How Can This Gene Prevent Iron Absorption from Food? (TMPRSS6)

TMPRSS6 (transmembrane protease serine 6 or matriptase-2) is a gene that encodes a liver cell enzyme. This enzyme is necessary for the liver to remodel and regenerate itself [R].

TMPRSS6 also decreases the production of a  hormone called hepcidin. Hepcidin regulates the amount of dietary iron that is absorbed into the bloodstream. Hence, TMPRSS6 helps keep blood iron levels from getting too low [R].

Hepcidin, Iron Regulation & the Immune System

TMPRSS6 and hepcidin are not only involved in regulating iron absorption, they are also required to mount a successful immune response to infection [R, R].

Liver cells produce hepcidin in response to IL-6 (an inflammatory cytokine) or high transferrin levels. Transferrin is a protein that binds iron in the blood, so a high amount of transferrin is a good indicator that blood iron levels are high [R, R].

Hepcidin is important because high levels of iron in the blood can be toxic. Decreasing iron levels is also beneficial during an infection, as almost all pathogens require iron to reproduce, and the iron in our bodies is their only source [R, R, R].

The TMPRSS6 gene regulates the expression of hepcidin, which in turn regulates the amount of iron absorbed from food.

Dangers of Iron Deficiency

If a person does not get enough iron from their diet or from supplements, their body’s iron stores will become depleted, leading to red blood cells being produced with below-normal oxygen-binding capacity. This level of deficiency gradually progresses to iron-deficiency anemia [R].

Common symptoms of iron-deficiency anemia include weakness, fatigue, and difficulty concentrating. In more severe cases, it can cause immune dysfunction, poor temperature regulation, and cognitive impairment [R].

Iron deficiency is the most common nutritional deficiency in the world, affecting 66 – 80% of the world’s population [R, R].

It is especially common during pregnancy, affecting 40% – 50% of women and their infants [R, R].

Iron deficiency is the leading nutritional cause of anemia [R, R].

Dangers of Iron Overload

Excessive blood iron, known as iron toxicity (or acute iron overload), can be just as dangerous as iron deficiency, so caution is recommended for those who decide to take iron supplements [R].

Taking 20 mg of elemental iron per kg of body weight can cause vomiting and diarrhea. In severe cases, taking about 60 mg of iron per kg of body weight can cause blood loss, multiple organ dysfunction, and death [R, R, R].

Even if you have detrimental TMPRSS6 variants and a predisposition toward iron deficiency, we strongly recommend talking to your doctor before supplementing with iron.

Both iron deficiency and iron overload can have serious health consequences, so it’s important to keep this vital nutrient in balance.

At least three TMPRSS6 variants have been associated with blood iron levels and incidence of iron deficiency: rs4820268, rs855791, and rs228916 [R, R].

At rs4820268, the less common ‘G’ allele is associated with lower blood iron levels and possible iron deficiency. Similarly, the less common ‘A’ allele at rs855791 is associated with relatively lower blood iron levels in the majority of studies, though its effect may vary with population [R, R, R].

At rs228916, the rare ‘C’ allele is associated with slightly higher blood iron than the common ‘T’ allele. Here, the ‘C’ allele may be somewhat protective against iron deficiency, but more common in those prone to iron overload [R].

SNP Summary and Table

TMPRSS6 rs4820268

• ‘A’ = Not associated with decreased blood iron
• ‘G’ = Associated with decreased blood iron and possible iron deficiency
• About 69% of all people worldwide have at least one copy of the ‘G’ allele.
• The ‘G’ allele is significantly less common in people of African descent (48%).

TMPRSS6 rs855791

• ‘G’ = Associated with relatively higher blood iron levels in most studies
• ‘A’ = Associated with relatively lower blood iron levels in most studies
• About 60% of all people worldwide have at least one copy of the ‘A’ allele.
• The ‘A’ allele is significantly less common in people of African descent (19%).

TMPRSS6 rs228916

• ‘T’ = Associated with relatively lower blood iron levels
• ‘C’ = Associated with relatively higher blood iron levels
• About 86% of all people worldwide have the ‘TT’ genotype.
• The ‘TT’ genotype is almost ubiquitous in people of East Asian descent (99.6%).