rs6013897 — CYP24A1

CYP24A1 — The Vitamin D Degradation Switch

Every cell that responds to vitamin D must also be able to shut the signal off. CYP24A1¹¹ CYP24A1
Cytochrome P450 Family 24 Subfamily A Member 1, also called 25-hydroxyvitamin D-24-hydroxylase — a mitochondrial enzyme that adds a hydroxyl group at the C-24 position of vitamin D metabolites, initiating their breakdown into inactive calcitroic acid encodes the enzyme that serves as the primary off-switch for vitamin D signaling. It degrades both the circulating storage form (25(OH)D²² 25(OH)D
25-hydroxyvitamin D, the form measured in standard blood tests and the primary indicator of vitamin D status) and the potent active hormone (1,25(OH)₂D³³ 1,25(OH)₂D
1,25-dihydroxyvitamin D (calcitriol), the hormonally active form of vitamin D that binds to VDR and regulates hundreds of genes). The variant rs6013897, located near the CYP24A1 gene on chromosome 20, influences how much of this catabolic enzyme your cells produce — and therefore how quickly your body breaks down its vitamin D supply.

The Mechanism

CYP24A1 sits in the mitochondrial inner membrane and catalyzes a multi-step oxidation that converts active vitamin D metabolites into calcitroic acid⁴⁴ calcitroic acid
The water-soluble end-product of vitamin D catabolism, excreted in bile; biologically inactive, which is excreted in bile. The enzyme acts on both 25(OH)D₃ and 1,25(OH)₂D₃, making it the central gatekeeper of vitamin D availability. Importantly, CYP24A1 expression is itself induced by active vitamin D through VDR — forming a negative feedback loop⁵⁵ negative feedback loop
When 1,25(OH)₂D activates VDR, one of the genes VDR upregulates is CYP24A1, which then degrades the 1,25(OH)₂D that activated it — an elegant self-limiting circuit that prevents vitamin D toxicity.

The rs6013897 variant sits in a regulatory region near CYP24A1 and influences the gene's expression level. The A allele is associated with altered enzyme activity that leads to faster degradation of circulating vitamin D metabolites, resulting in lower serum 25(OH)D concentrations. Each copy of the A allele reduces circulating 25(OH)D by approximately 0.74 nmol/L⁶⁶ 0.74 nmol/L
Jorde R et al. Bone mineral density is associated with vitamin D related rs6013897. PLOS ONE, 2017. While this per-allele effect appears modest in isolation, it compounds meaningfully with variants in other vitamin D pathway genes.

The Evidence

The landmark GWAS by Wang et al.⁷⁷ GWAS by Wang et al.
Wang TJ et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010 identified rs6013897 as the fourth genome-wide significant locus for serum 25(OH)D levels (P = 6.0×10⁻¹⁰ in 33,996 Europeans), alongside GC (vitamin D binding protein), DHCR7/NADSYN1 (synthesis), and CYP2R1 (25-hydroxylation). Critically, individuals in the highest quartile of a combined genetic risk score across these loci had 2.47-fold increased odds of vitamin D insufficiency (<75 nmol/L) compared to the lowest quartile.

This finding was reinforced by a larger GWAS in 79,366 individuals⁸⁸ larger GWAS in 79,366 individuals
Jiang X et al. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nat Commun, 2018 that confirmed CYP24A1 as one of six loci collectively explaining 38% of the total genetic variance in circulating 25(OH)D.

A randomized controlled trial⁹⁹ randomized controlled trial
Barry EL et al. Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D3 supplementation. J Clin Endocrinol Metab, 2014 demonstrated that rs6013897 modifies the response to 1,000 IU/day vitamin D3 supplementation, with each copy of the risk allele reducing the 25(OH)D increase by approximately 4.2% (P = 0.04). This means carriers of the A allele get less benefit from standard supplementation doses because they degrade vitamin D faster.

The Tromsø Study¹⁰¹⁰ Tromsø Study
Jorde R et al. Bone mineral density is associated with vitamin D related rs6013897. PLOS ONE, 2017 extended these findings to bone health, showing that each A allele was associated with lower total hip bone mineral density (β = −0.031, P = 0.024) in 4,039 participants, with AA homozygotes averaging 0.02 g/cm² lower hip BMD than TT homozygotes.

Practical Implications

If you carry one or two A alleles, your body degrades vitamin D faster than average. Standard supplementation doses may not raise your 25(OH)D levels as effectively as they would for someone with the TT genotype. The key implication is that you may need higher doses of vitamin D3 to achieve and maintain optimal blood levels, and you should verify with blood testing rather than assuming a standard dose is sufficient.

This becomes especially important in combination with other vitamin D pathway variants. If you also carry risk alleles in GC (reduced transport), CYP2R1 (reduced activation), VDR (reduced receptor activity), or DHCR7 (reduced synthesis), the cumulative effect on vitamin D status can be substantial.

Interactions

CYP24A1 rs6013897 occupies a unique position in the vitamin D pathway — it is the only catabolic gene among the four GWAS-identified vitamin D loci. While GC (rs4588, rs7041) affects transport, CYP2R1 (rs10741657) affects activation, and DHCR7/NADSYN1 (rs7940244) affects synthesis, CYP24A1 controls degradation. Carrying risk alleles at multiple points in this pathway creates compounding insufficiency: less vitamin D synthesized, less efficiently activated, less effectively transported, AND faster degraded. The Wang et al. combined genetic risk score quantified this at 2.47-fold increased odds of insufficiency for the worst-case combination. VDR FokI (rs2228570) adds another layer — if the receptor itself is less active, even the vitamin D that survives CYP24A1 degradation has reduced biological effect.