Does the TMPRSS6 rs855791 A allele raise iron status and hemoglobin?

The TMPRSS6 rs855791 polymorphism (Val736Ala) is a major genetic determinant of systemic iron homeostasis, but the association between specific alleles and iron status is the opposite of what the original claim suggests. While this variant significantly influences hepcidin and iron regulation, the A allele is consistently linked to lower, rather than higher, iron markers.

Clinical evidence and hematological status

Evidence from genome-wide association studies (GWAS) involving tens of thousands of participants indicates that the G allele (Val736) is associated with higher iron status, while the A allele (Ala736) is associated with reduced iron availability and lower hemoglobin levels.

• Hemoglobin and Hematocrit: Each copy of the A allele is associated with a decrease in hemoglobin of approximately 0.13 g/dL (p < 10⁻¹⁰) and a corresponding reduction in hematocrit and mean corpuscular volume (MCV).
• Iron Markers: Carriers of the A allele exhibit significantly lower serum iron (beta = -0.187 μmol/L), lower transferrin saturation, and lower ferritin levels compared to G allele carriers.
• Clinical Risk: The A allele is recognized as a risk factor for iron deficiency and iron-refractory iron deficiency anemia (IRIDA), particularly in populations with high iron requirements.

Mechanistic explanations

The rs855791 variant alters the function of matriptase-2 (encoded by TMPRSS6), a transmembrane serine protease that acts as a negative regulator of hepcidin.

• Hepcidin Modulation: Matriptase-2 normally suppresses hepcidin production by cleaving membrane-bound hemojuvelin (mHJV), a co-receptor for the BMP/SMAD signaling pathway.
• Pathway Disruption: The A allele (Ala736) variant is less efficient at suppressing hepcidin than the G allele variant. This results in inappropriately high hepcidin levels relative to body iron stores.
• Iron Sequestration: Elevated hepcidin leads to the degradation of ferroportin, the only known cellular iron exporter. This prevents iron absorption from the diet and traps iron inside macrophages, limiting the amount available for red blood cell production.

Bottom line

The G allele—not the A allele—is associated with higher iron status, hemoglobin, and hematocrit. The A allele is the "low-iron" variant that promotes higher hepcidin levels and restricts iron availability for erythropoiesis.