rs10832310 — CYP2R1

Intronic tag SNP at the CYP2R1/PDE3B locus on chromosome 11 that marks a haplotype associated with reduced vitamin D 25-hydroxylase activity and lower circulating 25-hydroxyvitamin D levels

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CYP2R1 and the First Step of Vitamin D Activation

Vitamin D from sunlight or supplements is biologically inert until the liver converts it into 25-hydroxyvitamin D (25(OH)D)11 25-hydroxyvitamin D (25(OH)D)
Also called calcidiol — the main circulating form of vitamin D, and the standard measure of your vitamin D status on a blood test. From here, the kidneys make the fully active hormone calcitriol. This first hydroxylation step is performed primarily by a cytochrome P450 enzyme called CYP2R1, encoded on chromosome 11p15.2. Without this enzyme working efficiently, neither sun exposure nor dietary vitamin D can adequately raise circulating 25(OH)D levels.

The rs10832310 variant is an intronic tag SNP located in the neighboring PDE3B gene but in high linkage disequilibrium with regulatory variants at the CYP2R1 locus. The G allele marks a haplotype associated with reduced CYP2R1 expression or activity, resulting in less efficient 25-hydroxylation of vitamin D3.

The Mechanism

CYP2R1 is a microsomal cytochrome P450 enzyme expressed primarily in the liver, where it catalyzes the addition of a hydroxyl group to carbon-25 of vitamin D3 (cholecalciferol), converting it to 25(OH)D3. Cheng et al. 200422 Cheng et al. 2004
Cheng JB et al. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. PNAS, 2004 provided definitive evidence for this role by identifying a patient with an inherited homozygous L99P mutation in CYP2R1 who had very low circulating 25(OH)D despite normal sun exposure and dietary intake. The mutation abolished enzyme activity entirely.

The rs10832310 G allele does not alter the CYP2R1 protein sequence directly — it tags a haplotype block that likely includes regulatory variants affecting CYP2R1 transcription. Colocalization analysis in the Kämpe et al. 2019 GWAS33 Kämpe et al. 2019 GWAS
Kämpe A et al. Genetic variation in GC and CYP2R1 affects 25-hydroxyvitamin D concentration and skeletal parameters: A genome-wide association study in 24-month-old Finnish children. PLoS Genetics, 2019 found a 97.3% posterior probability of a shared causal variant between the GWAS signal and CYP2R1 expression in thyroid tissue, strongly implicating altered gene expression as the mechanism.

The Evidence

The primary GWAS identifying rs10832310 was conducted in 761 healthy term-born Finnish children at 24 months of age, who participated in a randomized clinical trial comparing 10 μg versus 30 μg daily vitamin D3 supplementation from age 2 weeks. The GWAS signal reached p = 4.24 × 10⁻¹¹, genome-wide significance. The G allele was associated with a decrease of approximately 7.5 units in serum 25(OH)D — a clinically meaningful reduction for a pediatric population. Critically, the effect size was consistent regardless of whether children received standard-dose or high-dose vitamin D3, indicating that this locus reduces baseline conversion efficiency rather than modulating supplementation response directly.

Haplotypes associating with low 25(OH)D at this locus also showed strong negative associations with pQCT (peripheral quantitative computed tomography) bone parameters at the distal tibia, consistent with vertical pleiotropy44 vertical pleiotropy
An effect where one variant influences multiple downstream traits through a single causal pathway — here, lower 25(OH)D leads to reduced calcium absorption and impaired bone mineralization mediated by vitamin D status.

The broader CYP2R1 locus has been replicated in multiple independent GWAS. The Wang et al. 2010 Lancet GWAS55 Wang et al. 2010 Lancet GWAS
Wang TJ et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010 of 33,996 Europeans confirmed the chromosome 11 CYP2R1 region as one of three genome-wide significant loci for 25(OH)D, alongside DHCR7 (chromosome 11q) and GC (chromosome 4). The MrOS Sweden cohort66 MrOS Sweden cohort
Björk A et al. Haplotypes in the CYP2R1 gene are associated with levels of 25(OH)D and bone mineral density, but not with other markers of bone metabolism. PLoS One, 2019 found 4.6–18.5% differences in mean 25(OH)D between CYP2R1 genotypes in a large adult cohort, with corresponding effects on femoral neck bone mineral density.

Beyond skeletal health, the CYP2R1 locus has been linked to type 1 diabetes risk77 type 1 diabetes risk
Ramos-Lopez E et al. CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. Diabetes Metab Res Rev, 2007, multiple sclerosis susceptibility, and immune function — likely mediated through the immunomodulatory effects of calcitriol on regulatory T cells and antigen-presenting cells.

