rs2228570 — VDR FokI C>T

VDR FokI — The Vitamin D Receptor Activity Switch

The vitamin D receptor¹¹ vitamin D receptor
A nuclear receptor protein that binds active vitamin D (calcitriol) and directly regulates the expression of hundreds of genes throughout the body (VDR) is the master mediator of vitamin D's effects in nearly every tissue — from bones and intestines to immune cells and the brain. The FokI variant (rs2228570) is unique among VDR polymorphisms because it actually changes the protein structure, not just expression levels. A single nucleotide change at the translation start codon determines whether your cells produce a shorter, more transcriptionally active receptor or a longer, less active one. This makes FokI the only VDR variant with a clear, direct functional mechanism.

The Mechanism

The FokI polymorphism sits at the first of two potential translation initiation codons²² translation initiation codons
ATG sequences where the ribosome can begin building the protein; the first ATG produces a 427-amino-acid protein, while the second produces a 424-amino-acid version (ATG) in the VDR gene. When the G allele is present (on the plus strand; C on the coding strand), the first ATG is abolished, forcing translation to begin at the second ATG three codons downstream. This produces a VDR protein that is three amino acids shorter (424 vs 427 amino acids). The shorter protein, designated "F" in the classical nomenclature, binds more efficiently to transcription factor IIB³³ transcription factor IIB
TFIIB: a general transcription factor that helps position RNA polymerase II at gene promoters; tighter VDR-TFIIB binding means more efficient gene activation (TFIIB), resulting in approximately 1.7-fold greater transcriptional activity⁴⁴ 1.7-fold greater transcriptional activity
Arai H et al. A vitamin D receptor gene polymorphism in the translation initiation codon. J Bone Miner Res, 1997 compared to the longer "f" form.

Crucially, FokI is independent of the other well-known VDR polymorphisms (BsmI, ApaI, TaqI), which are clustered in the 3' end of the gene and are in strong linkage disequilibrium⁵⁵ linkage disequilibrium
LD: the tendency of nearby genetic variants to be inherited together; FokI shows no meaningful LD with BsmI/ApaI/TaqI because it sits far away in exon 2 with each other. FokI, located in exon 2, segregates independently — so your FokI genotype tells you something that your BsmI genotype cannot.

The Evidence

The functional significance of FokI was established by Arai et al.⁶⁶ Arai et al.
Arai H et al. A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity. Biochem Biophys Res Commun, 1997 who demonstrated in cell-based assays that the shorter VDR protein (F/G allele) drives significantly stronger transcriptional activation of vitamin D target genes. This finding has been replicated in immune cells, where the F allele shows stronger induction of VDR-dependent antimicrobial peptides.

A meta-analysis of VDR polymorphisms and osteoporosis⁷⁷ meta-analysis of VDR polymorphisms and osteoporosis
Zhao L et al. VDR polymorphisms and postmenopausal osteoporosis, 2018 found the FokI variant associated with osteoporosis risk (OR 1.19 overall), with stronger effects in Asian populations. Individuals with the less active receptor (AA genotype) showed reduced calcium absorption and lower bone mineral density in multiple studies.

FokI has been extensively studied in immune function. A meta-analysis of tuberculosis susceptibility⁸⁸ meta-analysis of tuberculosis susceptibility
Selvaraj P et al. FokI VDR and tuberculosis, 2021 found the ff genotype (AA on 23andMe) associated with increased TB risk (OR 1.36, 95% CI 1.11-1.66), particularly in Asian populations (OR 2.0). The mechanism is straightforward: vitamin D activates monocytes and stimulates antimicrobial peptide production through VDR, and the less active receptor blunts this response.

Cancer associations have also been documented. An updated meta-analysis of 39 studies⁹⁹ updated meta-analysis of 39 studies
Xu G et al. VDR FokI and colorectal cancer, 2018 found a borderline association between FokI and colorectal cancer risk, while breast cancer meta-analyses showed the ff genotype associated with approximately 14% increased risk. Vitamin D's anti-proliferative effects are mediated through VDR, so reduced receptor activity could weaken this protective mechanism.

A systematic review of vitamin D supplementation response¹⁰¹⁰ systematic review of vitamin D supplementation response
Jolliffe DA et al. VDR polymorphisms and vitamin D supplementation response, 2022 found that FokI genotype modifies the response to vitamin D supplementation, with FF carriers (GG on 23andMe) showing better clinical responses to supplementation.

Practical Implications

If you carry one or two copies of the A allele, your vitamin D receptor is less transcriptionally active. This does not mean vitamin D is ineffective for you — it means you may need to maintain higher circulating vitamin D levels to achieve the same downstream biological effects. The key actions are:

Maintain optimal vitamin D status through regular testing. Aim for 25(OH)D levels of 40-50 ng/mL rather than settling for the minimum 30 ng/mL, especially if you carry two A alleles. Use vitamin D3 (cholecalciferol), taken with a fat-containing meal for optimal absorption. Ensure adequate calcium intake, since reduced VDR activity impairs intestinal calcium absorption.

Pay attention to immune health. The reduced receptor activity may mean you benefit more from maintaining robust vitamin D levels during winter months and illness seasons, when immune demands on the vitamin D system are highest.

Interactions

FokI interacts with VDR BsmI (rs1544410) and CYP2R1 (rs10741657). While FokI is genetically independent of BsmI (no linkage disequilibrium), their effects on vitamin D signaling can compound. If you carry FokI A alleles (less active receptor) AND BsmI T alleles (reduced receptor expression), you face a "double hit" — fewer receptors AND less active ones. Similarly, carrying CYP2R1 risk alleles (reduced vitamin D activation) on top of FokI A alleles means less active vitamin D reaching a less responsive receptor. In such combined scenarios, aggressive vitamin D optimization (higher target levels, consistent supplementation, regular monitoring) becomes particularly important.