rs855791 — TMPRSS6 Ala736Val

TMPRSS6 Ala736Val — The Iron Gate

Your body's ability to absorb iron from food is not just about what you eat — it is tightly controlled by a hormonal gatekeeper called hepcidin¹¹ hepcidin
A 25-amino-acid peptide hormone produced by the liver that acts as the master regulator of systemic iron homeostasis. Hepcidin blocks ferroportin²² ferroportin
The only known mammalian cellular iron exporter, present on the surface of enterocytes (gut lining cells) and macrophages, the only iron export channel on gut cells, effectively slamming the door on iron absorption when levels are sufficient. The TMPRSS6 gene encodes matriptase-2³³ matriptase-2
A type II transmembrane serine protease expressed primarily in the liver, a liver enzyme whose job is to keep hepcidin in check by cleaving hemojuvelin⁴⁴ hemojuvelin
A membrane-bound co-receptor that activates the BMP/SMAD signaling pathway, which drives hepcidin transcription on the cell surface. When matriptase-2 works well, hepcidin stays low and iron flows freely from the gut into the bloodstream. When it does not, hepcidin rises and iron absorption drops.

The Ala736Val variant (rs855791) sits in the catalytic domain of matriptase-2 — the business end of the enzyme. The A allele (Val736) reduces the enzyme's ability to suppress hepcidin, resulting in higher hepcidin levels and lower iron absorption. This is not a rare mutation causing disease. It is a common polymorphism carried by roughly half of Europeans and over half of East Asians, making it the single strongest common genetic determinant of iron status identified by genome-wide association studies.

The Mechanism

Matriptase-2 normally cleaves hemojuvelin from the liver cell surface, disabling the BMP/SMAD signaling pathway⁵⁵ BMP/SMAD signaling pathway
Bone morphogenetic protein / son of mothers against decapentaplegic — a signaling cascade that drives hepcidin gene transcription in hepatocytes that drives hepcidin production. The Val736 form of matriptase-2 is less efficient at this cleavage. In vitro experiments⁶⁶ In vitro experiments
Nai A et al. TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals. Blood, 2011 demonstrated that cells expressing the Ala736 form suppress hepcidin transcription more effectively than those expressing Val736. In living people, this translates to measurable differences: Ala736 homozygotes have lower serum hepcidin, higher transferrin saturation, and higher serum iron compared to Val736 homozygotes.

The downstream consequence is straightforward. Higher hepcidin means more ferroportin gets internalized and degraded on gut enterocytes. Less ferroportin means less iron crosses from the gut lining into the bloodstream. The effect is dose-dependent — each copy of the A allele (Val736) incrementally raises hepcidin and lowers iron absorption.

The Evidence

Two landmark genome-wide association studies published simultaneously in 2009 identified rs855791 as the top hit for iron-related traits. Benyamin et al.⁷⁷ Benyamin et al.
Benyamin B et al. Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat Genet, 2009 found associations with serum iron (P = 1.5 x 10^-20), transferrin saturation (P = 2.2 x 10^-23), and mean corpuscular volume (P = 1.1 x 10^-10). Each copy of the risk allele decreased serum iron and transferrin saturation by 0.18 and 0.20 standard deviations respectively, explaining about 2% of population variance in these traits. Chambers et al.⁸⁸ Chambers et al.
Chambers JC et al. Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nat Genet, 2009 reported that each A allele copy lowered hemoglobin by 0.13 g/dL, with AA homozygotes averaging 0.2 g/dL lower hemoglobin than GG homozygotes.

A stable iron isotope study⁹⁹ stable iron isotope study
Buerkli S et al. The TMPRSS6 variant (SNP rs855791) affects iron metabolism and oral iron absorption — a stable iron isotope study in Taiwanese women. Haematologica, 2021 directly measured iron absorption using labeled iron meals. At equivalent low iron stores (ferritin 15 ug/L), women with the CC genotype (Ala/Ala on the coding strand, GG on 23andMe) absorbed 26.6% of the iron dose, while TT women (Val/Val, AA on 23andMe) absorbed only 18.5% — a roughly 30% reduction in iron absorption capacity.

A systematic review¹⁰¹⁰ systematic review
Gichohi-Wainaina WN et al. Inter-ethnic differences in genetic variants within the transmembrane protease, serine 6 (TMPRSS6) gene associated with iron status indicators. Genes Nutr, 2015 confirmed that the A allele is consistently associated with approximately 0.11 g/dL lower hemoglobin across populations.

Practical Implications

For people with the AA genotype who already have adequate iron stores, this variant is clinically silent. The effect matters most when iron demand is high or dietary intake is marginal — during menstruation, pregnancy, rapid growth, vegetarian or vegan diets, or endurance athletics. In these contexts, a 30% reduction in absorption efficiency can tip the balance toward deficiency.

Iron absorption can be optimized by pairing iron-rich foods with vitamin C, choosing heme iron sources¹¹¹¹ heme iron sources
Heme iron from meat, poultry, and fish is absorbed 2-3 times more efficiently than non-heme iron from plants, and its absorption is less affected by hepcidin when possible, and avoiding calcium, tea, and coffee at iron-containing meals. For those who need supplements, iron bisglycinate¹²¹² iron bisglycinate
A chelated form of iron that is absorbed via a different pathway (peptide transporters) and is less affected by hepcidin-mediated ferroportin degradation may be preferable to ferrous sulfate because it is partially absorbed through peptide transporters rather than ferroportin alone.

Monitoring is simple: a serum ferritin test (ideally with transferrin saturation) tells you whether your iron stores are adequate. A ferritin below 30 ug/L suggests depleted stores even if hemoglobin is still normal.

Interactions

TMPRSS6 rs855791 interacts with rs4820268, another TMPRSS6 variant in linkage disequilibrium that independently affects iron parameters. More importantly, it interacts with HFE variants¹³¹³ HFE variants
HFE encodes a protein that also regulates hepcidin. The C282Y (rs1800562) and H63D (rs1799945) variants in HFE cause hereditary hemochromatosis by reducing hepcidin, leading to iron overload. In hereditary hemochromatosis (HFE C282Y homozygotes), the Val736 allele of TMPRSS6 acts as a protective modifier — its hepcidin-raising effect partially counteracts the hepcidin-lowering effect of HFE mutations, and Val736 carriers show reduced risk of cirrhosis¹⁴¹⁴ Val736 carriers show reduced risk of cirrhosis
Valenti L et al. Effect of the A736V TMPRSS6 polymorphism on the penetrance and clinical expression of hereditary hemochromatosis. J Hepatol, 2012 and hepatocellular carcinoma compared to Ala736 homozygotes.

Conversely, carrying both the AA genotype at rs855791 and being a menstruating woman, a vegetarian, or an endurance athlete compounds iron loss risk — these are the individuals most likely to benefit from proactive monitoring and dietary optimization.