Practical Implications

The G allele at rs10832310 reduces the liver's ability to convert vitamin D3 into its circulating form, 25(OH)D. This means that sun exposure and dietary vitamin D are converted less efficiently. Supplementing with vitamin D3 (cholecalciferol) bypasses none of this step — it must still be hydroxylated by CYP2R1 — so GG carriers may need higher doses than standard recommendations to achieve the same circulating 25(OH)D levels. Monitoring via blood testing becomes more important to confirm that supplementation is achieving adequate levels rather than assuming a standard dose is sufficient.

The G allele is relatively common (approximately 37% globally, 43% in Europeans), making this a frequently relevant consideration. The effect is additive, so GG homozygotes experience roughly double the impact of CG heterozygotes.

Interactions

The CYP2R1 locus interacts with three other major vitamin D pathway variants. DHCR7 (rs12785878) controls how much substrate (7-dehydrocholesterol) reaches the skin synthesis pathway. GC/DBP (rs2282679) determines how efficiently 25(OH)D is transported in the blood. VDR (rs2228570, rs1544410) determines receptor sensitivity to active calcitriol. Wang et al. 2010 found that individuals in the highest-risk quartile across all three confirmed loci had 2.47 times the odds of vitamin D insufficiency compared to the lowest-risk quartile. Users carrying G alleles at both rs10832310 and other vitamin D pathway variants face compounding impairments across synthesis, transport, and receptor sensitivity.

Nutrient Interactions

vitamin D impaired_conversion

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal CYP2R1 Conversion Normal

Normal vitamin D 25-hydroxylation capacity

The CC genotype at rs10832310 tags a CYP2R1 haplotype associated with normal expression and activity of the vitamin D 25-hydroxylase enzyme. In the Kämpe et al. 2019 GWAS of Finnish children, CC homozygotes had the highest circulating 25(OH)D levels at this locus, with the G allele associated with decreasing levels in an additive fashion.

While this genotype provides normal hydroxylation efficiency, circulating 25(OH)D levels are still primarily determined by sun exposure, dietary intake, body composition, and season. A blood test remains the most reliable way to assess actual vitamin D status.

CG Mildly Reduced CYP2R1 Activity Intermediate

One copy of the reduced-hydroxylation variant — mildly lower 25(OH)D conversion

The CG heterozygous state represents intermediate 25-hydroxylation capacity. The G allele tags a CYP2R1 regulatory haplotype associated with reduced expression of the 25-hydroxylase enzyme in liver tissue. In the Kämpe et al. 2019 Finnish children GWAS, each G allele was associated with an approximately 7.5-unit decrease in circulating 25(OH)D, placing CG heterozygotes midway between CC and GG homozygotes.

For CG carriers, standard vitamin D recommendations are a reasonable starting point, but seasonal testing is advisable — particularly at higher latitudes or in winter, when reduced sun exposure compounds the genetic shortfall in hydroxylation capacity.

GG Reduced CYP2R1 Activity Reduced

Reduced vitamin D 25-hydroxylation — both copies of the lower-activity variant

The GG homozygous state at rs10832310 represents the highest genetic burden at this CYP2R1 locus for impaired 25-hydroxylation. In the Kämpe et al. 2019 GWAS of 761 Finnish 24-month-old children, the G allele showed an additive effect on 25(OH)D with genome-wide significance (p = 4.24 × 10⁻¹¹). GG carriers showed substantially lower 25(OH)D compared to CC homozygotes.

A key finding from that study: the effect of rs10832310 on 25(OH)D was the same in children receiving either 10 μg or 30 μg daily vitamin D3 supplementation. This means the G allele impairs baseline hydroxylation capacity rather than the response to supplemental doses. GG carriers need adequate vitamin D3 input but also need to recognize that their conversion will be less efficient at any input dose.

The associated reduction in 25(OH)D was reflected in lower pQCT bone parameters (distal tibia), consistent with vitamin D's role in calcium absorption and skeletal mineralization. In adult cohorts (MrOS Sweden), CYP2R1 haplotypes associated with lower 25(OH)D showed 4.6–18.5% differences in mean vitamin D levels with corresponding effects on femoral neck bone mineral density.

Thacher et al. 2015 | Thacher TD et al. CYP2R1 mutations impair generation of 25-hydroxyvitamin D and cause an atypical form of vitamin D deficiency. J Clin Endocrinol Metab, 2015 documented that complete loss-of-function CYP2R1 mutations cause vitamin D deficiency that is resistant to normal-dose supplementation, requiring high-dose treatment to achieve adequate 25(OH)D levels — illustrating the dose-dependency of this metabolic step.