rs4820268 — TMPRSS6 TMPRSS6 D512E

TMPRSS6 missense variant affecting matriptase-2 activity; A allele (Asp512Glu) raises hepcidin and lowers iron absorption, particularly affecting iron status in menstruating women and those with marginal intake

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TMPRSS6 D512E — Iron Absorption's Hidden Brake

Iron deficiency is the world's most common nutritional deficiency, yet how much iron your gut actually absorbs is controlled less by what you eat and more by a hormone called hepcidin11 hepcidin
A 25-amino-acid peptide produced by the liver that acts as the master regulator of systemic iron homeostasis; high hepcidin blocks iron absorption and recycling. The TMPRSS6 gene encodes matriptase-222 matriptase-2
A type II transmembrane serine protease expressed primarily in the liver that cleaves hemojuvelin, suppressing hepcidin production, whose job is to keep hepcidin in check by cleaving a cell-surface protein called hemojuvelin33 hemojuvelin
A co-receptor for bone morphogenetic proteins (BMPs) that, when intact on the hepatocyte surface, drives hepcidin gene transcription. The rs4820268 variant — a single nucleotide change in the protein-coding sequence of TMPRSS6 — alters one amino acid in matriptase-2 and shifts the setpoint of this hormonal control system, with measurable consequences for iron status that play out across the lifespan.

The Mechanism

The A allele of rs4820268 changes aspartic acid to glutamic acid at position 512 of the matriptase-2 protein (p.Asp512Glu). This substitution falls within the functional region of the enzyme and impairs its ability to suppress hepcidin production. With less matriptase-2 activity, hemojuvelin remains intact on hepatocyte surfaces, activating the BMP/SMAD signaling pathway44 BMP/SMAD signaling pathway
Bone morphogenetic protein/SMAD — a signaling cascade that drives transcription of the hepcidin gene HAMP in liver cells and sustaining elevated hepcidin levels. Higher hepcidin causes ferroportin55 ferroportin
The only known mammalian iron exporter, expressed on gut enterocytes, macrophages, and hepatocytes; hepcidin binds ferroportin, triggers its internalization and degradation, blocking cellular iron export degradation in gut enterocytes, reducing the amount of dietary iron that crosses from gut lining into blood.

The effect is additive: each additional A allele incrementally reduces matriptase-2 activity, raises hepcidin, and lowers net iron absorption. The GG genotype (no amino acid change, synonymous) represents wild-type enzyme function.

The Evidence

A 2025 systematic review66 2025 systematic review
Fauzan R et al. Impact of TMPRSS6 Genetic Variants on Maternal Iron Status in Pregnancy: A Systematic Review. Birth Defects Research, 2025 of seven studies encompassing 1,094 pregnant participants found that the A allele consistently correlated with lower serum iron, reduced transferrin saturation, and elevated unsaturated iron-binding capacity. The review further identified associations with increased risks of iron-deficiency anemia, gestational diabetes mellitus, and preeclampsia — outcomes mediated through impaired iron absorption and downstream metabolic disturbances.

A recall-by-genotype study77 recall-by-genotype study
Jallow MW et al. Common Variants in the TMPRSS6 Gene Alter Hepcidin but not Plasma Iron in Response to Oral Iron in Healthy Gambian Adults. Current Developments in Nutrition, 2021 in 251 adults directly confirmed the hepcidin mechanism: AA homozygotes had baseline hepcidin of 9.50 ng/mL compared to 3.27 ng/mL in GG homozygotes (P = 0.002) — nearly a three-fold difference. This study also found that after a large oral iron dose (130 mg elemental iron), TMPRSS6 genotype altered the hepcidin response but did not fully overcome the absorption disadvantage.

An Egyptian study of 160 children (Hamed et al. 202488 Hamed et al. 2024
Hamed HM et al. The association of TMPRSS6 gene polymorphism with iron status in Egyptian children. BMC Pediatrics, 2024) found the GG genotype was linked to the highest hepcidin gene expression, lowest serum ferroportin, and lowest iron stores, confirming that the G allele (without the Asp512Glu change) confers the greatest risk in this specific direction in some ancestry contexts — underscoring the importance of considering both variants and population context together.

A Chinese Han study of 1,574 adults (Gan et al. 201299 Gan et al. 2012
Gan W et al. Association of TMPRSS6 polymorphisms with ferritin, hemoglobin, and type 2 diabetes risk in a Chinese Han population. AJCN, 2012) found rs4820268 significantly associated with plasma ferritin (P ≤ 0.006), hemoglobin (P ≤ 0.001), and iron overload risk (P ≤ 0.007), also detecting a link to type 2 diabetes risk (P ≤ 0.031) — likely mediated through iron's role in insulin signaling.

