rs5756506 — TMPRSS6

TMPRSS6 rs5756506 — An Intronic Modifier of Iron Regulatory Balance

Within the TMPRSS6 gene — the same gene that harbors the well-characterized Ala736Val variant (rs855791) — lies a cluster of common intronic polymorphisms that collectively fine-tune the activity of matriptase-2¹¹ matriptase-2
A type II transmembrane serine protease expressed in the liver that negatively regulates hepcidin, the master iron-regulatory hormone. The rs5756506 variant, located deep in intron 13 of TMPRSS6 approximately 320 bases upstream of the exon 14 splice acceptor, does not change any amino acid but appears to influence the overall iron-regulatory output of this gene at the population level.

TMPRSS6 encodes matriptase-2, whose primary job is to keep hepcidin²² hepcidin
A 25-amino-acid peptide hormone secreted by the liver that controls systemic iron homeostasis by blocking ferroportin, the only known iron exporter on gut and macrophage cell surfaces levels from rising too high. By cleaving hemojuvelin³³ hemojuvelin
A membrane-bound co-receptor that drives the BMP/SMAD signaling cascade responsible for hepcidin transcription off the liver cell surface, matriptase-2 acts as a natural brake on hepcidin production. When any variant — coding or non-coding — reduces the effective activity of this brake, hepcidin rises and iron absorption falls.

The Mechanism

rs5756506 is an intronic variant with no protein-level consequence. Intronic variants in this position can influence gene function through several mechanisms: altered splicing efficiency of the adjacent exon 14, modification of regulatory elements that affect transcription factor binding, or linkage disequilibrium with nearby functional variants. The variant falls within a 300-nucleotide intronic window upstream of the exon 14 splice acceptor (coding notation c.1556-320), a region where branch point sequences and polypyrimidine tracts critical for splicing fidelity are typically found.

The G allele at rs5756506 (GRCh38 plus-strand reference) is the common allele in European (~76%), South Asian (~95%), and East Asian (~97%) populations, while the C allele predominates in African populations (1000 Genomes: ~84% C in Africans). The C allele is associated with measurably higher hemoglobin and hematocrit in healthy individuals, consistent with enhanced matriptase-2 function — more efficient hepcidin suppression and therefore better iron absorption and utilization.

The Evidence

The primary association data comes from a Turkish candidate-gene study by Batar et al.⁴⁴ 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, which genotyped eight TMPRSS6 SNPs in 150 IDA patients and 100 healthy controls. Among all variants examined, rs5756506 was the only one associated with hemoglobin (P=0.02) and hematocrit (P=0.03) specifically in the healthy control group, while no significant difference was observed between patients and controls. This pattern suggests the variant modulates baseline iron regulatory tone rather than directly determining susceptibility to iron deficiency anemia.

A population genetics analysis⁵⁵ population genetics analysis
Phelan D et al. Differences in the frequency of genetic variants associated with iron imbalance among global populations. PLoS ONE, 2020 identified rs5756506 among TMPRSS6 variants with population branch statistic values exceeding the top 5% genome-wide threshold (AFR PBS=0.25), indicating this locus has been subject to different selective pressures in African versus non-African populations. The high C allele frequency in Africans — a population historically exposed to endemic malaria, which causes hemolytic anemia — may reflect positive selection for enhanced iron absorption capacity.

In contrast, a study of 1,316 healthy Gambians⁶⁶ 1,316 healthy Gambians
Jallow MW et al. Association of common TMPRSS6 and TF gene variants with hepcidin and iron status in healthy rural Gambians. Sci Rep, 2021 found no independent association of rs5756506 with hepcidin, iron biomarkers, or hematological parameters. The null result in this West African cohort — where the C allele is common and most individuals are C allele carriers — may reflect reduced statistical power to detect heterozygous effects when homozygous CC is the population norm.

Practical Implications

The evidence for rs5756506 is emerging and limited to small or population-specific studies. Individuals homozygous for the G allele (GG) represent the common European genotype and may have modestly lower hemoglobin and hematocrit than C allele carriers under the same dietary conditions. This is particularly relevant when iron demands are elevated — during menstruation, pregnancy, endurance training, or on plant-based diets where non-heme iron bioavailability is inherently lower.

Monitoring ferritin and hemoglobin provides the clearest picture of actual iron status regardless of genotype. For GG individuals who already show borderline iron stores, dietary iron optimization — pairing iron-rich foods with vitamin C, choosing heme iron sources where possible, and avoiding absorption inhibitors like tea and coffee at meals — can partially compensate for any genetically reduced absorption capacity.

Interactions

rs5756506 is in low linkage disequilibrium with the primary TMPRSS6 functional variants rs855791 (Ala736Val) and rs4820268 in non-African populations, meaning the variants contribute relatively independently to iron regulation. rs2235321, another intronic TMPRSS6 variant, has been reported to independently affect hepcidin levels in Gambian adults. Together, these common TMPRSS6 variants may explain a portion of the genetic variance in iron status that is not captured by the rs855791 variant alone.

The interaction with HFE hemochromatosis variants (C282Y, rs1800562; H63D, rs1799945) is worth noting: for GG individuals who also carry HFE mutations, any tendency toward higher hepcidin from reduced TMPRSS6 activity could provide a modest counterbalance to the hepcidin-suppressing effect of HFE mutations.