The VDR FokI polymorphism (rs2228570) is unique among vitamin D receptor variants because it actually changes the protein structure. This variant affects the start codon, resulting in a VDR protein that is either 424 or 427 amino acids long. The shorter version (F allele) is more transcriptionally active, influencing everything from bone health to immune function to skin aging.
What Makes FokI Special
Unlike most VDR variants that affect gene expression, FokI changes the protein itself:
- Location: Start codon region of VDR gene
- Effect: Determines which of two start codons is used
- Result: Two different VDR protein lengths
- Named for: FokI restriction enzyme that detects this variant
Understanding Your Genotype
- T/T (ff): Longer VDR protein (427 amino acids) - less active
- C/T (Ff): Heterozygous - mixed VDR proteins
- C/C (FF): Shorter VDR protein (424 amino acids) - more active
The shorter F form (C allele) is approximately 1.7 times more active in transcription assays than the longer f form.
Functional Differences
The F (Short) Form - More Active
- More potent transcriptional activation
- Stronger response to vitamin D
- More effective gene regulation
- Associated with various health benefits
The f (Long) Form - Less Active
- Reduced transcriptional activity
- May need higher vitamin D levels for same effect
- Associated with some disease risks
- May benefit more from vitamin D optimization
Health Implications
Bone Health
- FF genotype often associated with higher bone mineral density
- ff genotype may have increased osteoporosis risk
- Vitamin D's bone effects partly depend on VDR function
- ff carriers may need more aggressive osteoporosis prevention
Immune Function
- VDR regulates immune cell function
- FF genotype may have stronger antimicrobial responses
- ff genotype associated with increased risk of some infections (TB studies)
- Autoimmune disease associations vary by population
Cancer Risk
- Vitamin D has anti-cancer properties via VDR
- Some studies link ff genotype to increased cancer risk
- Prostate, breast, and colon cancer associations studied
- Results vary; vitamin D status likely modifies genetic effects
Skin Health Effects
Skin Cell Function
- VDR regulates keratinocyte proliferation and differentiation
- FF genotype may have more responsive skin cells to vitamin D
- Affects skin barrier function
- Influences skin immune responses
Skin Conditions
- Psoriasis: VDR variants may affect disease severity and treatment response
- Atopic dermatitis: Vitamin D/VDR pathway involved in skin barrier
- Skin aging: VDR activity affects collagen and skin repair
- UV response: VDR mediates some protective effects against UV damage
Topical Vitamin D
For skin conditions:
- Calcipotriol (vitamin D analog) used for psoriasis
- VDR genotype may influence response
- ff genotype might need more intensive treatment
Optimizing Based on Genotype
For ff Genotype (Less Active VDR)
- Ensure robust vitamin D status (test regularly)
- May benefit from higher supplementation doses
- Target 40-60 ng/mL 25-hydroxyvitamin D
- Pay extra attention to bone health
- Consider vitamin D's role in immune function
For FF Genotype (More Active VDR)
- Standard vitamin D recommendations often sufficient
- Still important to avoid deficiency
- May respond well to moderate vitamin D intake
- Watch for signs of vitamin D excess with high supplementation
For All Genotypes
- Test 25-hydroxyvitamin D levels annually
- Ensure adequate cofactors (K2, magnesium)
- Consider seasonal variation in vitamin D needs
- Don't rely on sun exposure alone in winter/northern latitudes
Prevalence
- European ancestry: f allele approximately 35-40%
- African ancestry: Higher f allele frequency
- Asian ancestry: Lower f allele frequency
- This is a functional variant: Genotype directly predicts protein function
Testing with NutraHacker
NutraHacker's Skincare Panel analyzes VDR FokI along with other vitamin D-related variants, helping you understand how your body responds to vitamin D and optimize for skin and overall health.
Frequently Asked Questions
Is ff genotype "bad"?
Not inherently. The ff genotype means your VDR is less transcriptionally active, so you may need to be more diligent about vitamin D status. With proper attention to vitamin D levels, you can compensate for the reduced receptor activity. It's about knowing your genetics and adjusting accordingly.
Should I take more vitamin D if I'm ff?
Possibly, but base decisions on your actual vitamin D blood levels, not just genetics. If your levels are optimal and you have no deficiency symptoms, your current intake may be sufficient. If you're on the low end of normal, ff carriers may benefit from increasing to achieve more robust levels.
How does this interact with other VDR variants?
FokI is unique because it changes protein structure, while other VDR variants (Cdx2, BsmI, TaqI) affect expression or mRNA stability. You might have FF (good receptor) but low expression from other variants, or ff (less active receptor) but high expression. Analyzing all variants together gives the complete picture.
References
- Arai H, et al. A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density. J Bone Miner Res. 1997;12(6):915-921.
- Uitterlinden AG, et al. Genetics and biology of vitamin D receptor polymorphisms. Gene. 2004;338(2):143-156.
- Raimondi S, et al. Review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Carcinogenesis. 2009;30(7):1170-1180.