rs1993116 — CYP2R1 CYP2R1 rs1993116

CYP2R1 rs1993116 — Your Vitamin D Activation Throttle

The CYP2R1 gene¹¹ CYP2R1 gene
Cytochrome P450 family 2 subfamily R member 1; encodes the primary liver enzyme responsible for converting vitamin D3 (cholecalciferol) into 25-hydroxyvitamin D, the storage and transport form measured in blood tests is the gatekeeper of vitamin D activation. Before vitamin D can do anything useful in the body, the liver must convert it from its ingested or sun-derived form into 25-hydroxyvitamin D (25(OH)D)²² 25-hydroxyvitamin D (25(OH)D)
Also called calcidiol; this is the form measured in standard blood tests and the main circulating vitamin D metabolite. The kidneys then convert it further into calcitriol, the active hormone. CYP2R1 performs this critical first hydroxylation step. rs1993116 is an intronic variant that influences how efficiently CYP2R1 is expressed — people carrying the G allele produce less of this enzyme, leaving more vitamin D unconverted.

The Mechanism

rs1993116 sits within an intron of CYP2R1 on chromosome 11 (GRCh38: chr11:14,888,688). Because CYP2R1 is on the minus strand, the variant is described using plus-strand alleles in genome files: A (the minor, protective allele) versus G (the major, risk allele). The intronic position suggests the variant affects splicing efficiency or enhancer activity³³ splicing efficiency or enhancer activity
Intronic variants can alter the binding of splicing regulatory proteins or transcription factors, changing the amount of functional mRNA produced without changing the protein sequence itself rather than the enzyme's catalytic activity directly. The net effect is that G allele carriers produce less CYP2R1 protein and therefore convert less dietary and sun-derived vitamin D into its measurable 25(OH)D form.

This variant is in partial linkage disequilibrium with rs10741657, the more commonly cited CYP2R1 GWAS locus, but the two variants are not perfectly correlated — each captures some independent variation in CYP2R1 expression. In European Americans, rs1993116 has been reported as the most strongly associated CYP2R1 variant with 25(OH)D levels⁴⁴ most strongly associated CYP2R1 variant with 25(OH)D levels
Batai et al. 2014, Human Genetics — rs1993116 showed the strongest CYP2R1 signal in European Americans, while rs12794714 was the leading variant in African Americans, demonstrating that the causal architecture differs by ancestry.

The Evidence

The clearest functional evidence comes from a 2019 Japanese study⁵⁵ 2019 Japanese study
Arai T et al. Association of vitamin D levels and vitamin D-related gene polymorphisms with liver fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease. Dig Liver Dis, 2019 of 229 NAFLD patients in which non-AA genotype at rs1993116 emerged as an independent predictor of vitamin D deficiency (≤20 ng/mL) in multivariate analysis — meaning the association held even after controlling for sun exposure, BMI, season, and other confounders.

A 2018 Egyptian study⁶⁶ 2018 Egyptian study
Sedky NK et al. Genetic Variants of CYP2R1 Are Key Regulators of Serum Vitamin D Levels and Incidence of Myocardial Infarction in Middle-Aged Egyptians. Curr Pharm Biotechnol, 2018 in 323 subjects found that AG/GG genotypes at rs1993116 defined the high-risk grouping for lower serum 25(OH)D and elevated myocardial infarction risk (combined OR 14.1 for all three high-risk CYP2R1 genotypes together).

In a Chinese rural population, Wang et al. (2018)⁷⁷ Wang et al. (2018)
Wang Y et al. Triangular relationship between CYP2R1 gene polymorphism, serum 25(OH)D3 levels and T2DM in a Chinese rural population. Gene, 2018 found that the non-AA genotype carried 64% higher odds of type 2 diabetes (OR 1.64, 95% CI 1.09–2.46, P=0.048) in 794 subjects, consistent with the established link between vitamin D insufficiency and insulin resistance.

Robien et al. (2013)⁸⁸ Robien et al. (2013)
Robien K et al. Genetic and environmental predictors of serum 25-hydroxyvitamin D concentrations among middle-aged and elderly Chinese in Singapore. Br J Nutr, 2013 replicated the association in 504 Chinese Singaporeans, confirming that rs1993116 and rs10741657 both contribute independently to circulating 25(OH)D levels across diverse populations.

A 2013 analysis of 5,604 hepatitis C patients found that genotypes associated with reduced 25(OH)D via CYP2R1 variants trended toward higher hepatocellular carcinoma risk (OR 1.13, P=0.07)⁹⁹ (OR 1.13, P=0.07)
Lange CM et al. Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development. PLoS One, 2013, further illustrating the downstream consequences of genetically lower vitamin D.

Practical Actions

The core intervention is the same regardless of which CYP2R1 variant is limiting your 25(OH)D production: increase the substrate (vitamin D3 input) to compensate for slower conversion. G allele carriers typically need higher supplementation doses than the general population to achieve the same circulating 25(OH)D level. Testing serum 25(OH)D is the only reliable way to calibrate the right dose — an optimal level is generally considered 40–60 ng/mL (100–150 nmol/L).

Magnesium is a cofactor for both CYP2R1 and the downstream CYP27B1 hydroxylase; deficiency impairs vitamin D conversion independently of genotype, so GG carriers have extra reason to ensure adequate magnesium intake.

Interactions

rs1993116 interacts with rs10741657, the other major CYP2R1 locus. Both variants influence CYP2R1 expression and are partially correlated; carriers of risk alleles at both loci have compounded 25-hydroxylation impairment.

Beyond CYP2R1, the vitamin D pathway involves several other gene variants already profiled: rs12785878 (DHCR7/NADSYN1, skin synthesis), rs4588 and rs7041 (GC/VDBP, transport), rs2228570 (VDR FokI, receptor sensitivity), and rs6013897 (CYP24A1, degradation). Individuals carrying risk alleles across two or more of these loci face compounded insufficiency risk; large GWAS data showed 2.47-fold increased odds of vitamin D insufficiency for the highest multi-locus risk score.