Hemochromatosis Genes in the Turkish Population

Why is this study important?

The most commonly analysed gene in HH diagnostics is HFE. The classic form of HFE-dependent hemochromatosis, known primarily from Northern European populations, is most strongly associated with the variant:

• C282Y, i.e. p.Cys282Tyr.

The second frequently tested variant is:

• H63D, i.e. p.His63Asp.

In clinical practice, these two variants are often treated very differently. C282Y in homozygous form — inherited from both parents — is the classic high-risk genotype for hemochromatosis in Northern European populations. H63D is much more common in many populations, but has considerably lower penetrance, meaning it much less frequently leads to overt disease on its own.

The new study from Turkey shows that applying interpretation frameworks developed for Northern Europe may be insufficient in other populations.

What did the authors study?

The researchers analysed the results of HFE gene sequencing in 643 patients tested between 2022 and 2025 at the medical genetics laboratory of Ankara Etlik City Hospital in Turkey.

This was a retrospective analysis, meaning it was based on previously performed tests. Patients were referred for diagnostics due to suspected iron metabolism disorders or as part of differential diagnosis.

In practice, people referred for such tests include those with, among other things:

• elevated transferrin saturation,
• increased ferritin concentration,
• certain abnormalities in blood count,
• chronic fatigue,
• abdominal pain,
• weight loss,
• joint pain,
• diabetes,
• liver enlargement,
• cardiac arrhythmias,
• skin hyperpigmentation.

Important: the authors of this study did not analyse clinical or biochemical data. The study focused exclusively on the frequency of HFE genetic variants.

Who participated in the study?

The study included 643 individuals:

• 190 women,
• 453 men.

The mean age was 46.8 years, and the median age was 49 years. The age range was very wide: from 6 months to 86 years.

The majority were adults, but the presence of paediatric and older patients allowed the authors to capture a broad cross-section of individuals referred for HFE testing.

Key finding: most patients had no detectable HFE variant

Of the 643 individuals, as many as 424 patients, i.e. 65.9%, had a wild-type result — no significant variant detected in the HFE gene.

This is an important clinical observation: in many patients referred for diagnostics due to suspected iron metabolism disorders, classic HFE variants may not be present. In such situations, the cause of abnormal iron parameters may lie in other genes, liver disease, inflammation, metabolic syndrome, alcohol, supplementation, transfusions, or other factors.

H63D was the most common variant

The most frequently detected variant was H63D.

The authors found:

• Heterozygous H63D in 166 individuals, i.e. 25.8% of those tested,
• Homozygous H63D in 32 individuals, i.e. 4.9% of those tested.

In total, H63D was present in 199 individuals, i.e. approximately 30.9% of the entire group — in heterozygous, homozygous, or compound form with another variant.

This confirms that H63D is relatively common in the Turkish population.

C282Y was rare

The variant C282Y — the classic variant associated with hemochromatosis in Northern European populations — was detected far less frequently.

The study found:

• Heterozygous C282Y in 7 individuals, i.e. 1.08%,
• Homozygous C282Y in 4 individuals, i.e. 0.6%,
• Compound heterozygosity C282Y/H63D in 1 individual, i.e. 0.1%.

This is highly significant. In Northern European populations, C282Y homozygosity accounts for the majority of classic HFE-dependent hemochromatosis cases. In this Turkish cohort, however, that genotype was rare.

Allele frequencies: H63D dominates, C282Y is low

The authors calculated allele frequencies based on 1,286 alleles, as each of the 643 patients has two copies of the gene.

The most common was:

• H63D — allele frequency 0.183, i.e. 18.3%.

For comparison:

• C282Y — allele frequency 0.012, i.e. 1.2%.

The remaining HFE variants were very rare. These included, among others:

• p.Arg224Trp,
• p.Arg71*,
• splicing variant c.340+1G>A,
• p.Pro70Thr,
• p.Leu167=,
• p.Ser65Cys.

Each of these occurred singly or nearly singly.

What does this mean for hemochromatosis diagnostics?

The key message of the study is the following: HFE genetic results must be interpreted in the context of the patient's population of origin.

In Northern Europe, the C282Y variant is relatively common and its homozygosity has significant diagnostic value. In Turkey — as in many Mediterranean, Middle Eastern, and Asian populations — C282Y is much rarer.

H63D, on the other hand, is common but its clinical significance is more limited. Simply detecting H63D, especially in one copy, does not automatically mean hemochromatosis.

H63D: a common variant, but usually of low penetrance

The authors emphasise that the clinical significance of H63D remains a matter of debate. This variant is widely distributed in many populations, but its penetrance is considerably lower than that of C282Y.

