have a meaningfully higher risk of iron overload than either variant alone (OR 32 vs OR 5.7 for H63D/H63D and OR 4.1 for C282Y heterozygotes). About 2% of Europeans are compound heterozygotes, and roughly 5% of these develop iron overload-related disease. This combination warrants iron studies monitoring: fasting transferrin saturation and serum ferritin annually, with referral if transferrin saturation exceeds 45% or ferritin rises above 300 ug/L (men) or 200 ug/L (women). This is a strong candidate for a compound implication linking rs1799945 CG/GG with rs1800562 genotypes.

H63D may also interact with TMPRSS6 (rs855791), which regulates hepcidin through a different pathway. Carrying iron-increasing alleles in both genes could have additive effects on iron stores, though this interaction has less clinical evidence than the HFE C282Y combination.