rs10741657 — CYP2R1 promoter variant

CYP2R1 — The Vitamin D Activation Enzyme

CYP2R1 is a cytochrome P450 enzyme in the liver that performs the first hydroxylation step in vitamin D activation. It converts vitamin D3 ¹¹ Cholecalciferol: the form of vitamin D produced in the skin from sunlight or taken as a supplement (cholecalciferol, from sun exposure or supplements) into 25-hydroxyvitamin D (25(OH)D, also called calcidiol) ²² Calcidiol is the circulating storage form with a half-life of about 3 weeks — the standard marker for vitamin D status, which is the form measured in standard blood tests. Without this conversion step, vitamin D3 remains biologically inactive.

The Mechanism

The rs10741657 variant is located in the promoter region of the CYP2R1 gene, affecting how much enzyme is produced ³³ Promoter variants don't change the protein itself — they change how much of the protein the cell makes. The A allele reduces CYP2R1 transcription, resulting in lower enzyme levels in the liver. This means that for a given amount of vitamin D3 intake (from sun or supplements), less is converted to the active 25(OH)D form. Genome-wide association studies (GWAS) have consistently identified this variant as one of the strongest genetic determinants of circulating 25(OH)D levels.

The Evidence

A GWAS meta-analysis involving over 79,000 individuals⁴⁴ A GWAS meta-analysis involving over 79,000 individuals
Jiang X et al. Nature Communications 2018 — GWAS in 79,366 Europeans on the genetic architecture of 25(OH)D levels confirmed that variants near CYP2R1, including rs10741657, significantly affect blood 25(OH)D concentrations. A systematic review and meta-analysis⁵⁵ systematic review and meta-analysis
Duan L et al. Effects of CYP2R1 gene variants on vitamin D levels and status, 2018 found that carriers of risk alleles had an increased risk of vitamin D deficiency (OR 1.09, 95% CI 1.03-1.15). Carriers of the A allele have lower baseline 25(OH)D levels and may require higher vitamin D3 doses to achieve the same blood levels as non-carriers.

The Double Hit with VDR

If you carry both a CYP2R1 activation variant (less D3 converted to 25(OH)D) and a VDR receptor variant (cells respond less to circulating vitamin D), you face a compounded challenge. You produce less active vitamin D AND your cells are less responsive to what you do produce. This makes vitamin D optimization through testing and supplementation particularly important.

Practical Implications

If you carry the A allele, you likely need higher vitamin D3 supplementation doses than the general recommendation to achieve optimal blood levels. The only way to know your ideal dose is to test, supplement, and retest. Many people with this variant find they need 3,000-5,000 IU daily (or more) to maintain optimal levels, especially in winter months or at higher latitudes.

Interactions

CYP2R1 interacts with VDR (rs1544410) — reduced activation combined with reduced receptor sensitivity creates a compounded vitamin D challenge.