rs2413450 — TMPRSS6 TMPRSS6 iron regulation variant

TMPRSS6 rs2413450 — A Second Window on the Iron Gate

TMPRSS6¹¹ TMPRSS6
Transmembrane serine protease 6, also called matriptase-2 — a liver-expressed enzyme that negatively regulates iron absorption by cleaving hemojuvelin from the hepatocyte surface, thereby suppressing hepcidin production sits at the centre of the body's iron-sensing machinery. Its most studied variant — Ala736Val (rs855791) — is the single strongest common genetic determinant of iron status. rs2413450 is a second, independent marker at the same locus: an intronic variant located approximately 426 nucleotides downstream of exon 14 in the TMPRSS6 transcript. It does not itself change the protein sequence, but its alleles tag functional variation in TMPRSS6 expression or splicing regulation, and it has been independently replicated in GWAS for red blood cell traits.

The Mechanism

Because rs2413450 is intronic, it does not directly alter the matriptase-2 protein. Instead, it acts as a regulatory tag variant²² regulatory tag variant
A non-coding variant in linkage disequilibrium with nearby functional variants, or one that directly affects intronic splicing enhancer/silencer sequences or gene expression levels. The T allele at rs2413450 is associated with lower matriptase-2 activity, either through altered splicing efficiency or by tagging a haplotype that carries reduced-function regulatory elements. Less active matriptase-2 means less cleavage of hemojuvelin³³ hemojuvelin
A co-receptor of BMP receptors on hepatocyte surfaces that amplifies BMP/SMAD signalling and thereby drives hepcidin transcription, which in turn raises hepcidin. Higher hepcidin degrades ferroportin⁴⁴ ferroportin
The only known iron exporter on the basolateral surface of duodenal enterocytes and macrophages — hepcidin binding triggers its internalization and degradation, blocking iron release into the bloodstream on gut enterocytes, limiting iron entry into the circulation. The net result is the same as for the coding variant rs855791: smaller red blood cells (lower MCV), less hemoglobin per cell (lower MCH), and modestly reduced hemoglobin concentration.

The Evidence

The association was first reported in the landmark CHARGE Consortium GWAS⁵⁵ CHARGE Consortium GWAS
Ganesh SK et al. Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nat Genet, 2009, which studied 24,167 Europeans and confirmed rs2413450 associated with MCV (P = 3 × 10⁻⁴¹), MCH (P = 9 × 10⁻³⁴), and hematocrit (P = 2 × 10⁻¹³) — effect sizes comparable to the primary TMPRSS6 missense variant.

A large trans-ethnic meta-analysis Chen et al.⁶⁶ Chen et al.
Chen MH et al. Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations. Cell, 2020 confirmed the T allele reduces MCH by 0.126 standard deviations (P = 5 × 10⁻¹⁶) across European, East Asian, African, South Asian, and Latino populations, establishing this as a robust multi-ethnic signal.

In African-ancestry cohorts⁷⁷ African-ancestry cohorts
Gichohi-Wainaina WN et al. Associations between Common Variants in Iron-Related Genes with Haematological Traits in Populations of African Ancestry. PLoS One, 2016, rs2413450 T carriers showed a 0.19 g/dL reduction in hemoglobin (P = 0.02), one of only four TMPRSS6 variants that successfully replicated European GWAS signals in African populations — suggesting the functional variant it tags is ancestrally shared rather than population-specific.

A Turkish case-control study Batar et al.⁸⁸ Batar et al.
Batar B et al. The role of TMPRSS6 gene variants in iron-related hematological parameters in Turkish patients with iron deficiency anemia. Gene, 2018 found that rs2413450 was associated with elevated total iron-binding capacity in IDA patients — a marker of iron-starved erythropoiesis — consistent with the GWAS direction.

The evidence level is rated strong: the association has been replicated in multiple independent cohorts spanning diverse ancestries and total sample sizes exceeding 700,000 individuals. Effect sizes are modest (fractions of a standard deviation per allele) but robust.

Practical Implications

Carrying one or two copies of the T allele does not cause iron deficiency on its own. The effect is sub-clinical under conditions of adequate dietary iron. But when iron demand rises — during heavy menstrual cycles, pregnancy, vegetarian or vegan eating, endurance athletics, or blood donation — T carriers have a narrower margin before iron stores drop into deficiency range.

The most actionable step is knowing your ferritin level. Serum ferritin below 30 µg/L indicates depleted stores even when hemoglobin is still within range; below 12 µg/L is overt deficiency. If stores are adequate, standard dietary guidance applies. If stores trend low, dietary strategies to maximize absorption become important: pairing iron-rich foods with vitamin C, avoiding tea and coffee within an hour of iron-containing meals, and choosing iron bisglycinate⁹⁹ iron bisglycinate
A chelated form absorbed via peptide transporters, partially bypassing hepcidin-controlled ferroportin, and better tolerated than ferrous sulfate in sensitive individuals over ferrous sulfate if supplementing.

Interactions

This variant operates through the same hepcidin pathway as the primary TMPRSS6 missense variant rs855791. Carrying the T allele at rs2413450 in addition to the A allele at rs855791 may compound the iron-reducing effect, since both tag haplotypes with reduced matriptase-2 function — though the two variants are not in perfect linkage disequilibrium and capture partially overlapping and partially independent variance.

Interaction with HFE variants (rs1800562 C282Y, rs1799945 H63D) is the most clinically relevant context: HFE loss-of-function raises hepcidin sensitivity and causes iron overload, while TMPRSS6 T alleles raise hepcidin and limit absorption. In someone with borderline HFE heterozygosity, TMPRSS6 T alleles may actually attenuate iron accumulation. In someone with purely nutritional iron deficiency risk, no HFE context is needed — the TMPRSS6 effect stands alone.