rs228918 — TMPRSS6 TMPRSS6 upstream regulatory variant

TMPRSS6 Upstream Variant — Iron Regulation at the Regulatory Level

The TMPRSS6 gene encodes matriptase-2¹¹ matriptase-2
A type II transmembrane serine protease expressed primarily in the liver, whose primary role is to cleave hemojuvelin and thereby suppress hepcidin production, the master regulator of hepcidin²² hepcidin
A 25-amino-acid peptide hormone produced by the liver that controls systemic iron homeostasis by degrading ferroportin, the sole iron export channel on gut enterocytes and macrophages. When matriptase-2 functions normally, it suppresses hepcidin, allowing dietary iron to cross from the gut into the bloodstream. When matriptase-2 activity is reduced — whether from coding variants like rs855791 or regulatory variants that modulate gene expression — hepcidin rises and iron absorption falls.

The rs228918 variant sits approximately 2 kilobases upstream of the TMPRSS6 transcription start site, within the gene's 5' regulatory region. Unlike the well-characterized coding variant rs855791 (Ala736Val), rs228918 does not change the matriptase-2 protein itself. Instead, it lies in a region that influences how much matriptase-2 the liver produces. Variants in this region have been examined across multiple ethnic cohorts as part of the broader TMPRSS6 locus.

The Mechanism

As a regulatory variant, rs228918 is thought to influence TMPRSS6 expression levels rather than enzymatic function directly. The upstream region of TMPRSS6 contains binding sites for transcription factors involved in liver iron sensing, including elements responsive to the BMP/SMAD signaling pathway³³ BMP/SMAD signaling pathway
Bone morphogenetic protein / son of mothers against decapentaplegic: a liver-expressed signaling cascade that drives hepcidin gene transcription in response to iron loading. A variant that reduces TMPRSS6 transcription would produce less matriptase-2, leave more hemojuvelin intact on liver cell surfaces, and consequently drive higher hepcidin production — the same downstream consequence as a loss-of-function coding variant, achieved through reduced gene expression.

The C allele (minor allele at rs228918) is associated with the iron-reducing direction. This is consistent with the broader TMPRSS6 locus pattern in GWAS: several upstream and intronic variants near rs228918 (including rs228921, rs228919, and the coding rs4820268) travel together as a haplotype, and the minor allele consistently tags lower iron stores compared to the reference allele.

The Evidence

A systematic review with meta-analyses⁴⁴ systematic review with meta-analyses
Gichohi-Wainaina WN et al. Inter-ethnic differences in genetic variants within the transmembrane protease, serine 6 (TMPRSS6) gene associated with iron status indicators. Genes Nutr, 2015 examined eight TMPRSS6 SNPs — including rs228918 — across 11 Caucasian, 4 Asian, and 1 African-American study cohort. The analysis documented inter-ethnic differences in minor allele frequencies, with rs228918 showing consistent directionality across populations. Effect sizes for this regulatory variant were smaller and less precisely estimated than for rs855791, reflecting its role as a locus-depth signal rather than the primary functional driver.

In a cohort of 686 South African women⁵⁵ cohort of 686 South African women
Gichohi-Wainaina WN et al. Common variants and haplotypes in the TF, TNF-alpha, and TMPRSS6 genes are associated with iron status in a female Black South African population. J Nutr, 2015, the haplotype carrying the protective (T) allele at rs228918 combined with the protective allele at rs228921 was associated with lower odds for elevated soluble transferrin receptor concentrations above 8.3 mg/L (OR 0.79; 95% CI 0.63, 0.98). Elevated soluble transferrin receptor is a sensitive marker of iron deficiency at the tissue level, rising before hemoglobin falls.

A 2016 multi-cohort study⁶⁶ 2016 multi-cohort study
Gichohi-Wainaina WN et al. Associations between common variants in iron-related genes with haematological traits in populations of African ancestry. PLoS One, 2016 in 2,073 individuals across four African ancestry cohorts (Kenya, Tanzania, South Africa, African Americans) confirmed that TMPRSS6 variants contribute to hemoglobin variation even in populations where the primary coding variant rs855791 has lower frequency.

Practical Implications

The practical consequences of rs228918 are directionally identical to those of rs855791 but likely smaller in magnitude. The C allele tags a modest reduction in iron absorption efficiency, mediated through lower TMPRSS6 expression and consequently higher hepcidin. For most people carrying one or two C alleles and eating a balanced diet with adequate iron, this has no clinical consequence.

The effect becomes relevant when iron demand increases: during menstruation, pregnancy, adolescent growth, vegetarian or vegan dietary patterns, or endurance athletics. In these situations, even modest reductions in iron absorption efficiency can contribute to suboptimal iron stores over time. Prioritizing bioavailable iron sources, pairing plant iron with vitamin C, and periodic ferritin monitoring are proportionate responses.

If you also carry the more potent coding variant rs855791 AA genotype, the regulatory effects of rs228918 add to the functional deficit. The combination of reduced TMPRSS6 expression (this variant) and reduced matriptase-2 enzymatic activity (rs855791) compounds the hepcidin-raising effect.

Interactions

rs228918 and rs855791 are both in the TMPRSS6 locus on chromosome 22. They are partially correlated through linkage disequilibrium but are not identical signals — rs228918 captures variation in TMPRSS6 expression while rs855791 captures variation in matriptase-2 enzyme activity. The combined effect of carrying the C allele at rs228918 and the A allele at rs855791 is likely additive within the hepcidin pathway.

rs228918 also has documented haplotype structure with rs228921 (located approximately 196 bp downstream at chr22:37,110,836), and these two upstream variants often travel together. The protective allele combination (T at both loci on the plus strand) is associated with better iron status than the risk haplotype (C at both loci) in population studies.

For people who also carry HFE variants (rs1800562 C282Y or rs1799945 H63D), the directionality matters: TMPRSS6 variants raise hepcidin (reducing absorption) while HFE variants lower it (increasing absorption). These opposing effects require blood-test confirmation of actual iron status rather than relying on genetics alone.