GC Thr436Lys (rs4588): Vitamin D Binding Protein

The GC rs4588 polymorphism (Thr436Lys) is the second major variant in the vitamin D binding protein gene, working together with rs7041 to determine your VDBP isoform. This variant particularly affects VDBP concentration in the blood - how much carrier protein is available - which influences vitamin D transport, storage, and delivery to tissues including skin cells.

Understanding rs4588

This variant causes an amino acid change at position 436:

• C allele (Thr): Threonine - associated with Gc1 isoforms
• A allele (Lys): Lysine - defines the Gc2 isoform

The Three VDBP Isoforms

Combined with rs7041, rs4588 determines which isoform you have:

Understanding Your Genotype

• C/C: Higher VDBP levels - more vitamin D storage capacity
• C/A: Intermediate VDBP levels
• A/A: Lower VDBP levels - less storage, more free vitamin D

VDBP Concentration Effects

Why VDBP Levels Matter

• VDBP acts as a circulating reservoir for vitamin D
• Higher VDBP = more total vitamin D can be stored in blood
• Lower VDBP = smaller reservoir, vitamin D may deplete faster
• Affects how quickly vitamin D levels drop without supplementation

The A/A Genotype

• Approximately 50-60% lower VDBP concentrations
• Lower total vitamin D levels on standard tests
• But may have adequate or higher FREE vitamin D
• May need more frequent vitamin D replenishment

The C/C Genotype

• Higher VDBP levels - larger storage capacity
• May maintain vitamin D levels longer between doses
• Higher total 25(OH)D measurements
• Less free vitamin D available at any given total level

Skin Health Implications

Vitamin D Delivery to Skin

• VDBP concentration affects total vitamin D available for skin
• Lower VDBP may mean faster local depletion
• Skin's own vitamin D production becomes relatively more important
• May affect topical vitamin D analog effectiveness

Specific Skin Considerations

• Psoriasis: VDBP variants may influence treatment response
• Wound healing: Vitamin D availability affects repair
• Skin barrier: Continuous vitamin D supply supports function
• Photoprotection: Vitamin D has some protective effects against UV damage

Sun Exposure Strategy

For A/A genotype (lower VDBP):

• Skin-made vitamin D may be used more quickly
• More frequent, moderate sun exposure may be beneficial
• Or consistent supplementation to maintain levels
• Single large doses may not last as long

Health Associations

Bone Health

• VDBP concentration affects bone mineral density
• A/A genotype associated with lower BMD in some studies
• But free vitamin D may be more relevant than total
• Fracture risk associations vary by study

Immune Function

• VDBP is precursor to Gc-MAF (macrophage activating factor)
• Lower VDBP may affect immune activation
• Associations with infection susceptibility in some research
• Autoimmune disease connections under investigation

Cancer Risk

• Some studies link A allele to cancer risk
• Gc-MAF has anti-tumor properties
• Lower VDBP may reduce Gc-MAF availability
• Research ongoing - not conclusive

Metabolic Health

• Type 2 diabetes associations in some populations
• Obesity relationships (adipose tissue stores vitamin D)
• Metabolic syndrome connections

Population Distribution

Ancestry Patterns

• African ancestry: Lower A allele frequency (~10%)
• European ancestry: Higher A allele frequency (~25-30%)
• Asian ancestry: Intermediate frequencies

Evolutionary Perspective

• High-affinity, high-concentration VDBP favorable in high UV environments
• Lower-affinity VDBP may have advantages in low UV settings
• Allows more efficient use of limited vitamin D

Optimizing Vitamin D Status

For A/A Genotype (Lower VDBP)

• More frequent vitamin D supplementation may be beneficial
• Daily dosing rather than weekly high-dose
• Total vitamin D levels may appear lower - not necessarily concerning
• Consider free vitamin D testing for accurate picture
• Maintain consistency rather than sporadic high doses

For C/C Genotype (Higher VDBP)

• Weekly or less frequent dosing may maintain levels well
• Large storage capacity - levels stay stable longer
• May need higher total 25(OH)D to have adequate free vitamin D
• Standard vitamin D guidelines generally appropriate

For All Genotypes

• Test vitamin D status regularly
• Consider testing schedule based on genotype
• Ensure adequate cofactors (K2, magnesium)
• Take vitamin D with fat for absorption
• Adjust for seasonal variation

Supplementation Strategies

Daily vs. Weekly Dosing

• A/A genotype: Daily dosing may maintain more stable levels
• C/C genotype: Weekly dosing often adequate
• Individual variation: Test to confirm what works for you

Vitamin D3 vs D2

• D3 (cholecalciferol) binds VDBP more effectively than D2
• D3 generally preferred for supplementation
• This applies across all genotypes

Loading vs. Maintenance Doses

• Loading doses may be less effective for A/A genotype
• Lower storage capacity means vitamin D clears faster
• Better to establish consistent daily/weekly routine

Interaction with Other Variants

GC rs7041

• Together determines complete VDBP isoform
• Both affect binding affinity and concentration
• Analyze together for complete picture

VDR Variants

• GC determines supply (transport)
• VDR determines demand (response)
• High-activity VDR + low VDBP = may need consistent vitamin D supply
• Low-activity VDR + high VDBP = larger buffer, more stable

Testing with NutraHacker

NutraHacker's Skincare Panel analyzes GC rs4588 along with rs7041 and VDR variants, giving you a comprehensive understanding of your vitamin D transport and response genetics.

Frequently Asked Questions

If I have A/A, are my vitamin D levels always going to be low?

Not necessarily. Your total 25(OH)D may measure lower on standard tests because you have less carrier protein. However, your free (bioavailable) vitamin D may be adequate or even higher than someone with C/C genotype and the same total level. Focus on symptoms, functional markers, and consider free vitamin D testing rather than just total levels.

Should I take higher doses of vitamin D if I'm A/A?

Not necessarily higher doses, but more consistent dosing may be beneficial. Because your VDBP reservoir is smaller, daily dosing may maintain more stable levels than weekly high doses. Some A/A individuals do well with standard doses taken daily. Test your levels to find what works for you.

How does this interact with rs7041?

The two variants work together to determine your VDBP isoform. rs7041 primarily affects binding affinity, while rs4588 affects concentration. You need to know both to understand your complete vitamin D transport genetics. NutraHacker's Skincare Panel analyzes both variants.

References

1. Powe CE, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med. 2013;369(21):1991-2000.
2. Arnaud J, et al. Vitamin D binding protein gene polymorphism and circulating vitamin D binding protein levels. J Clin Endocrinol Metab. 2005;90(11):6185-6190.
3. Malik S, et al. Common variants of the vitamin D binding protein gene and adverse health outcomes. Crit Rev Clin Lab Sci. 2013;50(1):1-22.