TMPRSS6 rs855791 (V736A) raises hepcidin and reduces iron indices.

The TMPRSS6 rs855791 polymorphism (V736A) is a major genetic determinant of iron homeostasis. It functions as a primary regulator of systemic iron availability by modulating the production of hepcidin, the "master regulator" hormone of iron absorption and distribution.

Clinical and effectiveness evidence

Large-scale genome-wide association studies (GWAS) and meta-analyses consistently confirm that the rs855791 variant is a robust predictor of iron status across diverse populations.

• Iron Indices: Each copy of the G (or C) allele is associated with a significant decrease in serum ferritin (effect size β = -0.068) and transferrin saturation (TSAT) (β = -0.197).
• Genotypic Differences: Individuals carrying the GG genotype typically exhibit the lowest iron stores. In clinical cohorts, mean serum hepcidin concentrations in GG individuals have been measured at approximately 9.50 ng/mL, compared to 4.96 ng/mL in those with the AG or AA genotypes.
• Population Impact: This variant is frequently cited as the strongest common genetic signal influencing hemoglobin levels and iron deficiency risk in non-anemic individuals.

Mechanistic explanations

The relationship between rs855791 and iron status is governed by the BMP-SMAD signaling pathway in the liver.

• Matriptase-2 Function: The TMPRSS6 gene encodes matriptase-2, a transmembrane serine protease whose primary role is to suppress hepcidin production when iron levels are low. It achieves this by cleaving membrane-bound hemojuvelin (mHJV), a coreceptor required for hepcidin induction.
• Molecular Alteration: The rs855791 polymorphism results in a valine-to-alanine substitution (V736A) in the catalytic domain of matriptase-2. The variant associated with lower iron (the G/C allele) produces a less efficient enzyme that fails to adequately cleave HJV.
• Hepcidin Tone: This impaired enzymatic activity leads to "inappropriately" high hepcidin levels (higher hepcidin tone). Elevated hepcidin then binds to and degrades ferroportin—the only cellular iron exporter—effectively trapping iron within macrophages and blocking its absorption from the diet.

Bottom line

The claim is strongly supported by science. The TMPRSS6 rs855791 variant is a validated marker where the G/C allele leads to higher hepcidin levels, which subsequently restricts iron availability and results in lower ferritin and transferrin saturation. Individuals with this genotype may be more susceptible to iron deficiency, even in the presence of adequate dietary intake.