Hemochromatosis in Your Raw DNA: C282Y and H63D
HFE variants rs1800562 and rs1799945 are among the most actionable results in a raw file: what each genotype means, how often iron overload follows, what to do.
Most of what a raw DNA file tells you is a nudge - a slightly higher or lower tendency that is easy to overstate. Hereditary hemochromatosis is different. It is a common, well-understood, genuinely treatable condition, its genetics come down to two SNPs that sit in nearly every consumer file, and the check-up it calls for is a routine blood test. If any result in your file deserves a follow-up, it is this one.
What hemochromatosis is
The body has no efficient way to excrete iron, so it regulates absorption in the gut instead. The HFE gene helps control that thermostat. When both copies are faulty, the gut keeps absorbing iron as if the body were short of it. Over decades the excess builds up in the liver, joints, pancreas and heart. Left alone, it can lead to cirrhosis, arthritis, diabetes and heart disease; caught early, it is managed by removing blood at intervals, which is about as low-tech as treatment gets.
The two variants
Feder and colleagues identified the gene in 1996 and the two variants that matter most:
- C282Y - rs1800562. Forward-strand common allele G; the variant allele is A. This is the major one. In people of northern European ancestry about one in eight carries a copy and roughly one in 200 carries two.
- H63D - rs1799945. Common allele C; the variant allele is G. Much more common (about a quarter of Europeans carry at least one copy) and much milder.
In your file, the genotypes to look for are:
| rs1800562 | rs1799945 | Meaning |
|---|---|---|
| AA | any | C282Y homozygous - the classic high-risk genotype |
| AG | CG | Compound heterozygous - modestly elevated risk |
| AG | CC | C282Y carrier - very low risk of disease |
| GG | GG | H63D homozygous - minimal risk |
| GG | CG | H63D carrier - not clinically significant on its own |
Having the genotype is not having the disease
This is the part that matters most, and it cuts both ways. Being homozygous for C282Y is called having the genotype, not the disease. The disease is the iron overload, and most homozygotes do not develop the severe form.
The clearest numbers come from a large Australian cohort followed by Allen and colleagues and reported in the New England Journal of Medicine in 2008. Among C282Y homozygotes, about 28 percent of men and 1 percent of women developed iron-overload-related disease. Most women are protected for much of their lives by menstruation and pregnancy, which remove iron. Raised iron measures without symptoms were far more common than actual disease.
Compound heterozygotes (one C282Y and one H63D) occasionally develop mild overload, usually when something else - heavy drinking, hepatitis, obesity-related liver disease - is also stressing the liver. Simple carriers and H63D homozygotes rarely do.
What to do with an AA result
Two blood tests settle whether the genotype is doing anything: transferrin saturation and ferritin. Both are inexpensive and part of many routine panels. If they are normal, most guidelines suggest rechecking every few years rather than doing anything else. If they are elevated, a doctor will look at the liver and decide whether to start removing blood (phlebotomy), which brings iron down and prevents the long-term damage.
A raw-data result is a reason to ask for those two tests. It is not a diagnosis, and it is not a reason to change your diet or start avoiding iron on your own - dietary iron matters less than most people assume, and untreated overload is not fixed by skipping steak.
It is also information your siblings may want. Each full sibling of a homozygote has a one-in-four chance of also being homozygous, and the variants are equally common in men and women even though the disease is not.
A note on ancestry
C282Y is largely a northern and western European variant; it is uncommon in people of African, East Asian or South Asian ancestry, in whom hemochromatosis, when it occurs, more often involves other genes that consumer chips do not read. A GG result at rs1800562 lowers the probability of HFE-related overload but does not rule out iron problems from other causes.
For a broader view of how to read letter pairs like AG and CG - and why the order of the two letters does not matter - see our explainer on heterozygous and homozygous genotypes. To check these markers without uploading your file anywhere, the health and wellness analysis reads them in your browser.
References
- Feder JN, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genetics. 1996. PubMed 8696333
- Allen KJ, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. New England Journal of Medicine. 2008. PubMed 18199861
- National Institute of Diabetes and Digestive and Kidney Diseases. Hemochromatosis.
- dbSNP entries for rs1800562 and rs1799945, NCBI.
This article is educational only and is not medical advice. A genotype result should be followed up with a doctor, not acted on directly.