Does the CYP2R1 rs10741657 AG genotype lower vitamin D status?

The CYP2R1 gene plays a fundamental role in systemic vitamin D metabolism, and its common genetic variations are key determinants of individual clinical vitamin D status.

Mechanistic pathways

• Enzymatic bioactivation: The CYP2R1 gene encodes cytochrome P450 2R1, a microsomal enzyme located in the endoplasmic reticulum of hepatocytes. It serves as the primary hepatic vitamin D 25-hydroxylase, catalyzing the essential first step of vitamin D bioactivation by converting vitamin D₂ and D₃ into 25-hydroxyvitamin D [25(OH)D], or calcidiol.
• Promoter variant effects: The rs10741657 G allele functions as a promoter variant. Carrying this risk allele directly decreases the expression and downstream functional activity of the CYP2R1 enzyme, resulting in a less efficient rate of vitamin D conversion.

Clinical evidence and phenotype

• Intermediate phenotype: Individuals with the heterozygous AG genotype present an intermediate clinical phenotype. They possess moderately reduced enzymatic capacity and lower baseline circulating 25(OH)D levels compared to those with the wild-type AA genotype, though they maintain higher levels than homozygous GG individuals.
• Elevated deficiency risk: Cohort studies and meta-analyses consistently link the risk G allele to poorer vitamin D status. A dominant genetic model (comparing AG/GG against AA) demonstrates an odds ratio (OR) of approximately 1.42 for vitamin D deficiency.
• Supplementation resistance: Evidence indicates that carrying the G allele may also blunt the expected increase in circulating 25(OH)D levels following standard oral vitamin D supplementation or UVB exposure.

Bottom line

• The claim is fully supported: the CYP2R1 gene encodes the principal hepatic 25-hydroxylase enzyme, and the rs10741657 AG genotype acts as a key genetic determinant that reduces enzyme expression, leading to lower circulating 25-hydroxyvitamin D levels and an increased risk of clinical insufficiency.