In practice, this means that a person with:

• Heterozygous H63D

most often does not have classic hereditary hemochromatosis solely because of this variant.

Greater clinical relevance may attach to:

• Homozygous H63D, especially when other risk factors are present,
• C282Y/H63D, i.e. compound heterozygosity,
• the presence of other genetic variants,
• coexisting liver disease,
• alcohol,
• metabolic syndrome,
• chronic inflammation,
• iron supplementation.

Therefore, an H63D result should always be considered alongside biochemical parameters, especially ferritin and transferrin saturation.

Why is C282Y rare in Turkey?

The C282Y variant is strongly associated with Northern European ancestry. Literature describes a clear geographic gradient: it is more common in Northern Europe and less common towards the south, the Middle East, and Asia.

Turkey occupies a unique genetic and historical position — it lies at the crossroads of Europe, Anatolia, the Middle East, and Central Asia. The Turkish population was shaped by many historical migrations and the mixing of ethnic groups.

This is precisely why the HFE variant profile in Turkey is not the same as in Ireland, the United Kingdom, Scandinavia, or northern France. The authors describe it as intermediate between European and Middle Eastern–Asian populations.

Key insight: not every patient with iron overload has classic HFE disease

The study also highlights a practical diagnostic challenge. If a patient from Turkey or a similar region presents with symptoms or parameters suggesting iron overload, and the classic C282Y/C282Y genotype is not detected, this does not automatically mean the problem does not exist.

In some patients it is worth considering:

• other genes associated with hemochromatosis,
• large deletions or duplications in HFE,
• other iron metabolism disorders,
• secondary causes of hyperferritinaemia,
• liver disease,
• environmental and metabolic factors.

The authors note that in populations where C282Y is rare, when clinical hemochromatosis is suspected, broader diagnostics become more important — not just a panel of the two most common HFE variants.

What does the study say about men and women?

The study group included significantly more men than women. This is consistent with the clinical observation that overt hemochromatosis more often manifests in men.

One reason is the physiological iron loss in women of reproductive age — through menstruation and pregnancies. In women, iron accumulation may be delayed and symptoms may appear later.

It should be noted, however, that this study did not analyse disease penetrance or symptom severity in women and men. It only showed that among those referred for HFE testing, men predominated.

Study limitations

The study provides important data, but has significant limitations.

First, it was a single-centre analysis. It may therefore partly reflect the profile of patients referred to a specific hospital, rather than the entire Turkish population.

Second, the study included individuals referred for diagnostics, not a randomly selected population sample. This means a potential referral bias — the group may have been over-represented by individuals with suspected iron disorders.

Third, the authors did not include clinical and biochemical data. It is therefore unknown which individuals actually had elevated ferritin, high transferrin saturation, disease symptoms, or organ damage.

Fourth, the study does not allow assessment of the penetrance of specific genotypes. It therefore does not answer the question of what proportion of individuals with H63D/H63D or C282Y/H63D will actually develop iron overload.

Fifth, large deletions and duplications of the HFE gene were not analysed using methods considered the gold standard.

What does this mean for patients?

For patients, the most important message is practical: a genetic result alone should not be interpreted in isolation from blood tests and the clinical picture.

If the result shows:

• C282Y/C282Y — this requires particular attention, as it is the classic high-risk genotype for HFE-dependent hemochromatosis.
• C282Y/H63D — may increase the risk of iron overload, but clinical expression is variable.
• H63D/H63D — may be associated with mild or moderate iron overload in some individuals, especially with additional risk factors.
• H63D in one copy — usually insufficient on its own for a hemochromatosis diagnosis.
• no HFE variants — does not exclude other causes of high ferritin or iron overload.

In every case, the key parameters are:

• ferritin,
• transferrin saturation,
• liver enzyme activity,
• blood count,
• family history,
• coexisting conditions,
• medical assessment.

This study is a useful reminder that hemochromatosis is not a single, straightforward disease with an identical genetic basis in all people. The best-known HFE-dependent form with the C282Y variant is common primarily in Northern European populations. In other regions of the world, the distribution of variants may look different.

In the Turkish population, according to the study discussed, H63D predominates while C282Y is rare. This means that diagnostics and genetic counselling should take the patient's population background into account.

Key conclusion

A study of 643 patients from Turkey revealed an HFE variant profile different from that known in Northern European populations. The H63D variant was the most common, especially in one copy, while the classic C282Y variant was rare.

The practical conclusion is clear: interpretation of HFE testing should be population-adjusted and always combined with biochemical results and the clinical picture. Simply detecting H63D, particularly in heterozygous form, should not automatically lead to a diagnosis of hemochromatosis. Conversely, the absence of C282Y does not exclude other forms of iron metabolism disorder.