rs5756504 — TMPRSS6 TMPRSS6 variant

TMPRSS6 rs5756504 — A Secondary Node in the Hepcidin Circuit

Iron absorption is not a passive process — it is under continuous hormonal control by hepcidin¹¹ hepcidin
A 25-amino-acid peptide hormone produced by the liver that blocks ferroportin, the only known mammalian iron export channel, on gut and macrophage cell surfaces. When hepcidin rises, iron absorption falls, and TMPRSS6 is the gene whose job it is to keep that hormone in check. TMPRSS6 encodes matriptase-2²² matriptase-2
A type II transmembrane serine protease expressed in the liver that cleaves hemojuvelin from the hepatocyte surface, disabling the BMP/SMAD signaling cascade that drives hepcidin transcription. Loss of matriptase-2 activity leads to chronically elevated hepcidin and iron-refractory anemia, the molecular brake on hepcidin production. While the coding-change variant rs855791 (Ala736Val) alters the catalytic efficiency of this enzyme directly, the TMPRSS6 locus harbors additional intronic variants that collectively refine the iron-regulatory output of the gene at the population level. rs5756504 is one of these.

Located at position c.1556-198 within intron 13 of TMPRSS6 — 122 nucleotides downstream of the nearby intronic variant rs5756506 — rs5756504 carries no amino acid change and no direct protein consequence. Instead, it falls within a region of the TMPRSS6 pre-mRNA that influences downstream splicing or transcriptional regulation. The C allele, which is the GRCh38 reference and the population-major allele in European and South Asian populations, is associated with lower hemoglobin. The T allele, more common in African populations, is associated with higher hemoglobin and better erythrocyte parameters.

The Mechanism

Like its neighbor rs5756506, rs5756504 is an intronic variant with no direct protein consequence. Intronic variants in this position can alter TMPRSS6 expression or processing through several routes: modification of branch point or polypyrimidine tract sequences affecting spliceosome recruitment, disruption of intronic regulatory elements that influence transcription factor occupancy, or tag-SNP effects reflecting LD with a causal nearby variant. The net effect — reflected in population-level hemoglobin differences — is consistent with modulation of the TMPRSS6/hepcidin axis: higher T allele dosage correlates with more effective hepcidin suppression and therefore greater iron absorption and higher hemoglobin.

The variant is located approximately 122 nucleotides from rs5756506 within the same intronic region. Whether these two variants act independently or tag the same causal signal has not been formally resolved in published fine-mapping studies, though their coexistence in multiple independent TMPRSS6 iron-status studies suggests each contributes information.

The Evidence

The primary association evidence comes from a large GWAS of hematological traits³³ large GWAS of hematological traits
Kamatani Y et al. Genome-wide association study of hematological and biochemical traits in a Japanese population. Nat Genet, 2010 in 14,402 Japanese individuals, which identified rs5756504-T as associated with higher hemoglobin at genome-wide significance (P = 2 × 10⁻¹⁰, effect size approximately +0.076 g/dL per T allele). This signal is independent of the lead TMPRSS6 coding variant rs855791 based on the study's locus-wide analysis.

A subsequent replication study⁴⁴ replication study
Seiki T et al. Association of genetic polymorphisms with erythrocyte traits: Verification of SNPs reported in a previous GWAS in a Japanese population. Gene, 2018 in 4,971 Japanese participants from the Japan Multi-Institutional Collaborative Cohort Study confirmed the rs5756504 association with erythrocyte traits, including hemoglobin and related red cell indices. A systematic review⁵⁵ systematic review
Timmer T et al. Associations between single nucleotide polymorphisms and erythrocyte parameters in humans: a systematic literature review. Mutat Res Rev Mutat Res, 2019 subsequently listed rs5756504 among fourteen SNPs consistently associated with mean corpuscular hemoglobin across multiple cohorts.

The evidence base is moderate — two independent cohort populations with replicated association, a biologically coherent mechanism via the TMPRSS6/hepcidin pathway, and a signal that appears distinct from the established coding variant rs855791. The effect size (~0.076 g/dL per allele) is comparable to that of other common TMPRSS6 intronic variants.

Practical Implications

For individuals homozygous for the C allele (CC), the functional consequence mirrors that of other low-hemoglobin TMPRSS6 genotypes: modestly reduced iron absorption efficiency through the hepcidin pathway. The margin of iron sufficiency is thinner. During periods of elevated iron demand — menstruation, pregnancy, endurance training, or reliance on plant-based diets with lower non-heme iron bioavailability — CC individuals may deplete iron stores more readily than T allele carriers.

For heterozygotes (CT), the effect is intermediate. For TT individuals, the genotype is associated with the highest hemoglobin in this locus and confers no additional monitoring burden beyond standard practice.

Interactions

rs5756504 sits within the same TMPRSS6 locus as the coding variant rs855791 (Ala736Val) and the adjacent intronic variant rs5756506. These three variants collectively shape the iron-regulatory output of the matriptase-2 axis. Whether rs5756504 and rs5756506 are in linkage disequilibrium with each other or tag independent functional signals is not fully established in published literature.

The rs855791 coding variant remains the primary determinant of TMPRSS6-mediated iron status, with each A allele reducing hemoglobin by approximately 0.13 g/dL — roughly twice the per-allele effect of rs5756504. Carrying the CC genotype at rs5756504 alongside the AA genotype at rs855791 represents additive pressure on hepcidin regulation, with both variants independently raising hepcidin and reducing iron absorption. In individuals who also carry HFE hemochromatosis variants (rs1800562 C282Y, rs1799945 H63D), the cumulative hepcidin-raising effect of TMPRSS6 variants may partially offset the pathological iron loading driven by HFE dysfunction.