Practical Implications

For most people with adequate dietary iron and normal iron demand, even the AA genotype does not guarantee iron deficiency — the body's iron regulatory system has multiple compensatory mechanisms. The risk becomes clinically meaningful when demand increases (menstruation, pregnancy, adolescent growth) or intake is marginal (plant-based diets, food insecurity, malabsorption). In these contexts, impaired matriptase-2 function can tip the balance toward depleted iron stores faster than average.

Practical strategies to compensate: pair non-heme iron sources with vitamin C (which reduces ferric to ferrous iron and forms a soluble chelate resistant to hepcidin-mediated inhibition); prefer heme iron (meat, organ meats, shellfish) where possible — heme iron enters enterocytes via HCP1 rather than through ferroportin, making it less sensitive to elevated hepcidin; avoid tea, coffee, and calcium supplements within 60 minutes of iron-rich meals. For supplementation, iron bisglycinate is partially absorbed via peptide transporters, offering a partial bypass of the hepcidin-ferroportin bottleneck.

Serum ferritin is the most sensitive early marker of iron depletion; it falls before hemoglobin drops, allowing intervention before anemia develops.

Interactions

rs4820268 is in linkage disequilibrium with rs855791 — the other major TMPRSS6 coding variant (Ala736Val) — and the two together explain more variance in iron status than either alone. Carriers of risk alleles at both loci have compounded impairment of matriptase-2 function. In the context of hereditary hemochromatosis (HFE C282Y or H63D variants, rs1800562 or rs1799945), TMPRSS6 risk alleles may partially counteract the pathological iron overload driven by reduced hepcidin from HFE mutations — the same hepcidin-raising effect that impairs absorption in healthy people acts as a modest brake on iron loading in hemochromatosis carriers.

Nutrient Interactions

iron reduced_absorption

Genotype Interpretations

What each possible genotype means for this variant.

GG Full Matriptase-2 Activity Normal

Normal matriptase-2 function — no iron absorption impairment from this variant

The GG genotype means the amino acid sequence of matriptase-2 is unchanged at codon 512 — aspartic acid is retained. This preserves the enzyme's ability to cleave hemojuvelin and suppress hepcidin through the BMP/SMAD pathway. Population data confirm that GG individuals have lower hepcidin levels (~3.27 ng/mL baseline in the Jallow et al. 2021 study) compared to AA individuals (~9.50 ng/mL), with correspondingly more efficient dietary iron absorption.

Note that rs4820268 is not the only TMPRSS6 variant affecting iron status — the linked variant rs855791 (Ala736Val) independently modulates matriptase-2 activity. Your full iron absorption picture depends on both variants together.

AG Mildly Impaired Matriptase-2 Intermediate

One copy of the iron-absorption variant — slightly elevated hepcidin

With one Asp512 copy (normal) and one Glu512 copy (altered), your matriptase-2 cleavage of hemojuvelin is intermediate. Hepcidin levels fall between the GG and AA extremes. For most people on adequate iron diets, this genotype has no clinical consequences.

It becomes relevant during periods of elevated iron demand — heavy menstruation, pregnancy, rapid adolescent growth, intense endurance training — or when dietary iron is restricted (vegetarian and vegan diets, low caloric intake). In these contexts, even mildly reduced absorption efficiency can contribute to slower iron store replenishment.

The Turkish IDA study (Batar et al. 2018) found rs4820268 associated with increased total iron-binding capacity (P < 0.05) in IDA patients, consistent with iron-depleted status.

AA Reduced Iron Absorption Reduced

Two copies of the iron-absorption variant — elevated hepcidin and lower absorption

The AA genotype produces two copies of matriptase-2 with glutamic acid at position 512 (Glu512/Glu512). This impairs the enzyme's suppression of hemojuvelin, leaving hepcidin transcription constitutively elevated. In the Jallow et al. (2021) recall-by- genotype study, AA homozygotes had baseline hepcidin of 9.50 ng/mL vs. 3.27 ng/mL in GG individuals (P = 0.002) — a nearly 3-fold difference that persists after supplemental iron loading.

The 2025 systematic review (Fauzan et al., seven studies, 1,094 pregnant participants) confirmed that this genotype consistently correlates with lower serum iron, reduced transferrin saturation, and elevated unsaturated iron-binding capacity. Beyond iron deficiency risk, the review noted associations with gestational diabetes mellitus and preeclampsia — complications linked to dysregulated iron metabolism in pregnancy.

The A allele is notably common in African populations (~72% frequency), which may partly explain population-level differences in iron status responses to supplementation programs in sub-Saharan Africa.