Is CYP2R1 rs10741657 AG associated with lower vitamin D status and weaker supplementation response?

The CYP2R1 gene encodes the principal hepatic 25-hydroxylase enzyme responsible for converting vitamin D into circulating 25-hydroxyvitamin D [25(OH)D]. The rs10741657 single nucleotide polymorphism directly influences this metabolic process, impacting baseline status and response to therapy.

Clinical evidence

• Carrying the heterozygous AG genotype is associated with an intermediate, stepwise decrease in circulating 25(OH)D levels (GG < AG < AA).
• Quantitative genetic data show that carrying the G allele correlates with an average reduction of approximately 5.2 nmol/L in achieved 25(OH)D.
• A meta-analysis of over 52,000 individuals demonstrated that under a dominant model (AG + GG vs. AA), carriers of the G allele have a significantly higher risk of vitamin D deficiency (OR 1.42; 95% CI: 1.11–1.83).

Mechanistic explanations

• The G allele at rs10741657 is a functional variant associated with reduced expression and catalytic activity of the hepatic 25-hydroxylase enzyme.
• This reduction in enzyme availability leads to less efficient conversion of vitamin D into its primary circulating biomarker, 25(OH)D, directly lowering overall systemic status.

Clinical implications

• The AG genotype blunts the expected rise in serum 25(OH)D levels following oral vitamin D supplementation, diminishing overall status resilience.
• Due to this attenuated response, standard supplementation regimens may underperform, often requiring closer clinical monitoring and higher or more sustained cholecalciferol doses to achieve and maintain optimal sufficiency targets.

Bottom line

• The CYP2R1 rs10741657 AG genotype is associated with lower baseline 25-hydroxyvitamin D levels and reduced status resilience, meaning carriers exhibit a blunted response to oral supplementation and may require individualized, higher-dose strategies to achieve sufficiency.