rs2075674 — TFR2 TFR2 Ala617 variant

TFR2 rs2075674 — The Synonymous TFR2 Variant Linked to Retinal Iron Accumulation

The TFR2 gene encodes transferrin receptor 2, a sensor protein expressed primarily in hepatocytes and erythroid precursors that detects iron bound to transferrin in the bloodstream and helps calibrate the master iron hormone hepcidin¹¹ hepcidin
A peptide hormone made in the liver that controls how much iron is absorbed from the gut and released from recycling macrophages. rs2075674 is a synonymous coding variant in exon 16 of TFR2 — the nucleotide change (c.1851C>T, i.e. G→A on the genomic plus strand) does not alter the encoded alanine at position 617, but lies near the polypyrimidine tract of the adjacent intron and may influence mRNA splicing efficiency. It has been studied both as a tag SNP for the TFR2 locus in iron-trait GWAS and as an independent candidate in age-related macular degeneration²² age-related macular degeneration
AMD — the leading cause of vision loss in adults over 65; iron accumulates in the retinal pigment epithelium with aging and promotes oxidative damage to photoreceptors studies.

The Mechanism

TFR2 is expressed in the retinal pigment epithelium (RPE), the metabolic support layer for photoreceptors, in addition to its primary hepatic role. Iron in the RPE is essential for the visual cycle but accumulates excessively with aging, catalyzing the Fenton reaction³³ Fenton reaction
Fe²⁺ + H₂O₂ → Fe³⁺ + OH⁻ + OH• — generating hydroxyl radicals that damage lipid membranes, DNA, and proteins to generate reactive oxygen species that damage photoreceptors and RPE cells — a major driver of AMD pathogenesis. Variants in iron metabolism genes expressed in the RPE, including TFR2, are therefore plausible modulators of AMD risk through an oxidative stress pathway rather than through systemic iron dysregulation alone.

rs2075674 occupies a position in the TFR2 coding sequence near a splice-relevant regulatory element. Ensembl VEP annotates the A allele as a splice_polypyrimidine_tract_variant in addition to the synonymous coding change, suggesting the variant may subtly alter splicing of the downstream intron and thereby change TFR2 isoform ratios in tissues where alternative splicing is active. This mechanism is not yet verified by experimental splicing assays.

The Evidence

The AMD association for rs2075674 comes from two Polish and Chinese case-control studies. Wysokinski et al. 2014⁴⁴ Wysokinski et al. 2014
Disease Markers — 493 AMD cases and 171 controls; CC and TT genotypes (coding-strand notation equivalent to GG and AA on the plus strand) associated with AMD occurrence; TT genotype specifically enriched in obese AMD patients. The same group's earlier study with 278 patients found no interaction with smoking, suggesting the AMD association is not confounded by tobacco exposure.

Xu et al. 2022⁵⁵ Xu et al. 2022
Current Eye Research — 400 AMD patients (200 wet, 200 dry) and 200 controls in northeastern China; A allele of rs2075674 identified as a potential wet AMD risk factor, consistent with the direction reported by Wysokinski et al.

Importantly, a larger case-control study Shi et al. 2014⁶⁶ Shi et al. 2014
J Cardiovasc Med — 1,264 CHD cases and 1,264 controls in Chinese Han population; rs2075674 and rs7385804 used as TFR2 tag SNPs; no association with CHD risk or plasma ferritin found no effect on systemic iron markers, suggesting that rs2075674's potential functional effect is tissue-specific (retinal) rather than systemic. The iron GWAS evidence for the TFR2 locus derives primarily from the adjacent intronic variant rs7385804.

Practical Actions

For AA homozygotes, the most clinically relevant implication is the emerging AMD signal. Since the proposed mechanism is iron-driven retinal oxidative stress, the actionable response is to support antioxidant capacity in the eye and undergo regular retinal imaging — not to alter dietary iron intake, for which no specific effect has been demonstrated for this variant. The iron antioxidant minerals zinc and copper, and the carotenoids lutein and zeaxanthin (which concentrate in the retinal macula and quench reactive oxygen species), are the nutrients with the strongest evidence base for retinal protection.

Interactions

rs2075674 sits in the same TFR2 gene region as rs7385804, the intronic TFR2 variant with stronger evidence for systemic iron marker effects. The two variants tag partially overlapping LD blocks in the TFR2 locus on chromosome 7 and were used together as TFR2 tag SNPs in the Shi et al. CHD study. Combined carrier status at both loci could reflect broader TFR2 haplotype effects on iron sensing, though this has not been formally studied. The HFE C282Y variant (rs1800562) and TMPRSS6 Ala736Val (rs855791) operate in the same hepcidin-regulation pathway and would be expected to interact biologically with TFR2 variation in modulating iron homeostasis.